Name: Job's Syndrome (Hyper-IgE Syndrome)
Creator: Dr Sean James Ledger

Authorship & review

Dr Sean James Ledger, BSc Physio (Hons) MSc PhD FHEA

Director and Principal Physiotherapist
Ahpra registration PHY0002298174

Version

1.0

Last updated

31 August 2026

Next review

31 August 2027

Every guide on this site is reviewed at least once a year, and sooner when the evidence changes.
How these guides are written and reviewed →

Part 1 · In plain language

Job’s syndrome, more precisely called hyper-IgE syndrome, is a rare inherited condition in which part of the immune system does not work properly. People with it have very high levels of an antibody called IgE, eczema from early childhood, and repeated bacterial infections of the skin and lungs. The lung infections are what concern a cardiorespiratory physiotherapist: repeated pneumonia can leave permanent damage — thin-walled air pockets called pneumatoceles, abscess cavities, and widened, scarred airways that trap sputum and become infected again. That cycle is the central problem, and breaking it is where airway clearance physiotherapy does real work. Treatment also involves long-term preventative antibiotics and antifungals, and careful specialist follow-up. This page explains the condition, the lung damage it causes, and how physiotherapy fits into managing it.

Definition

Hyper-IgE syndrome is a primary immunodeficiency — a condition where the immune system is faulty from birth because of a genetic change, rather than becoming weakened later by illness or medication. The most common form is caused by changes in a gene called STAT3, which is involved in signalling inside immune cells. There is a rarer form linked to a different gene, DOCK8, which behaves somewhat differently.^2,3

The older name, Job’s syndrome, comes from the biblical figure afflicted with boils, and reflects the recurrent skin abscesses that are one of its features. Both names remain in use.¹

The characteristic triad is very high blood IgE, eczema, and recurrent abscesses of the skin and lungs. Because eczema and chest infections are individually common in childhood, the diagnosis is often made late — sometimes not until permanent lung damage has already occurred.^1,5

Pathophysiology

The immune defect impairs the response to particular bacteria and fungi, especially Staphylococcus aureus and Aspergillus.⁴ In the lung, that produces a sequence which is worth following through, because each step explains a different part of the treatment.

Repeated pneumonia

Infections are frequent, and they are often more destructive than the same infection would be in someone with a normal immune system. A striking and well-described feature is that people can be much less unwell than the scan suggests — fever and inflammatory markers may be modest despite extensive infection, which is one reason infections are missed or treated late.⁶

Pneumatoceles and abscess cavities

Destructive pneumonia can leave pneumatoceles — thin-walled air-filled spaces within the lung — and abscess cavities. These do not heal back into normal lung. They are relevant in three ways: they can become very large and compress working lung, they can become secondarily infected with fungi, and they can rupture, causing air to leak into the space around the lung.⁷

Bronchiectasis and the infection cycle

Repeated infection also damages and widens the airways themselves, producing bronchiectasis. Widened, scarred airways do not clear mucus effectively. Retained mucus becomes colonised with bacteria, which causes further inflammation and further damage, which impairs clearance further. This self-sustaining cycle is the single most important concept in managing the lungs in this condition, and it is the specific target of airway clearance physiotherapy.^8,9

Other features

The condition affects more than the lungs, which is why care is shared across several specialties:

Skin — eczema from infancy, and recurrent abscesses that are often notably lacking in the redness and heat usually seen with infection.
Bones and joints — reduced bone density, fractures with little trauma, scoliosis, and unusually flexible joints.¹⁰
Face and teeth — characteristic facial features develop over childhood, and retained baby teeth are common.
Blood vessels — aneurysms, including of the coronary arteries, are recognised and are a reason for cardiac surveillance.¹¹
Fungal infection — persistent thrush of the mouth and nails, and susceptibility to Aspergillus infection in damaged lung.

Important: infection may be less obvious than you expect

In this condition the usual warning signs of infection can be blunted. That changes the threshold for seeking help. Contact your specialist team promptly for:

Any change in your usual sputum — more of it, thicker, a change in colour, or a new smell.
New or increasing breathlessness, or a drop in your exercise tolerance.
Coughing up blood.
Sudden sharp chest pain with breathlessness — a pneumatocele can rupture, and this needs urgent assessment.
Feeling generally unwell, even without fever.

