Recurrent infection workup: immunodeficiency in Australian general practice

Most people who see their GP with repeated chest infections, recurrent sinusitis, or frequent ear infections do not have an underlying immune deficiency. Six to eight upper respiratory tract infections per year in a child under five in childcare is normal. But a subset of patients carry an immune problem that is diagnosable, treatable, and — if missed — progresses to preventable complications like bronchiectasis, opportunistic infection, or lymphoma. The clinical question is not whether to investigate every patient with infections, but how to identify the minority who merit a structured workup.

ASCIA’s Primary Immunodeficiency Working Group and the Jeffrey Modell Foundation 10 Warning Signs provide validated screening tools for identifying this group. In adults, the most common symptomatic primary immunodeficiency is common variable immunodeficiency (CVID), occurring in approximately one in 25,000 people, with a diagnostic delay averaging five to ten years from symptom onset to diagnosis. Secondary immunodeficiency from HIV, haematological malignancy, and iatrogenic immunosuppression (rituximab, corticosteroids, chemotherapy) is far more prevalent in adult general practice than primary disease, and is the first thing to exclude.

A. Core clinical — the AU general-practice framework

Recognising the pattern

Two complementary frameworks help identify patients who warrant workup:

The SPUR-PI mnemonic (endorsed by ASCIA): Severe · Persistent · Unusual (atypical organism or anatomical site) · Recurrent · family history of Primary Immunodeficiency. At least two features should be present before initiating the immunodeficiency workup.

The Jeffrey Modell 10 Warning Signs (info4pi.org) — two or more are the threshold for investigation:

1. ≥4 ear infections in one year
2. ≥2 serious sinus infections in one year
3. ≥2 months on antibiotics with little effect
4. ≥2 pneumonias in one year
5. Failure of an infant to gain weight or grow normally
6. Recurrent deep skin or organ abscesses
7. Persistent thrush or fungal infection on skin
8. Need for IV antibiotics to clear infections
9. ≥2 deep-seated infections including septicaemia
10. A family history of primary immunodeficiency

Pattern recognition by immune compartment

The infection pattern narrows the differential:

• Recurrent sinopulmonary infection (pneumonia, sinusitis, bronchitis) → antibody deficiency — CVID, IgG subclass deficiency, specific antibody deficiency, XLA.
• Single episode of meningococcal disease in an otherwise well adult → terminal complement deficiency (C5–C9 or properdin); test CH50 and AH50.
• Recurrent skin and lymph node abscesses with catalase-positive organisms (Staphylococcus aureus, Aspergillus, Serratia) → chronic granulomatous disease; neutrophil oxidative burst (DHR or NBT test).
• Persistent oropharyngeal candidiasis, Pneumocystis pneumonia, CMV, disseminated atypical mycobacteria → T-cell defect or HIV — lymphocyte subsets and HIV are the urgent tests.
• Recurrent giardiasis or enteroviral infections → antibody deficiency.
• Autoimmune cytopenias with recurrent infection → CVID with immune dysregulation.

History

Beyond the SPUR-PI screen, the history targets:

• Medication review: corticosteroids, methotrexate, biologics (rituximab causes secondary hypogammaglobulinaemia), JAK inhibitors, chemotherapy, anti-epileptics (phenytoin, carbamazepine — secondary IgA deficiency).
• HIV risk factors: sexual history, intravenous drug use, blood product exposure, country of birth.
• Cancer, chemotherapy, radiation, splenectomy: all direct causes of secondary immunodeficiency.
• Nutrition: weight, protein status, micronutrient deficiencies (zinc, vitamin D, B12), eating disorders — malnutrition is the most common cause of secondary immunodeficiency globally.
• Family history: parental consanguinity, sibling deaths in infancy, known PID diagnosis in a family member, anyone on immunoglobulin replacement.

First-line investigations

The GP first-line panel is sufficient to triage most patients:

• FBC with differential — lymphopenia (SCID or T-cell defect), neutropenia, anaemia of inflammation.
• Immunoglobulins IgG, IgA, IgM (MBS item 71161) — low IgG ± IgA ± IgM defines humoral deficiency; isolated low IgA is selective IgA deficiency.
• Lymphocyte subsets — CD3, CD4, CD8, CD19, CD16+56 by flow cytometry — low T-cell count in SCID or combined immunodeficiency; absent B cells in XLA.
• Complement C3 and C4 (MBS item 71165) — screens for immune complex-driven consumption and provides triage prior to total haemolytic complement.
• HIV serology (MBS item 69384) — always, in every patient with unexplained recurrent infection.
• Serum protein electrophoresis plus serum free light chains in adults over 50 — rule out multiple myeloma and lymphoma as drivers of secondary hypogammaglobulinaemia.
• CXR if respiratory features — bronchiectasis (CVID complication), thymic absence in neonates, TB.

