Alpha-1-Antitrypsin Deficiency

Clinical Snapshot

Alpha-1-antitrypsin deficiency (AATD) is an inherited, substantially underdiagnosed disorder of the SERPINA1 gene on chromosome 14, which encodes alpha-1 antitrypsin (AAT) — a serine protease inhibitor made mainly in the liver and released into the circulation, where its principal job is protecting the delicate elastin architecture of the alveoli from neutrophil elastase.^[1]

AATD produces two clinically opposite disease mechanisms in two different organs, and understanding that difference is the single most important concept in this chapter:

Lung disease is a loss-of-function problem. Too little functional AAT reaches the alveoli, leaving neutrophil elastase unopposed to progressively destroy alveolar walls — producing early-onset, basal-predominant panacinar emphysema, often decades before the age typically associated with smoking-related COPD.
Liver disease is a toxic gain-of-function problem. The abnormal Z-variant AAT protein misfolds and polymerizes inside hepatocytes instead of being secreted normally, and it is this intracellular accumulation — not a lack of circulating AAT — that injures the liver, driving neonatal cholestasis, chronic hepatitis, cirrhosis, and hepatocellular carcinoma risk.

Because these are two different mechanisms, intravenous augmentation therapy — which simply raises circulating AAT — treats the lung disease and does nothing for the liver disease. This distinction, and the equally important question of who should be tested in the first place, run through the entire chapter.^[2]

The clinically significant severe-deficiency genotype is homozygosity for the Z allele (PiZZ). AATD is estimated to affect roughly 1 in 2,000-5,000 people of European ancestry, yet diagnosis is typically delayed for years after the first symptoms, because both the lung and liver presentations are easily mistaken for far more common diagnoses — usual COPD, asthma, or cryptogenic liver disease — unless a clinician specifically thinks to test for it.^[3]

Recognize the Condition

Three distinct presenting pictures

A patient with AATD can present through any one of these pathways — recognizing all three is what actually catches the diagnosis.

Lung disease

Progressive exertional dyspnea, chronic cough, and wheeze indistinguishable at first from ordinary COPD — except that it typically begins in the 30s to 50s, well before the age usually associated with smoking-related emphysema, and is disproportionately severe relative to the patient's smoking history, if any. A basal-predominant emphysema pattern on imaging — the opposite distribution from the apical-predominant pattern typical of ordinary smoking-related COPD — is a useful clue once imaging is obtained (see Assessment & Diagnosis).

Liver disease

In infancy: prolonged neonatal jaundice with conjugated hyperbilirubinemia, sometimes progressing to childhood cholestatic hepatitis. In adulthood: unexplained abnormal liver enzymes, hepatomegaly, or cirrhosis discovered incidentally or through a standard cirrhosis work-up — sometimes with no preceding history of liver disease in childhood at all (see the Cirrhosis chapter for staging and decompensation management once liver disease is confirmed).

Skin disease — necrotizing panniculitis

A rare but distinctive presentation: painful, erythematous, sometimes ulcerating subcutaneous nodules and plaques, most often on the trunk and proximal limbs, that can be mistaken for cellulitis or vasculitis. Biopsy characteristically shows a neutrophil-predominant lobular panniculitis. This finding alone is a testing trigger (see Red Flags & Refer).

Risk Factors

Homozygosity for the Z allele (PiZZ) — the clinically significant severe-deficiency genotype and the greatest risk factor for both lung and liver disease.
Compound heterozygous genotypes such as PiSZ — intermediate risk, clinically meaningful especially with smoking or alcohol exposure, but lower absolute risk than PiZZ.
PiMZ heterozygosity ("carrier" status) — not generally associated with a significantly increased risk of clinical emphysema in a nonsmoker, but risk rises meaningfully with smoking.
A first-degree relative with confirmed AATD, or with early-onset emphysema or unexplained liver disease that was never formally worked up.
Cigarette smoking — by far the single largest modifiable risk factor for lung disease in a person with a deficiency genotype (see Non-Pharmacologic Treatment).
Occupational dust, fume, or biomass-fuel exposure — the same lung-disease risk factors that apply in ordinary COPD compound the risk in AATD.
Alcohol use, and other coexisting liver insults such as viral hepatitis or metabolic dysfunction-associated steatotic liver disease — these compound, rather than cause, AATD-related liver injury.