Waiting for a temperature before acting is not a reliable strategy here. If your baseline changes, that is the signal.

Diagnosis

Diagnosis combines the clinical pattern with laboratory findings, and is usually led by an immunologist:

Serum IgE — characteristically very high, though it can fall in adulthood and a lower level does not exclude the diagnosis once it is established.
Blood counts — often showing raised eosinophils.
Genetic testing — for STAT3 and related genes, which confirms the diagnosis and distinguishes the subtypes.
Scoring systems — clinical scores combining the various features, used to decide who warrants genetic testing.⁵
Chest imaging — CT to define bronchiectasis, pneumatoceles and cavities. This is the assessment that matters most for planning physiotherapy.
Sputum culture — to identify which organisms are present, including fungi, and to guide antibiotic choice.

Management

Preventing infection

Long-term preventative antibiotics, usually directed against Staphylococcus aureus, are a mainstay, and antifungal prophylaxis is used where there is cavity disease or previous fungal infection. Vaccinations are kept up to date, and some people receive immunoglobulin replacement.

Treating infections early and for longer

Acute infections are treated promptly and often with longer courses than would be usual, guided by sputum results. Because the signs are blunted, treatment decisions frequently rest on a change from the person’s own baseline rather than on classical features of infection.

Managing the structural damage

Bronchiectasis is managed as bronchiectasis: airway clearance, treatment of exacerbations, and monitoring.^8,9 Large or complicated pneumatoceles occasionally need surgical or interventional management. Skin care, bone protection and dental care each need their own attention.

Where transplant fits

Haematopoietic stem cell transplantation is used in some forms — more established in DOCK8 deficiency than in STAT3 disease — and is a specialist decision made in immunology centres.³

Living with it

Most adults with hyper-IgE syndrome are managing a long-term condition rather than recovering from an illness. What tends to shape daily life is:

A daily airway clearance routine, which is the part most within your own control and the part most likely to reduce exacerbations.
Reduced exercise tolerance, from a combination of lost lung units, deconditioning and repeated setbacks.
Repeated courses of antibiotics, and the vigilance that goes with knowing your own baseline.
Fatigue, which is both a symptom of chronic infection and a consequence of reduced fitness.
Bone fragility, which is a genuine consideration when choosing exercise — it argues for a well-designed strengthening programme, not for avoiding loading.

Exercise is not a risk to be avoided in this condition. Done properly it improves clearance, capacity and bone density,¹² and the programme simply needs to account for the fracture risk and the cardiac surveillance.

How it differs from other causes of recurrent chest infection

Repeated pneumonia and bronchiectasis have several possible causes, and people are often investigated for the others first. The distinctions matter because the treatments differ.

Cystic fibrosis

Also causes bronchiectasis and chronic infection from childhood, but through a completely different mechanism — a defect in salt and water transport that thickens secretions. It is distinguished by sweat testing and genetic analysis, and it involves the pancreas and gut in ways hyper-IgE syndrome does not. Very high IgE and recurrent skin abscesses are not features.

Primary ciliary dyskinesia

The cilia that sweep mucus out of the airways do not beat effectively. It causes bronchiectasis, chronic sinus disease and glue ear from early life, and roughly half of those affected have their internal organs mirrored. Immune function is normal, so skin abscesses and fungal infection are not part of it.

Common variable immunodeficiency

The other immunodeficiency that commonly presents with bronchiectasis. Here the problem is low antibody levels rather than a very high IgE, and immunoglobulin replacement is the central treatment. Eczema and abscesses are not typical.

Allergic bronchopulmonary aspergillosis

Worth mentioning because it also produces a high IgE and involves Aspergillus, and it can coexist with the structural damage seen in hyper-IgE syndrome. It is an allergic response to the fungus rather than an inherited immune defect, occurs mainly in people with asthma or cystic fibrosis, and is treated with steroids and antifungals.

