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- Corticosteroids -

11/30/05 re: Allergies associated with Addison's Disease
Q

Has there been any literature on Addison's Disease and it's relation to allergic reactions to medications, foods, etc? Is there a correlation between Addison's and these types of reactions?
A

Allergic problems including asthma have occasionally been reported in patients with Addison's Disease (see enclosed abstract). However, I am not aware of any published evidence suggesting an increased frequency of allergic reactions to foods, drugs, or inhalants in those with Addison's Disease. One would expect an increased frequency/severity of allergic reactions in such patients if they are not receiving replacement corticosteroid therapy since corticosteroids are normally an important control mechanism in down-regulating allergic inflammation. Indeed, blood eosinophilia occurs commonly in Addison's Disease because of the lack of corticosteroid control of eosinophil dynamics in the body. If an anaphylactic reaction does occur in someone with Addison's Disease, the patient could be at increased risk for a severe reaction, requiring aggressive therapy.

Respiration. 1993;60(4):241-2.
Bronchial asthma with Addison's disease.
Saraclar Y, Turktas I, Adalioglu G, Tuncer A.
Department of Allergy, Hacettepe University School of Medicine, Ankara, Turkey.

A 14-year-old boy with bronchial asthma who was subsequently diagnosed to have coexistent Addison's disease is presented. Both diseases responded to continuous replacement steroid therapy. We suggest that worsening of bronchial asthma symptoms in this patient may be due to the hypocortisolemia produced by the coexistent Addison's disease. Patients with Addison's disease with clinical evidence of bronchial asthma have rarely been reported [1, 2].
10/25/05 re: Corticosteroid treatment in chronic urticaria
Q

I would like to get some advice on the management of a patient with type1 diabtetes and initial episode of angioedema about 6 months ago, followed by periodic recurrence of urticaria. He is on Zyrtec 10 mghs as needed , Allegra 10 mg/d, Zantac 150 mg bid and Singulair 10 mg hs. however on this regimen he gets break-thrus not responding to prn Benadryl. I am starting him on Doxipen, but wanted to find out which steroid could be given with the least likelihood of increasing his blood sugars. He is on an insulin pump and requires high boluses of Humalog to control his sugars and in the interim he feels very fatigued. He was on Lisinopril, but that has been stopped. Any other thoughts on managing this patient.

A

To my knowledge, there is no difference in the potential for aggravating diabetes among doses of different corticosteroid (CS) agents with equivalent anti-inflammatory effects. I could also find no reference to such differences in a brief Medline search.

Therefore, I would search very hard for other types of therapy that would control the chronic idiopathic urticaria (CIU) or at least allow reduction of the CS dose required for control of the CIU. I have listed below some suggestions:

1) Is there any temporal relationship between onset of the CIU and start of the Humalog? One would not expect an urticarial allergic reactions to a human insulin prep, but such have been occasionally reported

2) Does the patient have auto-immune thyroid disease? Anti-thyroid antibodies are present in about 20% of those with CIU (vs about 3% in normals). I would check for anti-thyroid peroxidase and anti-thyroglobulin antibodies as well as thyroid function. If the patient is hyperthyroid, this could be aggravating the hyperglycemia.

3) Do individual urticarial lesions last more than 24 hours and/or leave pigmented areas in the site? If so, I would obtain a punch biopsy of a fresh urticarial lesion looking for vasculitis. A skin biopsy may also be indicated when the CIU is not controlled by intensive antihistamine/anti-leukotriene therapy. One is looking for “neutrophilic urticaria” characterized by prominent neutrophil accumulation in the lesions. Such urticaria may be better controlled by colchicine.

4) I have found doxepin to be helpful occasionally. However, it can be quite sedating, so I have generally prescribed full doses only at bedtime. If prescribed for daytime use, I generally start with 10 mg/day for average-sized adults, increasing the dose gradually as tolerated and needed.

