Primary Immunodeficiency in Adults — Viva

Long Case Viva Defence

Candidate's opening statement (model answer)

"Ms Sarah Connell is a 34-year-old administration officer, previously well apart from an 8-year history of recurrent chest and sinus infections, who presents with newly diagnosed common variable immunodeficiency (CVID). Her syndrome is recurrent sinopulmonary infection — two episodes of radiologically confirmed pneumonia in the past 12 months, one with Streptococcus pneumoniae bacteraemia, and chronic sinusitis requiring three prolonged antibiotic courses — together with Giardia lamblia enteritis and immune thrombocytopenia diagnosed 2 years ago. Her serum immunoglobulins show IgG 3.2 grams per litre, IgA less than 0.07, IgM 0.3, with a poor pneumococcal vaccine response, her HIV test is negative, and she has bilateral basal crackles and mild splenomegaly on examination, consistent with early bronchiectasis and lymphoproliferation. [1]

Her main problems are:

1. Common variable immunodeficiency with hypogammaglobulinaemia and impaired functional antibody response, the most common symptomatic primary immunodeficiency in adults.
2. Recurrent sinopulmonary infection with early bronchiectasis and a recent pneumococcal bacteraemia.
3. Autoimmune thrombocytopenia (Evans-pattern), currently in partial remission on a reducing dose of prednisolone.
4. Giardia enteritis, now resolved, reflecting the mucosal antibody deficiency.
5. Mild splenomegaly, likely lymphoproliferation, requiring baseline characterisation and surveillance.
6. A 6-year diagnostic delay, which is typical for this condition. [1]

Her management will be lifelong immunoglobulin replacement, airway clearance and surveillance for bronchiectasis, surveillance for the non-infectious complications of CVID — particularly lymphoma and autoimmune disease — and a coordinated multidisciplinary approach with a clinical immunologist, a respiratory physician, and a haematologist." [1]

Examiner probing questions and model answers

Q1: "Walk me through why you are confident this is CVID and not a secondary cause of hypogammaglobulinaemia." [1]

"I am applying the ICON consensus diagnostic criteria for CVID: a marked decrease in IgG below 5 grams per litre with a marked decrease in IgA and/or IgM; impaired antibody response to vaccines — she has a poor pneumococcal polysaccharide response; onset after age 4; and exclusion of secondary causes [3]. On the secondary causes, her HIV test is negative, she has no nephrotic-range proteinuria or ongoing protein-losing enteropathy to account for immunoglobulin loss, she takes no immunosuppressive drugs, and I would send a serum protein electrophoresis and free light chains to exclude a plasma cell dyscrasia such as multiple myeloma, which can produce secondary hypogammaglobulinaemia. The clinical phenotype is the other piece of evidence — recurrent sinopulmonary infection with encapsulated organisms, Giardia enteritis, and autoimmune thrombocytopenia is the classic CVID presentation, and the 6-year diagnostic delay is itself typical, the median being 4 to 7 years [1]. Once the electrophoresis returns normal, the diagnosis is secure. Selective IgA deficiency is excluded by the low IgG and IgM; specific antibody deficiency is excluded by the hypogammaglobulinaemia. The key teaching point is that the single most common error in adult CVID is the diagnostic delay, because recurrent infection is attributed to asthma or chronic sinusitis and immunoglobulins are never measured."

Q2: "How will you decide between intravenous and subcutaneous immunoglobulin, and what dose will you start?" [1]

"Both routes are therapeutically equivalent for the primary goal of preventing serious bacterial infection — this is established by meta-analyses of IVIG versus SCIG in primary immunodeficiency [5]. The choice is patient-centred. Intravenous immunoglobulin, at 400 to 600 milligrams per kilogram every 3 to 4 weeks, is given in a day unit and suits a patient who prefers less frequent dosing and does not want to self-manage, but it produces peaks and troughs in IgG and carries a higher rate of systemic reactions, including aseptic meningitis with rapid high-dose infusion. Subcutaneous immunoglobulin, at 100 to 200 milligrams per kilogram per week, is self-administered at home via a pump into the abdominal wall or thighs, produces steady IgG levels, and has fewer systemic reactions but more local infusion-site reactions. For Ms Connell I would present both options, involve the specialist immunoglobulin nursing team for home-infusion training if she chooses SCIG, and start at a dose calculated to reach a trough IgG above 8 grams per litre given her recent pneumococcal bacteraemia — so likely 600 milligrams per kilogram every 4 weeks IVIG or the SCIG equivalent. I would monitor her infection frequency and trough IgG over the first 6 months and titrate the dose to clinical response, because the dose is individualised by infection frequency rather than by weight alone. I would not use intramuscular immunoglobulin, which is obsolete because of the small volumes tolerable by that route."

