Immunoglobulin Replacement for Primary Immunodeficiency

From Immunology and Allergy Clinics:

Immunoglobulin replacement therapy has been standard treatment in patients with primary immunodeficiency diseases for the past 3 decades. Until recently, it was mostly IVIG, with SCIG taking a large share nowadays.

The goal of therapy is to reduce serious bacterial infections in individuals with antibody function defects.

Approximately one-third of patients receiving intravenous immunoglobulin (IVIG) treatment experience adverse reactions. Recent advances in manufacturing processes have resulted in products that are safer and better tolerated.

Self-infusion by the subcutaneous route (SCIG) has become popular and resulted in better quality of life.


Immunoglobulin Replacement Therapy for Primary Immunodeficiency - Immunology and Allergy Clinics

'Extrafine' dry powder aerosols did not improve lung deposition in the small airways

There is increasing interest in the use of 'extrafine' aerosols to target the small airways in the management of asthma and COPD.

This study from The Netherlands used previously presented deposition data to assess if submicron (less than 1μm) particles can improve central and deep lung deposition. Prior data had shown that particles in the range 1-3μm are more relevant in this respect.

The following ICS/LABA combination dry powder inhalers were tested in vitro as a function of the pressure drop (2, 4 and 6kPa) across the inhaler: Symbicort Turbuhaler, Seretide Diskus, Rolenium Elpenhaler and Foster (Fostair) NEXThaler.

Obtained fine particle fractions (FPFs) <5μm (as percent of label claim) were divided into subfractions <1, 1-3 and 3-5μm. Differences of up to a factor of 4 were found between the best (Turbuhaler) and worst performing DPI (Elpenhaler), particularly for the FPF in the size range 1-3μm.

The NEXThaler, described as delivering 'extrafine' particles, did not appear to be superior in this size range.

The marked differences in amount and size distribution of the aerosols between the devices in this study likely translates into differences in the total lung dose and drug distribution over the airways.

References: Can 'extrafine' dry powder aerosols improve lung deposition? de Boer AH et al. Eur J Pharm Biopharm. 2015 Jul 26. pii: S0939-6411(15)00316-1. doi: 10.1016/j.ejpb.2015.07.016. [Epub ahead of print]
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Autoimmune Disease in Primary Immunodeficiency (PIDD)

From Immunology and Allergy Clinics:

The association of autoimmunity and primary immunodeficiency is well known. It suggests the existence of links between the various elements of the immune system and the maintenance of self-tolerance.

In monogenic primary immunodeficiencies (PID), genetic lesions on tolerance may correlate with autoimmune and inflammatory syndromes.


Autoimmune Disease in Primary Immunodeficiency - Immunology and Allergy Clinics

Do you need to stop a beta blocker before a drug challenge? Food challenge? For how many days? What about an ACE inhibitor?

It is generally advised to stop medications that may increase the risk of anaphylaxis before any procedure that may induce anaphylaxis. Such procedures include a drug challenge or an oral food challenge. The medication should be stopped for enough period of time to allow for 5 half lives to pass after the last dose.

For example, the elimination half-life of oral atenolol is approximately 6 to 7 hours. Atenolol should not be detectable after 5 half lives, 5 x 7 hours = 35 hours (1.45 days).

From the EAACI guidelines:

Concomitant medications and pretreatments

Before beginning any desensitization procedure, patients should be in a stable clinical condition (e.g., FEV1 ≥ 70% of the normal value for asthmatics, controlled cardiac insufficiency). Any concomitant medication used for treating underlying diseases must be continued. However, drugs such as beta-blockers, which can interfere with the treatment of a severe hypersensitivity reaction, should be discontinued whenever possible. Indications should be strictly observed, e.g., sudden withdrawal of beta-blocker therapy in patients with arrhythmia may be life threatening.


Desensitization to culprit drugs should generally not be performed in patients at increased risk because of a co-morbidity, such as those with uncontrolled asthma (FEV1 < 70% of their normal value), hemodynamically unstable ones, or those with uncontrolled cardiac diseases. In patients treated with beta-blockers and subjects who have experienced severe anaphylaxis, as well as in patients with hepatic, renal, or other diseases, in whom exposure might provoke a potentially harmful complication, desensitization should also only be considered after a careful individual risk/benefit evaluation. Desensitization is absolutely contraindicated in patients who have experienced severe, life-threatening immunocytotoxic reactions, vasculitis, or bullous skin diseases like SJS/TEN, and DIHS/DRESS.

I did not find guidelines on ACEI inhibitors.

Related reading:

General considerations on rapid desensitization for drug hypersensitivity – a consensus statement. Allergy, 2010.

Immunotherapy with ocular beta blocker. AAAAI Ask the Expert 2015.