5) Some studies, mainly in Europe, have reported that H. pylori infection is causal in CIU with improvement following treatment of H. pylori

6) Other medications reported occasionally to be helpful in controlling CIU have included hydroxychloroquine, azulfidine analogs (usually used in inflammatory bowel disease) and even coumadin. Cyclosporine has been reported to control CIU uncontrolled by other meds. However, the potential for adverse effects generally limits such treatment to quite severe CIU.

12/21/04 re: Effect of corticosteroid therapy in vitro lymphocyte
Q In a patient who is being evaluated for cell mediated immunity - if the patient has been on 1-2mg/kg of prednisone for the previous 7 days for an exacerbation of his asthma, will it interfere with a lymphocyte antigen or mitrogen proliferation test?
A

The answer to your question depends on when the blood specimen is obtained with relationship to the prednisone dosing:

1) A major effect of corticosteroid administration on blood lymphocytes is to cause a transient lymphopenia, with the decrease predominantly in the CD4+ population. My group has shown that a single IV injection of methylprednisolone, 1 mg/kg is followed by a significant decrease in CD4+ cell levels, with return to baseline levels 24 hours after the IV injection (see enclosed abstract).

2) In addition, corticosteroids exert a direct inhibitory effect on mitogen and antigen-stimulated lymphocyte proliferation (see enclosed abstract). This is dependent on the plasma corticosteroid level. Usually, there is insufficient corticosteroid left in the plasma by 24 hours after a single 1mg/kg dose to inhibit lymphocyte proliferation.

Therefore, if the blood specimen is obtained at least 24 hours after the last oral prednisone dose (in the range of 1 mg/kg) there should be little if any alteration by the corticosteroids of the lymphocyte proliferative responses to mitogen or antigen. A good example of this pattern of events comes from studies of blood specimens obtained on the day on vs the day off corticosteroids in someone being treated with an "alternate day" steroid regimen.

J Clin Immunol. 1984 Mar;4(2):151-5.

Corticosteroid effects on circulating lymphocyte subset levels in normal humans. Zweiman B, Atkins PC, Bedard PM, Flaschen SL, Lisak RP.The effects of in vivo corticosteroid administration on levels of lymphocyte subsets in normal humans require further definition. Using monoclonal antibodies, we carried out a double- blind, placebo-controlled study of oral and intravenous methylprednisolone in 10 normal volunteers. Four hours after a 7-day oral course of 0.5 mg/kg/day, there was modest lymphopenia but no significant selective alteration in lymphocyte subsets. In contrast, 4 hr after a single intravenous injection of 1.0 mg/kg, there was more pronounced lymphopenia (P less than 0.01), a selective, relative decrease in T4 cells (P less than 0.001), and a more modest decrease in the percentage of T3 cells. The possible mechanisms and implication of these changes are discussed.

Immunopharmacology. 1980 Apr;2(2):95-101.

In vivo and in vitro effects of methylprednisolone on human lymphocyte proliferation. Wang SR, Zweiman B.Lymphocytes obtained from normal volunteers 4 hr after intravenous methylprednisolone (1 mg/kg of body weight) were significantly less stimulated in vitro by several concentrations of phytohemagglutinin and concanavalin A. This effect was not due to diurnal variations. Significant decreases in the levels of circulating T lymphocytes (p < 0.001) at this time suggested cellular redistribution as a factor in decreased mitogen responsiveness. However, incubation of plasma, obtained 1 hr after methylprednisolone injection, with normal autologous lymphocytes suppressed the in vitro responses as well, indicating an additional direct corticosteroid effect on the lymphocytes.
12/17/04 re: Nebulized steroids
Q I have an adult patient with asthma, and I would like to use a nebulized steroid. Any recommendations?
A

Inhaled corticosteroids (ICS) play a key role in the management of persistent asthma. My question is why you feel that delivery of the ICS by nebulization is needed in an adult patient. Metanalyses of controlled studies have shown that delivery of ICS with a metered-dose inhaler (MDI) and connecting valved holding chamber is as clinically effective as delivery by the nebulized route at considerably lower cost (see enclosed below my reviews of these reports written previously for the Current Literature section of this Web site).