Q3: "She has immune thrombocytopenia. How does that change your management, and is there a trap with the treatments you might use for it?" [1]

"The immune thrombocytopenia is a recognised autoimmune manifestation of CVID — about 25 per cent of CVID patients have autoimmune disease, and ITP and autoimmune haemocytic anaemia, alone or together as Evans syndrome, are the dominant manifestations. The ITP does not change the CVID management — she still needs immunoglobulin replacement for the antibody deficiency — but it does change the way I would treat the ITP if it relapses. The trap is that rituximab, a common second-line agent for chronic ITP, depletes B-cells for 6 to 12 months and would worsen an already-defective humoral immune system; and splenectomy, another second-line option, would add the asplenic risk of overwhelming encapsulated-organism infection to a patient who is already uniquely vulnerable to those organisms. So in Ms Connell I would prefer thrombopoietin receptor agonists (eltrombopag, romiplostim) for refractory ITP, use rituximab only after careful discussion with her immunologist about the B-cell depletion and the need to intensify immunoglobulin replacement and infection surveillance, and avoid splenectomy if at all possible. The teaching point is that the management of the autoimmune complication must account for the underlying immunodeficiency — treating the cytopenia in a way that worsens the defect is a recognised harm." [1]

Q4: "What is your surveillance plan for the non-infectious complications?" [1]

"The non-infectious complications drive much of the morbidity and mortality in CVID, so surveillance is as important as the immunoglobulin replacement [2]. My plan is: first, respiratory — baseline spirometry and a chest computed tomography now to characterise the bronchiectasis (she has bilateral crackles and recurrent pneumonia, so bronchiectasis is likely), with annual spirometry and biennial chest CT thereafter, plus airway clearance physiotherapy. Second, autoimmunity — annual full blood count for autoimmune cytopenia, annual thyroid function for thyroiditis, and clinical vigilance for new autoimmune disease. Third, malignancy — I would counsel her that the non-Hodgkin lymphoma risk is increased 30 to 200-fold in CVID (predominantly B-cell marginal zone or MALT), and that any new lymphadenopathy, B-symptoms such as night sweats or weight loss, or unexplained cytopenia warrants urgent investigation with imaging and biopsy; the mild splenomegaly she has now is likely lymphoproliferation and I would characterise it at baseline with imaging and monitor it. Fourth, the gastric carcinoma risk is also increased, so I would investigate any upper gastrointestinal symptoms promptly with endoscopy. Fifth, annual inactivated influenza vaccination and age-appropriate inactivated vaccines, with household contacts fully vaccinated."

Q5: "How will you explain this diagnosis to her, and what is the role of the general practitioner?" [1]

"I will sit down with her and explain, in plain language, that her immune system does not make enough of the protective antibodies that fight chest and sinus infections, which is why she has had the recurrent infections and the Giardia, and that the immune system's dysregulation also explains the low platelet count she had two years ago. I will explain that the treatment is regular immunoglobulin replacement, which gives her the antibodies her body cannot make, and that with this treatment most people live full and active lives, though we will need to monitor for the related problems of lymphoma and autoimmune disease. I will ask about her values, her work, her family plans, and how she wants to manage the treatment (home SCIG versus clinic IVIG), and I will involve a patient organisation such as the Immune Deficiencies Foundation for peer support, because the diagnosis after years of delay often carries significant frustration and anxiety. The general practitioner is central to the shared care: I would provide a written shared care plan documenting the diagnosis, the IgRT regimen, the standby antibiotic plan, the surveillance schedule, and the thresholds for review, so that the GP can manage intercurrent infection, monitor for complications, and refer back promptly. I would flag specifically that unexplained fever, new lymphadenopathy, a change in infection pattern, or a falling platelet count warrants urgent review." [1]

Q6: "Her 19-year-old sister asks whether she should be tested. What do you say?" [1]

