Primary Immunodeficiency in Adults — Clinical Case

DCE Long Case

Patient brief (provided to trainee)

Patient: Mr Liam O'Connor, 22 years old, university student, born and resident in Australia, of Irish and English ancestry. [1] />

Presenting complaint: Admitted to hospital 2 days ago with a 12-hour history of fever, rash, headache, and neck stiffness, diagnosed as meningococcal disease (Neisseria meningitidis serogroup Y on blood culture, consistent with meningococcaemia and meningitis). [1] />

History of presenting illness: Onset with fever to 39.2 degrees and a petechial rash on the lower limbs that progressed to purpura. He presented to the emergency department within 4 hours of onset. He was treated with intravenous ceftriaxone 2 grams and admitted. He has responded well and is now afebrile and recovering. [1] />

Relevant past history: Eighteen months ago he had an episode of invasive meningococcal disease (serogroup W) presenting as meningococcaemia without meningitis, from which he made a full recovery. At that time he was screened for immunodeficiency: his full blood count was normal, his HIV test was negative, and he had no history of splenectomy or immunosuppression. A serum immunoglobulin panel was normal (IgG 10.2 g per L, IgA 1.9 g per L, IgM 1.0 g per L). He was given the quadrivalent meningococcal ACWY vaccine and the serogroup B vaccine after the first episode. [1] />

Past medical history: Otherwise well. No history of recurrent chest or sinus infection, no autoimmune disease, no previous surgery. He had the routine childhood immunisations. [1] />

Family history: His parents and two siblings are well. There is no family history of recurrent infection, early death, or immunodeficiency. Both parents are of Irish ancestry. [1] />

Social history: Lives in a university hall of residence. Does not smoke, drinks alcohol socially. No recent travel. Not sexually active with a new partner. [1] />

Current medications: Nil regular. Intravenous ceftriaxone 2 grams daily (day 2). [1] />

Examination on the ward (day 2): Afebrile, heart rate 78, blood pressure 118/72, respiratory rate 16, oxygen saturation 98 per cent on room air. Alert and oriented. Resolving petechial rash on the lower limbs. No meningism. No lymphadenopathy or hepatosplenomegaly. No other stigmata of chronic infection or immunodeficiency. [1] />

Investigations during this admission:

• Full blood count: haemoglobin 138 g per litre, white cell count 9.2 x 10^9 per litre (neutrophils 6.8), platelets 210 x 10^9 per litre.
• C-reactive protein 84 mg per litre (falling).
• Blood cultures at admission: Neisseria meningitidis serogroup Y (within 12 hours of ceftriaxone).
• HIV test: negative.
• Serum immunoglobulins: IgG 10.8 g per litre, IgA 2.0 g per litre, IgM 1.1 g per litre (normal).
• Total haemolytic complement activity (CH50): less than 10 units per millilitre (reference 30 to 75) — markedly reduced.
• Alternative pathway haemolytic activity (AH50): less than 10 units per millilitre (reference 33 to 90) — markedly reduced.
• C3 1.1 g per litre (normal), C4 0.25 g per litre (normal). [1] />

Candidate's structured presentation (model)

SASPOP opening statement: [1]

"Mr Liam O'Connor is a 22-year-old university student, born in Australia of Irish ancestry, presenting with his second episode of invasive meningococcal disease in 18 months — the first serogroup W, this one serogroup Y — in the setting of a markedly reduced CH50 and AH50 with normal C3 and C4, indicating a terminal complement pathway deficiency, most likely C6 deficiency. He has normal immunoglobulins and a negative HIV test, no history of splenectomy, and no family history of immunodeficiency." [1] />

Structured problem list: [1]