The only situation in which I would use ICS by the nebulized route as chronic maintenance therapy in an adult is if the patient cannot carry out the inspiration/hand action coordination required for optimal use of a MDI/holding chamber setup. If that is the case, Pulmocort Respules, a preparation of budesonide made specifically for nebulization would be my choice (see enclosed abstract). Without knowing more about the individual patient, I would likely use a jet nebulizer using compressed air and a mask at the end of the delivery tubing. The assistance of a capable respiratory therapist would be advisable in setting up the mechanics of the delivery system.

Additional referenences:
3/5/04 re: Different types of corticosteroids
Q.

I was listening on cassette to the ACP update series in my auto--the speaker cited an article at www.aaaai.org/aadmc concerning the different chemical types of steroids--I don't recall if the cassette was from this year, last year, or the year before (I'm behind!) but I did scrawl the citation in my notebook while driving. Would you be able to direct me where to look?

A.

Enclosed is the only one of my Current Literature reviews in the past 2 years dealing with types of corticosteroids that I could find in a review of the AADMC website. If this is not the article in which you are interested, I will need a bit more information about the content involved.

Comparison of more potent vs less potent topical steroids in atopic dermatitis

Summary
The efficacy of topical corticosteroids (TCS) in reducing acute flare-ups of atopic dermatitis (AD) is well recognized. However, there are understandable concerns about adverse effects of TCS, particularly the more potent preparations. Thomas et al of Queen's Medical Center in Nottingham, UK performed a randomized, controlled comparison of the effects of 3-day courses of application of a potent TCS (0.1% betamethasone valerate) followed by 4 days of ointment base vs 7 days of a less potent TCS (1% hydrocortisone in the same ointment base) in 174 children with mild to moderate AD. They found both approaches to be effective to a similar degree as indicated by reduction of itching, aborting acute flares and improvement in overall quality of life.

Reference: BMJ 2002; 324:768

Editor's Comments
It has been recognized that adverse local effects of TCS such as thinning of the skin are seen more frequently with use of the more potent TCS. However, the duration of TCS therapy is also a factor in the induction of adverse effects. The assessment of skin thickness or other adverse effects was not addressed specifically in this study, likely because of its short duration. However, this assessment would be very important after the intermittent use of both TCS approaches over a period of months to years. Hopefully, the use of non-steroid topical agents such as tacrolimus and pimecrolimus (reports reviewed elsewhere in this Current Literature section) will reduce the need for TCS use.

11/11/03 re: Inhaled corticosteroid (ICS) dosing
Q. I have met several patients who have received instruction to take their corticosteroid metered-dose inhalers "1 to 2, 2 to 4, 2 to 3, or 3 to 4 puffs" bid or tid.

I am convinced that maintaining a scheduled and consistent daily dose of steroid versus variable dosing of steroid would offer better control of asthma. That is, providing the regular minimal dose needed to reduce exacerbations requiring rescue albuterol use to less than 4 or 6 times per month. Most clinicians, in my experience, start patients at the highest dose of steroid recommended (for mild-, moderate-, severe-persistent asthma) and reduce the dose gradually after a trial of 2 to 3 weeks to maintain control of symptoms.

I also believe that variable dosing of steroid inhalers may lull the patient into a false sense of security, that suddenly increasing the steroid dose will provide sufficient reduction of inflammation and relief of symptoms. That is, provided that no oral or parenteral steroids are needed or administered during an exacerbation, the anti-inflammatory effects of the steroid may take several days before significant reductions in inflammation and albuterol use are observed.

1. What do you and the current literature advise are the optimal dosing recommendations for inhaled Azmacort and Flovent MDI's for chronic therapy?

2. What do you and the current literature define as control of asthma symptoms if using the number of exacerbations per week (or per month) requiring rescue albuterol as a guide for effectiveness of therapy?