Red Flags & Refer

Test for AATD — and refer for specialist confirmation and management once found — for any of the following. None of these should be attributed to "just COPD" or "just cirrhosis" without at least considering AATD:

COPD diagnosed before age 45.
COPD with minimal or no smoking history (broadly, under about 20 pack-years, or any nonsmoker with airflow obstruction).
Unexplained liver disease of any kind — abnormal liver enzymes, hepatomegaly, or cirrhosis without an identified cause, at any age, including infancy.
A family history of AATD, or a family history of early-onset emphysema or unexplained liver disease that was never formally worked up.
Necrotizing panniculitis — painful, ulcerating subcutaneous nodules, particularly with a neutrophilic infiltrate on biopsy.
Unexplained bronchiectasis.
Adult-onset asthma with airflow obstruction that does not fully reverse with bronchodilator therapy.
A basal-predominant emphysema pattern on chest imaging, rather than the apical-predominant pattern typical of ordinary smoking-related COPD.
Unexplained rapid FEV1 decline that is disproportionate to the patient's smoking history.^[2]

Escalate urgently, beyond routine testing: signs of decompensated liver disease (see the Cirrhosis chapter's Red Flags & Refer — hematemesis/melena, new ascites, worsening encephalopathy); signs of respiratory failure (see the COPD chapter's Red Flags & Refer); and any new, painful, rapidly spreading, or ulcerating skin lesion suggestive of panniculitis, which needs urgent dermatology assessment and biopsy rather than empiric antibiotics for presumed cellulitis.

Assessment & Diagnosis

Step 1 — serum AAT level

Serum AAT level (usually measured by nephelometry) is the standard first test for a patient with moderate clinical suspicion. Because AAT is an acute-phase reactant, a level drawn during active infection or inflammation can be falsely normal or elevated in a genuinely deficient patient — check a concurrent CRP, and repeat testing once any acute illness has resolved if the result is inconsistent with the clinical picture.^[2]

Step 2 — genotype/phenotype confirmation

A low or borderline serum level should be confirmed with Pi genotyping or phenotyping (isoelectric focusing, sometimes called Pi typing) and/or SERPINA1 gene sequencing, which also detects rare null and deficient variants that isoelectric focusing alone can miss. For a patient with high pre-test clinical suspicion — for example, a sibling of a confirmed PiZZ patient, or classic early-onset basal emphysema — current Canadian guidance supports going directly to genetic testing rather than starting with a serum level.^[2]

Genotype	Typical serum AAT level	Clinical significance
PiMM	Normal	Normal — the common, non-deficient genotype.
PiMZ	Mildly reduced	Heterozygous carrier; not itself considered a significantly increased emphysema risk in a nonsmoker, but risk rises with smoking. Not an augmentation-therapy candidate.
PiSZ	Moderately-severely reduced	Compound heterozygote; intermediate risk between PiMZ and PiZZ, more clinically significant with smoking or alcohol use. Individualize augmentation-therapy candidacy (see Special Populations).
PiZZ	Severely reduced (roughly 10-20% of normal)	The clinically significant severe-deficiency genotype — accounts for the large majority of clinically recognized AATD, and is what the augmentation-therapy eligibility criteria are built around.
Null-Null	Undetectable	Very rare; no AAT protein is produced at all, giving the highest lung-disease risk of any genotype — but because no protein is made to misfold and accumulate, these patients do not develop the liver disease seen with PiZZ.

Confirming and staging lung disease

Once a severe-deficiency genotype is confirmed, obtain spirometry and assess for emphysema exactly as in ordinary COPD — see the COPD chapter's Assessment & Diagnosis for the full post-bronchodilator spirometry criteria and GOLD grading, which apply unchanged here. Chest CT in AATD-related emphysema characteristically shows a basal-predominant panacinar pattern, a genuinely useful distinguishing feature from the apical-predominant centrilobular emphysema typical of ordinary smoking-related COPD, though it is a supportive finding rather than a diagnostic requirement.