1. Recurrent invasive meningococcal disease — two episodes in 18 months, different serogroups, the clinical hallmark of terminal complement deficiency.
2. Terminal complement pathway deficiency — CH50 and AH50 both undetectable with normal C3 and C4, localising the defect to C5 to C9; the specific component (likely C6 in a Western population) to be confirmed by individual component assay.
3. The preventive plan — meningococcal vaccination, standby antibiotics, patient education, and family screening.
4. The psychosocial impact — a 22-year-old student facing a diagnosis of a lifelong immunodeficiency and the implications for his family. [1] />

Integrated management plan

1. Confirm the specific terminal complement deficiency: [1] />

The CH50 and AH50 are both undetectable with normal C3 and C4, which localises the defect to the terminal pathway (C5 to C9) — the convergent components shared by both the classical and alternative pathways. I would send the individual terminal complement components (C5, C6, C7, C8, C9) to define the precise defect; C6 deficiency is the most common terminal complement deficiency in Western European populations (consistent with his Irish ancestry), while C8 deficiency (specifically the beta chain) is more common in people of African ancestry, and C9 deficiency is most common in Japanese populations. The specific component matters less for the immediate management — which is the same for any terminal pathway deficiency — but it matters for genetic counselling and family testing. I would also involve a clinical immunologist to coordinate the workup and the family screening [2].

2. Meningococcal vaccination: [1]

He has already received the quadrivalent ACWY vaccine and the serogroup B vaccine after his first episode, but he has had a breakthrough infection with serogroup Y despite the ACWY vaccine — this is expected, because vaccination reduces but does not eliminate the risk of meningococcal disease in complement deficiency, and the antibody response is intact (the defect is in serum bacteriolysis, not antibody generation). I would reinforce the vaccination schedule: a booster of the quadrivalent ACWY every 3 to 5 years, the serogroup B series with boosters as recommended, and I would add pneumococcal vaccination (PCV15 followed by PPSV23) and Haemophilus influenzae type b vaccination given the overlapping pyogenic risk. I would document the vaccination status and the booster plan in writing for the patient and his general practitioner [1].

3. Standby antibiotics and patient education: [1]

I would issue a patient-held standby antibiotic plan — a first dose of ceftriaxone (or, where appropriate for self-administration, an oral antibiotic such as amoxicillin or ciprofloxacin) to take at the first sign of fever, with clear instructions to attend the emergency department immediately. I would provide a medical alert (bracelet or card) documenting the diagnosis and the need for urgent evaluation of any fever. I would consider long-term penicillin prophylaxis, which is used in some centres for terminal complement deficiency (and is more strongly indicated for properdin deficiency, where per-episode mortality is higher). The education must be thorough and repeated: the patient and his close contacts must understand that any fever is a potential emergency and that early antibiotic treatment is life-saving. [1] />

4. Family screening: [1]

Terminal complement deficiencies are autosomal recessive. Both of his parents are likely obligate carriers (heterozygous, and carriers typically have half-normal CH50 but are clinically well). His siblings have a 25 per cent chance of being affected. I would offer the parents and siblings a CH50 screening test, and confirm the specific component deficiency in any family member with a low CH50. Genetic counselling is offered, and the implications for future reproduction are discussed (the risk to offspring depends on the carrier status of the partner). The screening is coordinated through the clinical immunologist and the clinical genetics service. [1] />

5. Distinguishing from properdin deficiency — why it is not properdin: [1] />

The pattern here — recurrent episodes with full recovery, equal sex distribution possible (he is male, but the family history is negative for X-linked transmission), and a CH50 and AH50 both low — points to terminal pathway deficiency rather than properdin deficiency. Properdin deficiency is X-linked (affects males, transmitted through carrier females), produces fulminant single episodes with higher mortality, and characteristically shows a normal CH50 with a low AH50 (because the alternative pathway is selectively affected while the classical and terminal pathways remain intact). His recurrent but survivable episodes, the normal family history for X-linked transmission, and the low CH50 together exclude properdin deficiency and confirm a terminal pathway deficiency. This distinction matters because it changes the family counselling (autosomal recessive versus X-linked) and the strength of the recommendation for long-term penicillin prophylaxis (stronger for properdin). [1] />