3. What do you and the current literature advise regarding"burst" therapy of systemic corticosteroids versus "burst" inhaled steroids for exacerbations that are not well controlled by inhaled albuterol and/or inhaled steroids?
A. First, I should respond that I completely agree with you that the indefinite dosing instructions you described are not advisable. Anything that gets away from simple, straightforward instructions concerning medication dosing (particularly inhaled medications) has the real potential for confusing the patient and decreasing compliance with the medication plans. Indeed, one of the major objectives of developing ICS agents has been to obtain satisfactory asthma control with once daily dosing. This objective is particularly important in the treatment of school-age children, many of whom forget or are reluctant to use their ICS inhaler treatment during the hours of classes and post-class extra-curricular activities. In response to your specific questions:

1) A point worth mentioning is the increasing evidence that the beneficial effects of ICS in adult asthmatics usually start plateauing at total daily doses of about 800 mcg/day of most ICS agents (perhaps at a low dose for Flovent) while the potential for systemic adverse effects keep increasing as the dose is increased. Therefore, my personal policy has been to try to not exceed 400 mcg/day in adults (200-400 mcg/day for Flovent) as long-term maintenance therapy in adult asthmatics.

2) A suggested schedule for a step-down ICS regimen can be found in the guidelines of the National asthma Education and Prevention Program (NAEPP) composed by an expert panel sponsored by the NHLBI unit of the NIH. The most recent full guidelines (published in 1997) and selected updates in 2002 can be obtained through a link from this AADMC website. Go to the Current Literature section of this AADMC website, click on "Updated Asthma Guidelines" then click on the NAEPP Expert Panel Report (1997). Also look at the "Update 2002" Full Report to see additional material about ICS treatment in childhood asthma.

3) With regard to your question about what criteria to use for asthma control, I would suggest aiming for the symptom pattern characteristic of mild, intermittent asthma listed in the NAEPP guidelines or better. A question can be raised,- what one should do if this degree of asthma control cannot be achieved without ICS doses of >800 mcg/day in an adult? First, one must be sure that non-pharmacologic approaches to reduce the levels of allergenic and irritant triggers have been carried out to the best extent feasible (allergen and tobacco smoke avoidance). If allergen avoidance is not feasible/sufficient, a trial of cautiously administered allergy immunotherapy should be considered (see my review of a recent met-analysis of allergy immunotherapy in asthma enclosed below). Also, there is now convincing evidence that the minimum daily dose of ICS needed for asthma control may be reduced up to 50% by concomitant treatment with inhaled long-acting beta agonists (such as the combinations of salmeterol/fluticasone or formoterol/budesonide).

I should also mention a report suggesting that starting ICS therapy with a reasonable, but not high dose in asthmatic children, will achieve a similar degree of control after 1 year as a initial high dose, then step-down dose regimen, however, the asthmatic children treated with the high doses initially did better after 2 months (see my review of this report enclosed below).

4) In my experience, if an asthmatic manifests a prominent acute asthma flare while on maintenance ICS therapy, he/she will likely need systemic steroid therapy if for no other reason that the patient's capacity to inhale the ICS deeply may be limited during such flares. As a result, any increase in the ICS dose used may not reach the lower airways sufficiently to achieve the desired rapid effect.

ENCLOSURES
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Allergy immunotherapy for asthma - is it effective?

Summary
The efficacy of allergy injection immunotherapy (IT) for allergic rhinitis has been well documented. However, there is still controversy about the value of IT in asthma. The efficacy of IT has been demonstrated in some controlled trials. However, concerns about serious adverse effects of IT in asthmatics persist. Abramson et al of Monash Univ. in Melbourne, Australia reviewed findings in the Cochrane Database up to 6/01 dealing with IT in asthma. They analyzed the findings in 75 randomized, controlled studies involving a total of 3,506 asthmatic patients. Although there was some heterogeneity in findings there was an overall significant reduction in asthma symptoms, medication use and bronchial hyper-reactivity following IT as compared to placebo injections. Overall, it would have been necessary to treat 4-5 individuals with IT to see a significant reduction in asthma symptoms and/or prevent increased medication need in one patient. There was no consistent effect on lung function. The incidence of adverse effects of IT was not considered in this analysis although the authors stated that such adverse effects must be considered.

