STEROID RESISTANT ASTHMA

Abdullah Jan Pahtan, Consultant Chest Physician Hyd.

Individuals with steroid resistant asthma, which was first described in 1968 are of  ten the most difficult to manage asthmatic patients in that they have severe disease yet fail to respond to glucocorticoids. To make the diagnosis of steroid resistant asthma, the patient must fail respond to a 7 to 14 day course of daily prednisolone as measured by less than a 15% improvement in morning prebronchodilator FEV₁ following the glucocorticoids course. Ongoing inflammation is thought to play a major role in the pathogenesis of steroid resistant asthma, and recent studies have demonstrated diminished glucocorticoids receptor to DNA binding as possible mechanisms for diminished glucocorticoids responsiveness. Alternative asthma therapies, such as methotraxate, cyclosporine and intravenous gammaglobulin are often used in this group of asthmatic patient.

Dr. Donal Y.M. Leung of National jewish Medical & Research Center in Denver, Colorado, says that:

Cytokine – induced increases in glucocorticoid receptor beta expression may account for the steroid insensitivity seen in some asthmatics and could serve as a marker-for the early identification of theses patients.

If you read the asthma guidelines you get the feeling that every one should be taking inhaled steroids but atleast 10 – 15% of asthmatics, don’t respond to inhaled steroids, and 5% don’t respond to oral steroids.

Others say that steroid “resistance” is simple under treated asthma of possibly a cellular abnormality which could be a consequence of the inflammatory process or could be due to drug induced desensitization or a genetic abnormality in the glucocorticoid receptor. Certain mediators such as interferon Y and interferon- Y can alter gluconcorticoid response. While the mechanism of action of interferon-Y is unknown, it appears that interferon-I decreases the density, of glucocoricoid receptor.

Steroid resistant patients are divisible into two types. The vast majority, perhaps 90% are Type I, which is characterized by a reversible, decreased biding affinity of T-cells for glucocorticoids. The remaining SR patiens are Type II’s it appears that all cells in Type 11 patients carry an abnormally low number of glucocortricoid receptor binding sites.

Because there is only human glucocorticoid-receptor gene, the observation that type I patients can develop severe side affects from chronic, systemic steroid treatment and that their glucocorticoid receptor defect is limited to T-cells suggest that Type I SR asthma is an acquired disorder, possibly the result of an immune activation pathway.

In contrast, Type 11 asthma is not associated with the development of steroid-induced side effect and is not limited to T-cells. Type 11 resistance has the hallmarks of an irreversible innate (primary) defect.

It is suggested that the glucocorticoid receptor defect that appears in Type I SR occurs in response to the release of certain cytokines, such as interleukin (IL)-2 and IL-4 Level of cytokine activation is much higher in SR asthma patients compared to those who are steroid sensitive.

There is a possibility that Type I SR  asthma is the end result of ongoing immune activation that is no longer controlled by the immunosupperssive effects of steroids. This immune activation occurs because of the high level secretion of specific.

Cytokines, such as IL-2 and IL-4 by activated T-cell: the cells that are believed to have central role in the pathogenesis of asthma. A patient lost ability to respond to steroid leads to a vicious circle of unchecked immune activation. It suggests that early intervention with anti-inflammatory therapy-including the identification and elimination of the allergentrigger factors is critical to successful management of the patient’s asthma.

Another possible route to successful treatment may be use of the new generation in haled synthetic glucocorticoids, which have an enhanced binding affinity for the glucocorticoid receptor.

Management.

Try and determine the type of asthma. Patient education about steroid resistance, adjustment of steroid dose, and. Introduction of other immunomodulatory therapies. Different combination of treatments with troleandomyc in & methylpred-nisolone in several SR patients. This regimen led to normalization of T-cells sensitivity.

Other agents tried are cyclosporine, methotraxate, gold, intravenous gammaglobulin, hydroxychloroquines dapsone and interferon-Y.

Prognosis:

For SR patient is poor. The best approach is to recognize it early before the patient’s anyway becomes so damaged that the asthma is irreversible.

Reference:

I        Leung D.Y.M., Martin R.J., Szefler S.J. et.el. “Dysregulation of interlukin – 4 Interlukin-S and Interferon-Y, Gene Ex-pression in       Steroid Resistant Asthma, J.Expe Med. 181 : TK 1993,

2.                 Sher E.R., Leung D.Y.M., Surs et.el. “Steroid Resistance Asthma: Cellular Mechanism Contributing to Inadequate Response to Glacocorticoid therapy J. Clinical Invest. 93:’ 33-9. 1994.

3.                 Kam Jc, Szefler S.J, et.el Combinat 11-ceptor Binding affinity and T-Cell Responses to Glucocorticoids “Journal of Immunology 15 1:3460-6, 199’)

4.                 Karnda A.K., Leung –D.Y.M. & others “Steroid Resistance in Asthma – Our Current Understanding” Ped Pulmonol 14:180-60, 1992.