Examiner discussion questions

Q1: "Why did he get meningococcal disease despite having received the ACWY vaccine after his first episode?" [1] />

"In terminal complement deficiency, the antibody response to vaccination is intact — the defect is in the serum bactericidal activity of complement, not in antibody generation. So the patient makes antibody to the vaccine antigen, but the antibody-opsonised Neisseria cannot be cleared because the membrane attack complex that lyses the bacterium is absent. Vaccination reduces the risk of meningococcal disease in complement deficiency (by providing antibody that enhances phagocytic clearance, which is an alternative, complement-independent mechanism), but it does not eliminate it. His breakthrough infection with serogroup Y despite the ACWY vaccine is therefore expected, and it does not represent vaccine failure in the usual sense. The lesson is that vaccination is necessary but not sufficient in terminal complement deficiency — it must be combined with the standby antibiotic plan, patient education, and a low threshold for empiric treatment of any febrile illness. The mortality per episode of meningococcal disease in terminal complement deficiency is paradoxically lower than in immunocompetent hosts (estimated 1 to 5 per cent versus about 10 per cent), possibly because of antibody-enhanced phagocytic clearance or earlier recognition, but the recurrence rate without prevention is very high." [1] />

Q2: "His CH50 and AH50 are both undetectable. Walk me through how that localises the defect, and how it would differ if he had properdin deficiency or classical pathway deficiency." [1] />

"The CH50 measures the haemolytic activity of the classical pathway (C1, C2, C4) and the shared terminal pathway (C5 to C9); the AH50 measures the alternative pathway (factor D, factor B, properdin) and the same shared terminal pathway. Because the terminal pathway is shared, a deficiency in any terminal component (C5, C6, C7, C8, C9) makes both the CH50 and the AH50 undetectable — there is no lytic capacity through either pathway. That is exactly the pattern in Mr O'Connor, and it localises the defect to the terminal pathway, confirmed by the normal C3 and C4 (the upstream classical and alternative components are intact). If he had properdin deficiency, the alternative pathway would be defective but the classical and terminal pathways would be intact, so the AH50 would be low but the CH50 would be normal — that is the discriminator. If he had classical pathway deficiency (such as C1 inhibitor deficiency or C2 deficiency), the CH50 would be low but the AH50 would be normal, because the alternative and terminal pathways are intact. C3 deficiency, which affects the convergent component of all pathways, would make both CH50 and AH50 low, but the C3 level itself would be low — his C3 is normal, excluding C3 deficiency. So the combination of CH50, AH50, and individual C3 and C4 levels localises the defect precisely before the individual terminal component assay confirms it." [1] />

Q3: "What is his long-term prognosis, and what will you tell him about his future?" [1] />

"The prognosis in terminal complement deficiency is generally good with a structured preventive plan. The cumulative risk of recurrent meningococcal disease without prevention is very high, but with meningococcal vaccination (quadrivalent ACWY and serogroup B, with boosters), a standby antibiotic plan, patient education, a medical alert, and a low threshold for empiric treatment, the risk is substantially reduced. The per-episode mortality is lower than in immunocompetent hosts. There is no specific treatment that restores the terminal complement pathway (no replacement therapy analogous to immunoglobulin replacement for humoral defects), so management is preventive and expectant. I would tell him that he has a lifelong deficiency of one of the complement proteins that protects against meningococcal infection, that he will always be at higher risk of meningococcal disease than the general population, but that with the vaccination, the standby antibiotics, and the early-presentation plan he can live a full and active life. I would address the practical implications: he should carry his medical alert and his standby antibiotics at all times, he should inform any new doctor or dentist of his diagnosis, the condition is relevant to his future family planning (autosomal recessive — his children will be carriers unless his partner is also a carrier), and he should not be discouraged from a normal life including sport, travel, and career. I would arrange follow-up with the clinical immunologist and the general practitioner, provide written documentation, and connect him with patient support resources." [1] />