Reference - Cochrane Database Syst Rev 2003;4:CD001186.

Editor's Comments
These findings support the contention that IT can be effective in reducing (not necessarily eliminating) asthma with a demonstrated allergic pathogenesis. It is difficult to tell from this analysis whether IT using particular allergens is more likely to be effective since the results of all IT (mainly with dust mite, pollen, and animal allergens) were lumped together for the overall analysis.

It should be stressed that while IT may be effective in asthma management, the presence of active asthma is a risk factor for an increased likelihood of serious systemic adverse reactions to IT. Some authors have expressed the opinion that active asthma is a contra-indication to IT. At the least, the IT dosage should be increased very cautiously in such asthmatic individuals with perhaps a longer than usual time period of observation after each injection.
_________________________________

Dose-dependent effects of fluticasone in childhood asthma

Summary
There has been considerable debate about the optimal dosing regimen of inhaled corticosteroids (ICS) in childhood asthma with many authors recommending starting with a high dose and tapering the dosage as clinical improvement occurred. Visser et al of the University Hospital in Groningen, Netherlands compared 2 regimens of treatment with the ICS fluticasone propionate (FP). Children (ages 6-12 years) with persistent asthma were randomized to receive 1 year of treatment with either: 1) FP 200 microg/d (constant dose approach) or 2) to start with 1000 microg/d with two monthly reductions to 500, 200, and 100 microg/d (step-down approach). After 2 months of treatment, bronchial hyper-reactivity improved in both treatment groups, but significantly more in those treated with the step-down approach. However, after 1 year of treatment, there were no significant differences in the changes in bronchial reactivity or lung function between the 2 treatment groups. There were also no significant differences in changes in height in the 2 treatment groups at the end of 1 year. The authors concluded that their study showed no superior clinical effect of a step-down approach compared with a constant dose strategy of FP for 1 yr. in children with chronic persistent asthma.

Reference - Am J Respir Crit Care Med 2001; 164:2073-7

Editor's Comments
With the increasing concerns in some quarters about adverse systemic effects of ICS in asthma, particularly in growing children, various studies have addressed the lowest dose of ICS needed to control persistent asthma. Of course, the ICS dose required will depend on the severity of the asthma being treated. However, several investigators have concluded that the dose-response curve for beneficial effects of ICS is much flatter than the curve for systemic absorption. Therefore, one school of opinion is that the benefit/adverse potential decreases considerably when the daily ICS dose is increased above a certain level. The findings described above would support the contention that starting with higher doses of inhaled FP offers no prolonged advantage over constant lower dose FP in mild-moderate persistent childhood asthma. This conclusion may not apply to more severe asthma. Also to be considered are findings by several groups that concomitant treatment with inhaled salmeterol will allow control of persistent asthma with lower doses of ICS.
6/27/03 re: Adverse effects of depot corticosteroid injections
Q. I have recently been doing locum tenens work in a small community in which I have come across a practice that I had not previously encountered. A small army of allergic rhinitis patients parade through the clinic each spring when their symptoms are no longer controlled by nasal steroids and antihistamines asking for their "allergy shot". This shot consists of a single annual intradermal injection of whatever corticosteroid is handy. I have been declining to furnish the injections while trying to teach patients in the mildest terms possible that this is an unwise practice, but I find my resolve wavering. I have encountered no cases of skin atrophy at prior injection sites, and the patients swear despite my protestations that the injections provide long-lasting relief. It is not clear to me that these annual injections are significantly increasing the patients' risks of developing osteoporosis, cataracts, etc. Could you please reassure me that I'm doing the right thing or correct me if I'm not?
A. I share your feeling that systemic corticosteroids should not be used unless absolutely needed and where therapeutic approaches with less potential adverse effects are not sufficiently effective. This is especially true when dealing with the depot steroid injections. However, it is difficult to find published information showing that a single injection of a depot corticosteroid preparation induces adverse systemic corticosteroid effects in individuals with no risk factors for such effects. Most of the limited number of reports say "adverse effects rare" or the like. (see enclosed abstract) There are occasional reports of embolic or other adverse effects attributed to the depot-suspending media used in some of these preps. However, the big problem I have seen in the situation you describe is that such patients generally do no get just one such depot steroid injection. They return during other pollinating seasons with similar requests, sometimes 2 or 3 times per year. There is evidence of a cumulative effect of such repeated injections on bone density/strength, particularly in an at-risk population (e.g.- post-menopausal women with relatively little weight-bearing exercise). Also, there are occasional reports of cases of steroid-induced aseptic necrosis of the hip and possibly other joints in individual treated intermittently with depot steroid injections (although this is certainly less common than in individuals on long-term daily corticosteroids).