Confirming and staging liver disease

Obtain baseline and periodic liver enzymes, and refer to hepatology for any abnormality. Once cirrhosis is identified, stage and manage it exactly as in the Cirrhosis chapter — Child-Pugh and MELD scoring, hepatocellular carcinoma surveillance, and the same transplant-referral triggers (a first decompensation event, or MELD ≥15) apply without modification for an AATD-related cause.

Treatment Targets

Achieve smoking cessation — the single highest-impact intervention available, and dramatically more important in AATD than in ordinary COPD (see Non-Pharmacologic Treatment).
Control lung symptoms and slow the rate of lung function decline using standard COPD pharmacotherapy (see the COPD chapter), layered with augmentation therapy in eligible patients.
Correctly determine augmentation-therapy eligibility and, where eligible, arrange access without unnecessary delay.
Detect and manage AATD-related liver disease early, understanding that augmentation therapy plays no role in that management (see the Cirrhosis chapter for the actual liver-directed treatment ladder).
Recognize and treat AATD-associated panniculitis.
Complete genetic counseling and offer cascade testing to first-degree relatives.
Keep vaccination status current (see the COPD and Cirrhosis chapters).

Choose Initial Treatment

Direct treatment rule — lung disease

Every patient with AATD and confirmed emphysema/COPD-pattern lung disease receives standard COPD pharmacotherapy exactly as in the COPD chapter — the GOLD ABE assessment, bronchodilator selection, and eosinophil-guided inhaled-corticosteroid decision are not modified by an AATD diagnosis. Use the COPD chapter directly rather than re-deriving a separate regimen for this population.

Augmentation therapy — a narrow, adult, emphysema-only indication

Intravenous alpha-1 proteinase inhibitor (A1-PI) augmentation therapy is appropriate only for an adult who meets all of the following:

A confirmed severe-deficiency genotype/phenotype (PiZZ, or another genotype with an equivalently severely reduced level).
Serum AAT level below approximately 11 μmol/L (below about 57 mg/dL) before starting treatment.
Clinical evidence of emphysema, with FEV1 under 80% predicted.
Not currently smoking — the Canadian access program requires confirmed smoking cessation, generally at least 6 months, before approval.
No prior lung transplant.

Weekly intravenous infusion, typically 60 mg/kg, replaces circulating AAT and is the only currently approved augmentation regimen (see Drug Tables).^[4]

What augmentation therapy is not for

Augmentation therapy does not treat AATD-related liver disease. Raising circulating AAT does nothing to reduce the intracellular Z-variant polymer burden that actually causes hepatocyte injury, so it is never prescribed for liver disease alone, regardless of how severe that liver disease is.^[1]

It is also not indicated for a PiMZ heterozygote, for a patient who is still smoking, for a patient with preserved lung function and no emphysema, or following lung transplantation — the transplanted lung does not carry the recipient's genetic deficiency, so there is no lung-protective rationale for continuing it.

A further honest caveat: the product currently funded in Canada carries a Health Canada monograph stating that its effect on reducing exacerbations or slowing disease progression has not been proven in its own controlled trials. The class-wide CT-densitometry evidence supporting augmentation therapy (see Drug Tables) was generated with a different manufacturer's formulation. This distinction is worth knowing, not glossing over, when counselling a patient about what the infusion is realistically expected to do.^[5]

Panniculitis

Confirm the diagnosis with biopsy, then treat with dapsone first-line for most patients. Augmentation therapy is also used for severe or dapsone-refractory AATD-associated panniculitis specifically — a genuine, distinct indication from the emphysema indication above, since the neutrophil-driven skin injury responds to raising circulating AAT the same way the lung disease does.