These are separated by immunology and genetic testing rather than by symptoms, which overlap considerably. The reason it matters to physiotherapy is that the clearance regimen is broadly similar across all of them, while the caution about cavity disease is specific to conditions that destroy lung tissue — which is why the imaging, not the diagnostic label, drives technique selection.

Airway clearance in practice

Clearance is the part of treatment you carry out yourself, most days, for the rest of your life. That makes two things more important than which technique is theoretically best.

It has to be a routine you will actually do. A twenty-minute regimen performed most days achieves more than a perfect forty-minute one abandoned within a fortnight. We would rather design something sustainable and progress it than prescribe an ideal that does not survive a working week.

It has to match where your damage is. Bronchiectasis in the lower lobes needs different positioning from disease at the apices, and cavity disease changes which devices are appropriate. This is why a recent CT report is genuinely useful at a first appointment, rather than a formality.

A typical session combines a technique to loosen secretions, a controlled breathing pattern to move them centrally, and a huff or cough to clear them — done in a position that suits your anatomy, and often around nebulised treatment if you use it. Timing relative to meals, exercise and inhalers all affect how well it works, and these are worth getting right.

Technique also drifts over months without anyone noticing, which is the usual reason a previously effective routine stops working. Periodic review is not about learning something new; it is about checking that what you are doing is still what you were taught.

Role of the physiotherapist

The lung damage in this condition is permanent, but the infection cycle is not fixed — and that cycle is what drives most of the deterioration. Effective daily airway clearance is the intervention with the clearest role, and it is what a cardiorespiratory physiotherapist does.

We work alongside your immunologist and respiratory physician, not instead of them. Bring your most recent CT report and sputum results to a first appointment: clearance technique should be chosen against where the damage actually is, not prescribed generically.

How we treat this at the clinic

The lung damage is permanent, but the infection cycle that drives it is not. We match an airway clearance technique to where your cavities and bronchiectasis actually are, coach it until it works on a bad morning, and review it — technique drift is the usual reason a routine stops working.

Airway Clearance Therapy →Physiotherapy Assessment →Cardiorespiratory Rehabilitation →

Part 1 · References

Grimbacher B, Holland SM, Gallin JI, et al. Hyper-IgE syndrome with recurrent infections — an autosomal dominant multisystem disorder. N Engl J Med 1999;340(9):692–702.
Holland SM, DeLeo FR, Elloumi HZ, et al. STAT3 mutations in the hyper-IgE syndrome. N Engl J Med 2007;357(16):1608–1619.
Zhang Q, Davis JC, Lamborn IT, et al. Combined immunodeficiency associated with DOCK8 mutations. N Engl J Med 2009;361(21):2046–2055.
Milner JD, Brenchley JM, Laurence A, et al. Impaired T(H)17 cell differentiation in subjects with autosomal dominant hyper-IgE syndrome. Nature 2008;452(7188):773–776.
Woellner C, Gertz EM, Schäffer AA, et al. Mutations in STAT3 and diagnostic guidelines for hyper-IgE syndrome. J Allergy Clin Immunol 2010;125(2):424–432.
Freeman AF, Holland SM. Clinical manifestations, etiology, and pathogenesis of the hyper-IgE syndromes. Pediatr Res 2009;65(5 Pt 2):32R–37R.
Freeman AF, Renner ED, Henderson C, et al. Lung parenchyma surgery in autosomal dominant hyper-IgE syndrome. J Clin Immunol 2013;33(5):896–902.
Hill AT, Sullivan AL, Chalmers JD, et al. British Thoracic Society guideline for bronchiectasis in adults. Thorax 2019;74(Suppl 1):1–69.
Polverino E, Goeminne PC, McDonnell MJ, et al. European Respiratory Society guidelines for the management of adult bronchiectasis. Eur Respir J 2017;50(3):1700629.
Sowerwine KJ, Shaw PA, Gu W, et al. Bone density and fractures in autosomal dominant hyper-IgE syndrome. J Clin Immunol 2014;34(2):260–264.
Chandesris MO, Azarine A, Ong KT, et al. Frequent and widespread vascular abnormalities in human signal transducer and activator of transcription 3 deficiency. Circ Cardiovasc Genet 2012;5(1):25–34.
Lee AL, Hill CJ, McDonald CF, Holland AE. Pulmonary rehabilitation in individuals with non-cystic fibrosis bronchiectasis: a systematic review. Arch Phys Med Rehabil 2017;98(4):774–782.