"CVID has a recognised familial clustering but the inheritance is complex and polygenic in most cases, unlike the monogenic defects such as chronic granulomatous disease or hereditary angioedema where family screening is clearly indicated. I would not test the sister for CVID specifically in the absence of symptoms, but I would ask about her infection history — if she has recurrent sinopulmonary infection, I would measure her immunoglobulins and pneumococcal vaccine response; if she is well, I would reassure her and advise that any pattern of recurrent infection should prompt a serum immunoglobulin measurement in the future. I would also take a fuller family history, because a family history of recurrent infection, unexplained bronchiectasis, autoimmune cytopenia, lymphoma at a young age, or early death from infection would raise the possibility of a defined monogenic defect and prompt referral to a clinical geneticist. The teaching point is that family screening is essential for the monogenic, mendelian PIDs (HAE autosomal dominant, CGD X-linked, complement deficiencies autosomal recessive) and is symptom-directed and counselling-based for the polygenic PIDs like CVID." [1]

Short Case Discussion

Pattern recognition and the bedside clues to the four arms of the immune system

Examiner instruction: "You are called to see a 30-year-old man on the ward with a history of recurrent infection. Describe your structured approach to identifying which arm of the immune system is defective from the bedside pattern, and how the pattern drives the investigation." [1]

Candidate's model answer: [1]

"My first principle is that the type of infection predicts the arm of the immune system that is defective, and the arm predicts the diagnostic test and the treatment. I build the differential from the infection history, the examination, and a small set of first-line tests. [1]

The structured approach: [1]

1. Humoral (B-cell) defect — recurrent sinopulmonary and gastrointestinal infection with encapsulated organisms. If the history is recurrent pneumonia, sinusitis, otitis, bronchiectasis, Giardia, or Campylobacter, with or without autoimmune cytopenia or atopy, I think humoral defect — CVID, selective IgA deficiency, specific antibody deficiency. The first-line test is serum immunoglobulins (IgG, IgA, IgM, IgE); if normal, I add the pneumococcal vaccine response for specific antibody deficiency. Selective IgA deficiency is the most common PID overall (1 in 500); CVID is the most common symptomatic PID in adults. [1]

2. Cellular (T-cell) defect — opportunistic infection. If the history is Pneumocystis, Candida, mycobacteria, or severe herpes family virus infection, I think cellular defect — HIV first (the most common cause in adults), then a primary T-cell or combined defect. The first-line test is an HIV test and lymphocyte subsets (CD3, CD4, CD8). Severe combined immunodeficiency presents in infancy, but milder combined defects such as ataxia-telangiectasia and Nijmegen break syndrome can present in adulthood, often with ataxia, telangiectasia, or lymphoid malignancy. [1]

3. Complement defect — recurrent Neisseria, or recurrent non-urticarial angioedema. If the history is recurrent meningococcal or gonococcal infection, I think terminal complement deficiency (C5 to C9) — the rule is that two or more episodes of invasive meningococcal disease mandate a CH50. If the history is recurrent facial, limb, or abdominal swelling without urticaria or itch, often with a family history and no response to adrenaline, I think hereditary angioedema (C1 inhibitor deficiency) — I check C4, C1 inhibitor antigen and function, and C1q. [1]

4. Phagocyte defect — recurrent catalase-positive organisms and granulomas. If the history is recurrent staphylococcal abscesses, Burkholderia, Serratia, Nocardia, or invasive Aspergillus, with granulomatous complications such as obstructive lesions or a Crohn-like colitis, I think chronic granulomatous disease — the diagnostic test is the dihydrorhodamine flow cytometry, measuring the neutrophil oxidative burst. [1]

The examination adds to the pattern: I look for bronchiectasis (clubbing, crackles), chronic sinusitis, lymphadenopathy and splenomegaly (lymphoproliferation), the stigmata of ataxia-telangiectasia (ataxia, oculocutaneous telangiectasia), and the scars of previous abscess drainage. I always send an HIV test, because secondary immunodeficiency is far more common than primary in adults. And I remember that a normal immunoglobulin panel does not exclude a primary immunodeficiency — specific antibody deficiency and complement deficiency have normal immunoglobulins, and the next step is the pneumococcal vaccine response and the CH50 when the clinical pattern warrants it." [1]