Non-Pharmacologic Treatment

Smoking cessation — even more important than in ordinary COPD

Smoking cessation is the single most important intervention for anyone with a severe-deficiency genotype, and its impact is dramatically larger in AATD than in the general COPD population: a person with a severe-deficiency genotype who continues smoking loses lung function far faster than one who has never smoked or who quits early, often developing symptomatic emphysema decades earlier than they otherwise would.^[3] Use the same behavioural-counselling-plus-pharmacotherapy approach described in the COPD chapter (varenicline, nicotine replacement therapy, bupropion) — there is nothing AATD-specific about the cessation regimen itself, only about how much is at stake in using it.

Avoid occupational and environmental lung insults

Minimize occupational dust/fume exposure and indoor/outdoor air pollution — the same general measures as in ordinary COPD, again disproportionately consequential given the underlying deficiency.

Protect the liver

Avoid or strictly limit alcohol, and manage coexisting metabolic risk factors (obesity, diabetes) that independently worsen liver outcomes — see the Cirrhosis chapter's Non-Pharmacologic Treatment for the full nutrition, alcohol, and surveillance guidance, which applies unchanged once AATD-related liver disease is present.

Vaccination and pulmonary rehabilitation

Follow the COPD chapter's vaccination schedule and pulmonary rehabilitation referral guidance in full; also ensure hepatitis A and hepatitis B vaccination, if non-immune, once liver disease is present, per the Cirrhosis chapter.

Genetic counseling and cascade family testing

AATD is inherited in an autosomal codominant pattern — both SERPINA1 alleles contribute to the phenotype, so parents, siblings, and children of a confirmed patient are each at meaningful risk and should be offered testing, regardless of whether they currently have symptoms. Counsel that an asymptomatic relative who tests positive still benefits from early identification — earlier smoking-avoidance counselling, earlier recognition of respiratory or liver symptoms, and earlier access to augmentation therapy if lung disease eventually develops.^[1]

Pharmacologic Treatment Options

Drug / intervention	Role	Dose / use	Important adverse effects	Teaching points
Alpha1-Proteinase Inhibitor (GLASSIA) Special situation	Augmentation therapy — eligible adults with confirmed severe-deficiency emphysema	60 mg/kg IV once weekly	Infusion-related reactions (headache, dizziness, flushing, fever, chills); rare hypersensitivity	Only for the specific eligibility criteria in Choose Initial Treatment — never for liver disease alone, and never for a currently smoking patient.
Dapsone Preferred	First-line for AATD-associated panniculitis	Typically starting 50 mg PO once daily, titrated as tolerated	Dose-related hemolysis (screen G6PD status first), methemoglobinemia, agranulocytosis (rare)	Augmentation therapy is reserved for severe or dapsone-refractory panniculitis, not used first-line.
Varenicline Preferred	Smoking-cessation pharmacotherapy — full dosing/counselling in the COPD chapter	See the COPD chapter's Pharmacologic Treatment Options	Nausea, vivid dreams, neuropsychiatric symptoms (monitor mood)	Prioritize cessation before augmentation-therapy referral — current smoking is an exclusion criterion.
Nicotine Replacement Therapy Preferred	Smoking-cessation pharmacotherapy	See the COPD chapter's Pharmacologic Treatment Options	Local skin irritation (patch); mouth/throat irritation (gum/lozenge)	Combine a patch with an as-needed gum or lozenge, exactly as in the COPD chapter.

For the full bronchodilator/inhaled-corticosteroid/biologic regimen once emphysema is confirmed, and the full acute-exacerbation antibiotic and corticosteroid ladder, see the COPD chapter's Pharmacologic Treatment Options and Drug Tables — not reproduced here. For diuretics, nonselective beta-blockers, lactulose/rifaximin, and spontaneous bacterial peritonitis prophylaxis once cirrhosis is confirmed, see the Cirrhosis chapter.

Special Populations

Pregnancy

Augmentation therapy has not been studied in pregnancy — no controlled reproduction studies exist for the currently available product, and it should be continued or started in pregnancy only if the treating specialist judges the benefit clearly outweighs the unknown risk. Standard inhaled bronchodilator therapy is generally continued through pregnancy as described in the COPD chapter, since undertreated maternal hypoxemia poses a greater fetal risk than these agents. Smoking cessation is, if anything, even more urgent in a pregnant patient with a severe-deficiency genotype.