How do to a skin test for suspected drug allergy to CellCept (mycophenolate mofetil)?

Drug allergic reactions to immunosuppressants

The modern dermatologic armamentarium consists of a spectrum of T-cell immunosuppressant drugs, such as macrolides (cyclosporine, tacrolimus, pimecrolimus, sirolimus), dapsone, mycophenolate mofetil, and monoclonal antibodies. Dermatologic immunosuppressant drugs, such as macrolides (eg, cyclosporine, tacrolimus, pimecrolimus, and sirolimus), dapsone, and mycophenolate mofetil, have been reported to cause drug allergic reactions in addition to their known predictable adverse reactions.

CellCept (mycophenolate mofetil)

Mycophenolic acid. Image source: Wikipedia, public domain.

CellCept is available in multiple formulations: Capsules, Tablets, Oral Suspension, IV.

Allergic reactions to CellCept have been observed; therefore, CellCept is contraindicated in patients with a hypersensitivity to mycophenolate mofetil, mycophenolic acid or any component of the drug product. CellCept Intravenous is contraindicated in patients who
are allergic to Polysorbate 80 (TWEEN).

Urticaria and a severe papulosquamous skin eruption have been reported after use of CellCept (mycophenolate mofetil).

There is no validated protocol for CellCept (mycophenolate mofetil) skin testing.

General info about skin tests in drug allergy

The sensitivity of skin tests appears to be moderate to high for immediate hypersensitivity reactions to betalactam antibiotics, perioperative drugs, heparins, platinum salts, radiocontrast media, but low for many other drugs (moderate/weak).

The parenteral preparation of the suspected drug, preferably the intravenous form at the recommended concentration, should be used for SPT and IDT. For drugs suspected of causing severe reactions or where literature/experience is lacking, skin tests should use nonirritant concentrations of the drug. This can be established using different dilutions of increasing drug concentration. The nonirritant drug concentration should ideally be established in healthy controls. Where the drug is available only in tablet, capsule or topical form, only SPT and/or patch test can be performed (moderate/strong).

There are no standardized protocols or data on the optimal drug concentration available for skin testing using drug solution prepared from an oral formulation (moderate/weak). The common practice is to dissolve the tablet/capsule content in 0.9% saline and use the maximum concentration achievable to make the test as sensitive as possible.

A positive skin test to nonirritating drug concentrations is consistent with an allergic mechanism, although the precise test accuracy (sensitivity/specificity) remains unknown (high/strong).

Fatal systemic anaphylaxis has been reported after IDT without preceding SPT. Intradermal test has a high sensitivity, but also a higher risk of inducing irritant reactions and false-positive results.

Drug challenge is needed

Because of limited sensitivity, a negative skin test does not rule out drug hypersensitivity (high/strong). Before re-administration, a drug provocation test is necessary.

Chemotherapeutic drugs

Except for platinum salts, an IgE-mediated hypersensitivity to chemotherapeutic drugs has not been demonstrated (moderate/strong).

Skin tests are useful for platinum salt-related immediate hypersensitivity reactions (moderate/strong) [50], while for other chemotherapeutic drugs, experience is limited and test results often negative (low/weak).

The irritant potential of chemotherapeutic drugs appears to be low. For platinum salts, the use of undiluted drugs is recommended (high/strong). For other chemotherapeutic drugs, SPT with undiluted agents is probably nonirritant, but due to toxicity concerns, a general recommendation cannot be given.

For IDT, a 1/10 dilution of most chemotherapeutic drugs is nonirritant and may be used in clinical practice (moderate/strong), whereas higher concentrations appear to be irritant (MP, personal communication; low/weak).

How do to a skin test for suspected drug allergy to CellCept (mycophenolate mofetil)?

A skin prick test with 1:1000, 1:100, 1:10 and 1:1 concentrations can be done. If this is negative, an IDT test with 1:1000 and 1:100 and 1:10 can be done. If this is negative, an oral challenge is recommended.

Drug allergy management in 5 steps (click to enlarge the image).


CellCept® (mycophenolate mofetil) Information

Prescribing info (PDF)

Levin N, Mali A, Karussis D. Severe skin reaction related to mycophenolate mofetil for myasthenia gravis. Clin Neuropharmacol. 2005; 28:152–153. III.

Szyper-Kravitz M, Sheinberg P, Sidi Y, et al. Hypersensitivity to mycophenolate mofetil in systemic lupus erythematosus: diagnostic measures and successful desensitization. Int Arch Allergy Immunol. 2005;138:334 –336. III

Drug Allergy: An Updated Practice Parameter. AAAAI (PDF)

Skin test concentrations for systemically administered drugs – an ENDA/EAACI Drug Allergy Interest Group position paper. Allergy, 2013.
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