Part 2 of 2

Clinical evidence

Part 1 covers the same condition without the technical detail. What follows is the evidence base behind it, written for clinicians — the literature, the reasoning and the gaps.

For clinicians: this summary supports clinical reasoning and is not a protocol. Check current guidelines and local policy before applying it, and read it alongside the key references and guidelines directory.

Framing. Autosomal dominant hyper-IgE syndrome is caused by dominant-negative loss-of-function variants in STAT3, defining a combined immunodeficiency with connective tissue and skeletal features; autosomal recessive disease due to DOCK8 deficiency is a distinct entity with greater viral susceptibility and a different transplant rationale.^1,2,3 The classical triad of markedly elevated serum IgE, eczema and recurrent staphylococcal skin and pulmonary abscesses is well characterised, and impaired Th17 differentiation provides the mechanistic explanation for the specific susceptibility to Staphylococcus aureus and Candida.⁴ The NIH clinical scoring system remains widely used to select patients for genetic testing.⁵

Pulmonary phenotype and why it drives management

The distinguishing feature is not infection frequency but the architectural destruction that follows it — pneumatocele formation, cavitation and bronchiectasis, in a pattern more destructive than comparable infection in immunocompetent hosts.^6,7
Established cavities become the substrate for secondary infection with Aspergillus, Scedosporium and non-tuberculous mycobacteria, and secondary fungal infection of pneumatoceles is a recognised cause of major morbidity and of haemoptysis.⁷
The therapeutic target is prevention of further parenchymal loss, not eradication of colonisation.

Blunted inflammatory response

Inflammatory signalling is attenuated — described as “cold” abscesses in skin, and as pulmonary infection with disproportionately modest fever, symptoms and inflammatory markers.^1,6
This reframes exacerbation detection for a physiotherapy service: the trigger for escalation should be deviation from an individually established baseline in sputum volume, character, exercise tolerance or clearance efficacy, rather than conventional systemic markers of infection.
Establishing and documenting that baseline is a legitimate physiotherapy contribution, and is the mechanism by which we add safety rather than merely technique.

Airway clearance evidence base

There is no trial evidence specific to hyper-IgE syndrome, and none should be implied.
Practice is extrapolated from non-cystic fibrosis bronchiectasis, where airway clearance is supported by the British Thoracic Society guideline, the ERS guideline for adult bronchiectasis, and Cochrane review of airway clearance techniques in that population.^8,9,10
The extrapolation is mechanistically sound: mucociliary impairment, mucus retention and the infection-inflammation cycle are common to both.
Technique selection should be individualised to the distribution of disease and to tolerance, with no single modality demonstrating consistent superiority in the bronchiectasis literature.

Cavity disease alters technique selection, and this is the point most easily missed. Positive expiratory pressure devices and high-intensity manual techniques warrant caution where large pneumatoceles or thin-walled cavities are present, given the reported risk of rupture and pneumothorax.⁷ There is no direct evidence quantifying that risk during airway clearance, so the appropriate position is explicit caution rather than either prohibition or reassurance: clearance should be selected against current cross-sectional imaging, discussed with the respiratory physician where cavity disease is extensive, and any new pleuritic pain or acute breathlessness treated as a possible pneumothorax. Prescribing a clearance regimen in this condition without having seen recent imaging is not defensible.