Breastfeeding

No data exist on whether augmentation-therapy A1-PI passes into breast milk; weigh the infant's breastfeeding benefit against the mother's clinical need for the infusion on a case-by-case, specialist-directed basis.

Pediatrics

Augmentation therapy is not authorized for use under age 18 — no pediatric studies have been performed, and the approved indication is adult emphysema only. A child with AATD-related liver disease (classically neonatal cholestatic jaundice) is managed by pediatric hepatology using standard pediatric liver-disease supportive care; augmentation therapy has no role here regardless of age, for the same liver-mechanism reason it has no role in adult AATD-related liver disease.

PiSZ and other intermediate genotypes

Augmentation-therapy candidacy in a PiSZ (or other non-PiZZ severe-deficiency) genotype is individualized with specialist input rather than applied automatically — the eligibility criteria in Choose Initial Treatment were established primarily in PiZZ populations.

Post-lung-transplant

Augmentation therapy is not indicated after lung transplantation, since the transplanted lung does not carry the recipient's genetic deficiency.

Hepatic and renal impairment

Dose adjustment of augmentation therapy for hepatic or renal impairment has not been studied — the product monograph gives no adjustment guidance, and dosing is unchanged regardless of liver status, since the drug is given intravenously rather than hepatically processed the way an oral drug would be. This does not mean augmentation therapy is expected to help the liver disease — see Choose Initial Treatment.

Older adults

Only a small number of patients aged 65 and older were included in the pivotal trials — not enough to determine whether older adults respond differently. Individualize based on overall clinical status; no specific dose adjustment is recommended for age alone.

Monitoring & Follow-Up

Spirometry approximately annually, or per the interval the treating respirology team specifies — see the COPD chapter for the full monitoring approach, which applies unchanged.
Liver enzymes periodically, and, once cirrhosis is present, the full Cirrhosis-chapter monitoring schedule (electrolytes during diuretic titration, INR/albumin/bilirubin for Child-Pugh/MELD, hepatocellular carcinoma surveillance every 6 months indefinitely).
Confirm ongoing smoking abstinence at every visit — relapse is itself grounds to pause augmentation-therapy eligibility.
Track augmentation-therapy infusion adherence, and confirm the patient (or a trained caregiver) is administering it correctly if self-infusing at home.
Reassess for new or recurrent panniculitis lesions.
Confirm cascade family testing has actually been completed, not just discussed — this is easy to raise once and never follow up on.
Keep vaccination status current per the COPD and Cirrhosis chapters.

Treatment Failure / Next Step

Continued rapid lung function decline despite augmentation therapy and optimized COPD pharmacotherapy — first confirm infusion adherence and confirm smoking cessation has actually been sustained (not just reported), since both are common, correctable causes of apparent treatment failure before assuming the therapy itself has failed.
If adherence and cessation are both confirmed and decline continues, refer to a specialist AATD/respirology program for reassessment, including consideration of lung transplant referral using the same general triggers as in the COPD chapter's escalation pathway.
Progressive liver disease — there is no separate AATD-specific liver escalation pathway; follow the Cirrhosis chapter's Treatment Failure / Next Step ladder exactly (refractory ascites, recurrent hepatic encephalopathy, and the MELD ≥15/first-decompensation transplant-referral trigger all apply unmodified).
Panniculitis not responding to dapsone — reassess the diagnosis (confirm biopsy findings and AATD status), then add or switch to augmentation therapy; refer dermatology if lesions remain refractory.
A patient who appears to meet augmentation-therapy criteria but has been denied or delayed access — confirm the request was submitted correctly through the Canadian Blood Services Plasma Protein and Related Products Formulary pathway (or the Quebec-specific Prolastin-C pathway for Quebec residents) rather than assuming ineligibility; access-process errors are a real, correctable cause of a patient not receiving therapy they qualify for.