Q4: "How will you approach screening his siblings, and what does an autosomal recessive inheritance mean for his future children?" [1] />

"Terminal complement deficiencies are autosomal recessive, so both of his parents are obligate carriers (heterozygous, with approximately half-normal CH50 but clinically well) and each of his siblings has a 25 per cent chance of being affected. I would offer his parents and his siblings a CH50 screening test; any sibling with a low CH50 would have the specific component assay to confirm the same deficiency as Mr O'Connor, and would then enter the same preventive plan (vaccination, standby antibiotics, education) even if asymptomatic. For his future children: because the inheritance is autosomal recessive, all of his children will inherit one copy of the defective gene from him (they will be obligatory carriers) but will be affected only if their mother is also a carrier — the chance of an affected child is 25 per cent if the mother is a carrier and effectively zero if she is not. So the relevant step before he has children is to offer carrier testing to his future partner, and if she is a carrier, to offer genetic counselling and (if they wish) prenatal or preimplantation genetic diagnosis. I would involve the clinical genetics service to coordinate this. The counselling is sensitive because it touches on family planning, and I would deliver it with care and with written information for him to take away and discuss." [1] />

Q5: "How does the management of his terminal complement deficiency differ from the management of a patient with hereditary angioedema, which is also a complement-related disorder?" [1] />

"Both are complement-related primary immunodeficiencies, but they are managed very differently because the pathophysiology and the clinical problem differ. Terminal complement deficiency produces a failure of serum bacteriolysis of Neisseria, so the management is preventive against infection — meningococcal vaccination, standby antibiotics, patient education, and a low threshold for empiric treatment; there is no specific replacement therapy that restores the terminal pathway. Hereditary angioedema (C1 inhibitor deficiency) produces uncontrolled bradykinin-mediated vascular permeability, so the management is specific to the bradykinin pathway — acute attacks are treated with C1 inhibitor concentrate or icatibant (not adrenaline, antihistamines, or corticosteroids), and long-term prophylaxis uses lanadelumab, berotralstat, C1 inhibitor concentrate, or attenuated androgens, with short-term prophylaxis before dental or surgical procedures. The overlap is in the screening test: both produce a low C4 (in HAE, from uncontrolled classical pathway activation), but the clinical presentations — recurrent meningococcaemia versus recurrent non-urticarial angioedema — are completely different, and the treatments are pathway-specific. The teaching point is that 'complement deficiency' is not a single entity: the defect in the pathway determines the clinical syndrome and the treatment." [1] />

Q6: "He is a university student living in a hall of residence. Are there any public health or behavioural implications?" [1] />

"Yes, several. First, meningococcal disease is a notifiable condition, and the public health unit will be involved in contact tracing and in deciding on chemoprophylaxis for close contacts — though in his case the recurrence is due to his underlying complement deficiency rather than ongoing exposure, the public health response to each episode still applies. Second, the hall of residence is a recognised risk factor for meningococcal transmission (crowded living, young adults), and I would reinforce the meningococcal vaccination message for his household contacts and peers, recognising that carriage and transmission can occur even in vaccinated individuals. Third, I would address the behavioural implications of his diagnosis: he should avoid smoking (which impairs mucosal defence), he should be aware that alcohol intoxication can delay his recognition of a febrile illness and his adherence to the standby antibiotic plan, and he should tell a trusted friend or residential advisor about his condition and his emergency plan so that someone else can act if he becomes unwell. Fourth, I would address the psychosocial impact — a diagnosis of a lifelong immunodeficiency at 22 is significant, and I would offer him the support of the clinical immunology nurse specialist, the university student health service, and a patient organisation. The goal is for him to manage his condition confidently and to live a full student life, while having a robust plan for the inevitable risk of further episodes." [1] />