Antimicrobial and immunological management

Long-term anti-staphylococcal prophylaxis is standard practice, associated with reduced pulmonary infection in observational cohorts; antifungal prophylaxis is used where cavity disease or prior fungal infection exists.^1,6
Immunoglobulin replacement is used selectively.
Haematopoietic stem cell transplantation has an established role in DOCK8 deficiency, with outcomes in STAT3 disease less clear and the non-haematopoietic connective tissue features not corrected by transplant.^3,11

Exercise, bone and vascular considerations

Reduced bone mineral density, minimal-trauma fracture and scoliosis are described.^1,12
Coronary and cerebral arterial aneurysm and tortuosity are recognised vascular complications warranting surveillance.¹³
The fracture risk argues for progressive resistance and weight-bearing training rather than avoidance of loading.
Known aneurysmal disease requires cardiology input before high-intensity or heavy isometric work.
Pulmonary rehabilitation evidence is extrapolated from bronchiectasis, where supervised programmes improve exercise capacity and quality of life, with attenuation of benefit over time.¹⁴

Evidence gaps

No condition-specific evidence exists for airway clearance modality, exercise prescription or rehabilitation outcome in hyper-IgE syndrome.
The pneumothorax risk associated with clearance in cavity disease is unquantified.
The interaction between long-term prophylaxis, chronic colonisation and training response is uncharacterised.
Given the rarity of the condition these gaps are unlikely to close, which makes transparent extrapolation and individualised reasoning the standard of care rather than a shortfall from it.

References for the clinical evidence summary

Grimbacher B, Holland SM, Gallin JI, et al. Hyper-IgE syndrome with recurrent infections — an autosomal dominant multisystem disorder. N Engl J Med 1999;340(9):692–702.
Holland SM, DeLeo FR, Elloumi HZ, et al. STAT3 mutations in the hyper-IgE syndrome. N Engl J Med 2007;357(16):1608–1619.
Zhang Q, Davis JC, Lamborn IT, et al. Combined immunodeficiency associated with DOCK8 mutations. N Engl J Med 2009;361(21):2046–2055.
Milner JD, Brenchley JM, Laurence A, et al. Impaired T(H)17 cell differentiation in subjects with autosomal dominant hyper-IgE syndrome. Nature 2008;452(7188):773–776.
Woellner C, Gertz EM, Schäffer AA, et al. Mutations in STAT3 and diagnostic guidelines for hyper-IgE syndrome. J Allergy Clin Immunol 2010;125(2):424–432.
Freeman AF, Holland SM. Clinical manifestations, etiology, and pathogenesis of the hyper-IgE syndromes. Pediatr Res 2009;65(5 Pt 2):32R–37R.
Freeman AF, Renner ED, Henderson C, et al. Lung parenchyma surgery in autosomal dominant hyper-IgE syndrome. J Clin Immunol 2013;33(5):896–902.
Hill AT, Sullivan AL, Chalmers JD, et al. British Thoracic Society guideline for bronchiectasis in adults. Thorax 2019;74(Suppl 1):1–69.
Polverino E, Goeminne PC, McDonnell MJ, et al. European Respiratory Society guidelines for the management of adult bronchiectasis. Eur Respir J 2017;50(3):1700629.
Lee AL, Burge AT, Holland AE. Airway clearance techniques for bronchiectasis. Cochrane Database Syst Rev 2015;11:CD008351.
Aydin SE, Kilic SS, Aytekin C, et al. DOCK8 deficiency: clinical and immunological phenotype and treatment options — a review of 136 patients. J Clin Immunol 2015;35(2):189–198.
Sowerwine KJ, Shaw PA, Gu W, et al. Bone density and fractures in autosomal dominant hyper-IgE syndrome. J Clin Immunol 2014;34(2):260–264.
Chandesris MO, Azarine A, Ong KT, et al. Frequent and widespread vascular abnormalities in human signal transducer and activator of transcription 3 deficiency. Circ Cardiovasc Genet 2012;5(1):25–34.
Lee AL, Hill CJ, McDonald CF, Holland AE. Pulmonary rehabilitation in individuals with non-cystic fibrosis bronchiectasis: a systematic review. Arch Phys Med Rehabil 2017;98(4):774–782.

Important: This page is general information, not medical advice. If your breathing or symptoms change suddenly or severely, seek urgent medical care. For personalised assessment, contact Inspire Clinic.

Corrections: If something on this page is wrong, out of date or unclear, we want to know. Email reception@inspireclinic.au with the page name and what you believe is incorrect. Substantive corrections are made promptly, and the guide’s version and last-updated date are changed to reflect it.