Common Errors to Avoid

Assuming augmentation therapy treats or slows AATD-related liver disease — it does not, and prescribing it for that reason is a genuine, avoidable error.
Not testing a patient with COPD diagnosed young, or with a minimal smoking history, simply because they already carry a COPD diagnosis.
Offering augmentation-therapy referral to a patient who is still smoking, rather than securing cessation first.
Treating a PiMZ heterozygote as an augmentation-therapy candidate.
Diagnosing panniculitis as cellulitis and giving a course of antibiotics instead of recognizing the pattern and biopsying.
Interpreting a normal or borderline serum AAT level drawn during an acute illness as excluding AATD, without accounting for its behaviour as an acute-phase reactant.
Re-deriving a separate bronchodilator regimen for AATD-related COPD instead of using the COPD chapter's GOLD ABE algorithm directly.
Discussing family cascade testing once and never confirming it was actually completed.
Missing hepatocellular carcinoma surveillance once AATD-related cirrhosis is identified — the same error flagged in the Cirrhosis chapter.

Clinical Decision Algorithm

Who to test, and the diagnostic algorithm

Any testing trigger present: COPD before age 45, COPD with minimal/no smoking history, unexplained liver disease, family history of AATD, necrotizing panniculitis, unexplained bronchiectasis, or non-reversible adult-onset asthma

Obtain serum AAT level (check a concurrent CRP — AAT is an acute-phase reactant)

Normal level, low clinical suspicion

AATD unlikely — reconsider an alternative diagnosis

Low level, or high clinical suspicion regardless of level

Confirm with Pi genotype/phenotype (isoelectric focusing) and/or SERPINA1 gene sequencing

PiZZ or another severe-deficiency genotype confirmed

AATD confirmed — assess for lung disease AND liver disease in parallel; offer genetic counseling and cascade family testing

PiMZ (heterozygous carrier) or normal genotype

Carrier state, or AATD excluded — counsel accordingly; carrier status still matters for family-planning and cascade-testing discussion

Lung disease pathway once AATD is confirmed

Severe-deficiency genotype confirmed (e.g., PiZZ)

Assess for emphysema/COPD exactly as in the COPD chapter (spirometry; consider CT — look for a basal-predominant pattern)

No emphysema, preserved lung function

Smoking-cessation counselling and routine spirometry surveillance; no augmentation therapy yet — insufficient evidence of benefit before emphysema develops

Emphysema/COPD confirmed

Start standard COPD pharmacotherapy per the COPD chapter's GOLD ABE algorithm

Check augmentation-therapy eligibility: nonsmoking (generally ≥6 months), FEV1 <80% predicted, confirmed severe-deficiency genotype, serum AAT <11 μmol/L, no prior lung transplant

All criteria met

Refer respirology for Canadian Blood Services PPRP application (or the Quebec-specific Prolastin-C pathway) and begin weekly IV augmentation therapy

Criteria not yet met

Address the specific barrier first — most often ongoing smoking — rather than deferring the whole workup

Liver disease and panniculitis pathways

AATD confirmed — screen for liver disease and skin disease in parallel with the lung pathway

Abnormal liver enzymes, hepatomegaly, or known/suspected cirrhosis

Refer hepatology; stage and manage exactly per the Cirrhosis chapter (Child-Pugh/MELD, HCC surveillance, transplant-referral triggers)

Do not offer augmentation therapy for liver disease — it has no liver-directed mechanism of action

Painful, ulcerating subcutaneous nodules/plaques

Biopsy — look for a neutrophil-predominant lobular panniculitis

Confirmed AATD-associated panniculitis: dapsone first-line; augmentation therapy for severe or dapsone-refractory disease; refer dermatology

Drug Tables

How to use this table: Doses are adult doses and require patient-specific confirmation. This table covers only the therapy genuinely specific to AATD — augmentation therapy and panniculitis treatment. For standard COPD bronchodilator/inhaled-corticosteroid/biologic dosing and the acute-exacerbation antibiotic ladder, see the COPD chapter's Drug Tables. For diuretics, nonselective beta-blockers, lactulose/rifaximin, and spontaneous bacterial peritonitis prophylaxis once cirrhosis is confirmed, see the Cirrhosis chapter's Drug Tables. Select any drug name to open its complete Pharmasist Drug Database page.