Management framework

Management at the GP level is to investigate and refer; definitive treatment for most primary immunodeficiencies requires immunology specialist care. At the GP level:

• Exclude and treat secondary causes first: HIV, malignancy, drug-induced, nutritional.
• Vaccinate proactively: for all patients with any immunodeficiency, ensure vaccination is current per the Australian Immunisation Handbook immunocompromised schedule.
• No live vaccines in any patient with cellular or combined immunodeficiency pending specialist evaluation.
• Refer to immunology for any abnormal immunoglobulin, lymphocyte subset, or complement result, and for clinical suspicion with a normal screen if SPUR-PI features are strong.

B. Evidence — immunoglobulin replacement and SCID screening

Immunoglobulin replacement (IVIg or SCIg) is the cornerstone treatment for symptomatic humoral immunodeficiency. Target IgG trough above 7 g/L prevents the majority of serious bacterial infections in CVID and XLA. Where bronchiectasis is established, higher troughs of 8–10 g/L are associated with better lung function outcomes per Orange et al. (JACI 2009) and Lucas et al. (Clin Exp Immunol 2010).

Subcutaneous immunoglobulin (SCIg) is non-inferior to intravenous IVIg for infection prevention, produces steadier trough levels, and is home-administered weekly, removing the need for hospital infusion visits. The National Blood Authority Criteria for Clinical Use of Immunoglobulin v3 govern access through the BloodSTAR portal, with specialist (immunologist, haematologist, or relevant physician) prescriber authority required.

TREC newborn screening for SCID has been added to the Australian national newborn bloodspot programme, with national rollout completed from 2023 following NSW, Victoria, and South Australia pilot programmes. TREC (T-cell receptor excision circles) are DNA byproducts of T-cell development — absent in SCID. An abnormal TREC result requires immediate paediatric immunology referral. Early transplant before the first serious infection achieves approximately 95% survival versus around 70% when the diagnosis is made after a sentinel infection.

Pneumococcal polysaccharide vaccine response — measuring specific antibody titres before and four to six weeks after Pneumovax-23 — is the gold-standard functional test for specific antibody deficiency when total IgG is normal. Inadequate response to four or more polysaccharide serotypes confirms the diagnosis and is an indication for immunoglobulin replacement under National Blood Authority criteria.

C. Specific conditions — CVID, asplenia, and secondary immunodeficiency

Common variable immunodeficiency (CVID) is the most common symptomatic adult primary immunodeficiency in Australian practice. Low IgG (typically below 5 g/L), low IgA and/or IgM, and poor specific antibody responses are the diagnostic criteria per the IUIS 2022 classification (Tangye et al., J Clin Immunol 2022). Complications include bronchiectasis (approximately 30%), CVID enteropathy (approximately 25%), autoimmune cytopenia, granulomatous-lymphocytic interstitial lung disease (GLILD), and lymphoma at eight to thirteen times the general population risk. Treatment requires immunology-led IgG replacement, surveillance for complications (annual FBC, LDH, HRCT chest at intervals), and GPCCMP-coordinated allied-health input for complex cases.

Asplenia and functional asplenia from surgical splenectomy, haemoglobinopathies (sickle cell disease, thalassaemia), or infiltrative disease creates sustained vulnerability to encapsulated organisms. The GP bundle for any asplenic patient includes lifelong penicillin V 250 mg twice daily (or amoxicillin 250–500 mg daily), the full asplenia vaccination schedule funded under the National Immunisation Program and Australian Immunisation Handbook, standby antibiotics (amoxicillin/clavulanate 875/125 mg) for any febrile illness while the patient seeks review, and registration with Spleen Australia. The Spleen Australia registry provides ongoing reminder-based vaccination and prophylaxis support.

Secondary immunodeficiency from rituximab and biologics: rituximab commonly causes secondary hypogammaglobulinaemia, sometimes severe and prolonged. Measure baseline immunoglobulins before initiating rituximab, update relevant vaccines beforehand, and recheck IgG at six and twelve months and after any significant infection. Refer to immunology if IgG falls below 5 g/L with clinical infection burden.

D. Australian operations

MBS pathways: GP consultations (items 23, 36, 44). Immunology and complement tests: immunoglobulins (MBS 71161), complement C3/C4 (MBS 71165), HIV serology (MBS 69384), serum protein electrophoresis. Lymphocyte subsets by flow cytometry (MBS 73529) are typically specialist-requested. CH50/AH50 and neutrophil DHR are tertiary pathology tests available through immunology referral. GPCCMP (MBS items 965, 967) for patients with CVID, asplenia, or complex chronic immunodeficiency — direct allied-health referral to physiotherapy (airway clearance for bronchiectasis), dietitian, and psychologist.

Immunoglobulin access: SCIg and IVIg products (Privigen, Octagam — IVIg; Hizentra, Cuvitru — SCIg) are accessed through the National Blood Authority BloodSTAR portal, with specialist prescriber authority and documented antibody deficiency plus clinical infection or end-organ damage as eligibility requirements. Australian Red Cross Lifeblood governs immunoglobulin governance in Australia; patients on Ig replacement are deferred from blood donation.