Augmentation therapy

The only agents that raise circulating alpha-1 proteinase inhibitor (A1-PI) levels; indicated only for the specific adult emphysema criteria in Choose Initial Treatment.

Drug	Dosage	Adverse effects	Drug interactions	Comments
Alpha1-Proteinase Inhibitor (GLASSIA)	Dose: 60 mg/kg IV once weekly Infusion rate: Not exceeding 0.2 mL/kg/minute — approximately 15 minutes at the standard dose and rate Administration: First infusions supervised by an experienced healthcare professional; later infusions may be self-administered or given by a trained caregiver once properly instructed	Infusion-related reactions (headache, dizziness, flushing, fever, chills), rare hypersensitivity; theoretical pathogen-transmission risk of a plasma-derived product, mitigated by manufacturing pathogen-reduction steps	None clinically significant reported	The product currently funded through Canadian Blood Services' Plasma Protein and Related Products (PPRP) Formulary outside Quebec, accessed via a respirologist-submitted Request for Patient Designated PPRP form. Quebec residents access Prolastin-C through a separate provincial pathway instead. Not authorized under age 18. Health Canada's product monograph states its effect on exacerbations or on slowing emphysema progression has not been proven in its own controlled trials.^[4]^[2]

Evidence note: the pivotal CT-densitometry evidence that augmentation therapy slows the rate of emphysema progression — the RAPID trial — was conducted with a different manufacturer's formulation (marketed as Zemaira in the United States and Respreeza in the European Union, also dosed 60 mg/kg IV weekly), not the product currently funded in Canada.^[5]

Panniculitis therapy

Drug	Dosage	Adverse effects	Drug interactions	Comments
Dapsone	Typical starting dose: 50 mg PO once daily, titrated as tolerated, typically to 100-150 mg once daily	Dose-related hemolysis (more severe with G6PD deficiency), methemoglobinemia, agranulocytosis (rare, typically within the first 12 weeks), peripheral neuropathy, hypersensitivity syndrome	Rifampin reduces dapsone levels; trimethoprim increases levels of both drugs; folic acid antagonists increase hematologic toxicity risk	First-line for AATD-associated panniculitis. Screen G6PD status before starting given hemolysis risk. Augmentation therapy is reserved for severe or dapsone-refractory disease, and treats the panniculitis through the same elevated-circulating-AAT mechanism that helps the lungs, not through any antibiotic or immunosuppressive effect.

References

Alpha-1 Antitrypsin Deficiency — GeneReviews, University of Washington, Seattle (Stoller JK, Lacbawan FL, Aboussouan LS). GeneReviews (NCBI Bookshelf NBK1519)
Alpha-1-Antitrypsin Deficiency Targeted Testing and Augmentation Therapy: A Canadian Thoracic Society Meta-Analysis and Clinical Practice Guideline — Canadian Thoracic Society (Hernandez P, Bossé Y, Bush P, Chapman KR, Maltais F, Penz ED, et al.). Chest 2025;167(4):1044-1063
European Respiratory Society statement: diagnosis and treatment of pulmonary disease in α1-antitrypsin deficiency — European Respiratory Society (Miravitlles M, Dirksen A, Ferrarotti I, et al.). Eur Respir J 2017;50(5):1700610
Glassia Implementation FAQ — Plasma Protein and Related Products Formulary — Canadian Blood Services. Canadian Blood Services, 2024
Intravenous augmentation treatment and lung density in severe α1 antitrypsin deficiency (RAPID): a randomised, double-blind, placebo-controlled trial — The Lancet (Chapman KR, Burdon JGW, Piitulainen E, et al.). Lancet 2015;386(9991):360-368

Professional reference only. Apply clinical judgment and verify patient-specific decisions against current authoritative guidance and product information.