Vaccination funding (NIP-funded asplenia/PID schedule): Prevenar 20 plus Pneumovax 23 (five years apart), Hib, MenACWY every five years, MenB (Bexsero primary course plus boosters), annual influenza, and COVID-19 boosters per ATAGI — all NIP-funded for asplenic and immunocompromised patients. Recombinant zoster vaccine (Shingrix) is funded for adults ≥65 and selected immunocompromised cohorts.

Mandatory notifications: HIV is confidentially notifiable to the relevant state or territory health department. Meningococcal disease is urgently notifiable. TB is notifiable in all states.

NDIS and Centrelink: CVID with bronchiectasis, disabling fatigue, or neurocognitive impact may meet NDIS functional eligibility — detailed functional documentation from the GP and treating team is needed.

E. Special populations

Neonates with abnormal TREC result: GP or maternal and child health nurse who receives notification of an abnormal newborn bloodspot TREC must urgently refer to paediatric immunology — do not give any live vaccines (BCG, rotavirus, MMR, varicella, oral typhoid, yellow fever), isolate from infectious contacts where possible, and arrange same-day specialist contact. This is a medical emergency.

Children aged under five with frequent infections: six to eight upper respiratory infections per year in childcare is statistically normal. Investigate only when SPUR-PI features are present — unusually severe, prolonged, or complicated infections; unusual organisms; failure to thrive; family history. Paediatric immunodeficiency presentations include tonsils that are absent in XLA, eczema in Wiskott-Aldrich syndrome, telangiectasia in ataxia-telangiectasia, and albinism in Chediak-Higashi syndrome.

Pregnancy: most women with CVID on IgG replacement tolerate pregnancy without major immune deterioration. Immunology review during pregnancy to adjust IgG dosing is standard. Vaccines in pregnancy should follow Australian Immunisation Handbook guidance — live vaccines are generally contraindicated.

Travel and international visits: asplenic and immunodeficient patients require a specific pre-travel review — check Ig trough, update vaccinations where due, prescribe malaria prophylaxis for endemic regions, caution about animal bites (Capnocytophaga canimorsus from dog and cat bites is a life-threatening risk in asplenia). Spleen Australia provides a patient wallet card and emergency information card.

When to escalate

Refer to immunology routinely when:

• Immunoglobulins IgG, IgA, or IgM are below the reference range.
• Lymphocyte subsets show T-cell, B-cell, or NK-cell deficiency.
• Two or more Jeffrey Modell warning signs are present, even with a normal first-line screen if clinical suspicion is high.
• IgG subclass deficiency is found in the setting of recurrent sinopulmonary infection.

Refer to immunology urgently (same-week) when:

• Moderate hypogammaglobulinaemia (IgG below 4 g/L) with active recurrent infection or bronchiectasis.
• Recurrent meningococcal disease — complement deficiency workup.
• Recurrent catalase-positive organism abscesses — CGD workup.
• Post-rituximab IgG below 5 g/L with clinical infection burden.

Urgently to paediatric immunology or emergency department:

• Abnormal TREC newborn screening — SCID until proven otherwise; live-vaccine embargo, isolation, and same-day specialist contact.
• Neonate with failure to thrive and an opportunistic infection (Pneumocystis pneumonia, CMV, invasive candidiasis) — emergency immunology and transplant workup.

What this article is and is not

This is general health information drawn from current Australian clinical practice guidelines — ASCIA, National Blood Authority, Australian Immunisation Handbook, Spleen Australia, and the IUIS 2022 inborn errors of immunity classification. It is not personal medical advice and does not create a doctor–patient relationship. Decisions about immunodeficiency workup, specialist referral, and treatment are made collaboratively with your own GP and treating specialists based on your individual circumstances.

For Australian consumer resources: Immune Deficiencies Foundation Australia (IDFA) · ASCIA patient information · Spleen Australia · HealthDirect.

For mental health support during a chronic illness: Lifeline 13 11 14 · Beyond Blue 1300 22 4636.

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Sources cited

1. ASCIA — Primary Immunodeficiency Working Group
2. National Blood Authority — Criteria for the Clinical Use of Immunoglobulin in Australia v3
3. Australian Red Cross Lifeblood — Immunoglobulin Governance
4. Australian Immunisation Handbook (NCIRS / DoHAC)
5. National Immunisation Program Schedule 2024
6. NCIRS — TREC newborn bloodspot screening for SCID
7. Spleen Australia / Australian Spleen Registry
8. Immune Deficiencies Foundation Australia (IDFA)
9. Jeffrey Modell Foundation — 10 Warning Signs of PID
10. Tangye SG et al. — Inborn Errors of Immunity: 2022 IUIS Update (J Clin Immunol 2022)
11. Bonilla FA et al. — Practice parameter for primary immunodeficiency (AAAAI/ACAAI, JACI 2015)
12. HealthDirect