For these reasons, I would try to discourage use of depot steroid injections, trying nasal or bronchial inhaled steroids for rhinitis or asthma respectively as the first approach.
____________________________________________________________
Chest. 1988 Jan;93(1):11-3.
Oral vs repository corticosteroid therapy in acute asthma.
Hoffman IB, Fiel SB.
Pulmonary Disease Section, Temple University Hospital, Philadelphia.

Acutely ill asthmatic patients treated in the usual fashion in an emergency room setting and discharged within six hours were studied to determine whether therapy with a single injection of a repository corticosteroid (methylprednisolone sodium acetate) could be as effective as a tapering course of oral corticosteroids in decreasing asthma symptomatology and relapse within seven days. Seventeen patients (18 episodes of asthma) formed the study population. Eight episodes occurred in patients who received Depot methylprednisolone (group 1) and ten episodes in patients who received oral corticosteroid treatment (group 2). All patients in both groups improved following emergency room treatment. Relapse occurred in two of ten patients in group 2 and none in group 1. Symptoms attributable to asthma recurred in significantly more patients in group 2 than in group 1 (9 vs 0, p less than .01). Side effects from therapy with corticosteroids were rare. This study indicates that intramuscular repository corticosteroids are at least as effective as oral corticosteroids in the management of the acute asthmatic outpatient, with a distinct advantage with regard to patient compliance.
3/24/03 re: Allergy to prednisone?
Q. A 12 year old asthmatic girl was referred to me with a history of HIVES occurring about an HOUR after taking her first dose of PREDNISONE (orally) for an exacerbation of asthma. My questions are as follows:

1) In order to know what oral steroid to use for future exacerbations, would you do an oral challenge to another steroid? Which? (dexamethasone? methyprednisolone? other?)

2) Would you do skin tests of any sort or RAST tests prior to doing an oral challenge with another corticosteroid? If so, how?

3) Are such urticarial reactions after prednisone usually due to an IgE mediated reaction?

4) Any other thoughts on evaluation or treatment?
A. As you know, the erratic occurrence of acute urticaria episodes of unknown cause is not unusual and could be coincidental in the patient you described. Therefore, one would want to know whether the urticaria described occurred on more than one occasion shortly after the prednisone ingestion. If the urticaria occurred on more than one occasion, the next question is whether the reaction was against another ingredient in the tablet, such as a preservative, etc. If the latter is not the case, there have been a limited number of cases reports (generally in single-case reports) suggesting allergic or pseudo-allergic reactions to the corticosteroid itself. I have enclosed a review written recently by me for the Current Literature section of this AADMC website. It discusses a recently published analysis of the case reports of presumed corticosteroid allergy. In a limited number of such reports, skin testing was attempted, while in the likely majority of cases a graded -dose challenge with another type of corticosteroid was the approach used. I am not familiar with the use of a RAST or similar in vitro test in such cases. In many cases, one would not expect to find specific IgE antibodies. The skin test may serve as the first, very low dose, in vivo challenge. I suggest that you read the article reviewed below.

In response to your specific question, I think that a graded dose challenge with dexamethasone would be reasonable in your case, since there are significant difference in the chemical structure of dexamethasone and prednisone.
____________________

Current Literature Item

Corticosteroid hypersensitivity reactions

Summary
Allergic or pseudo-allergic systemic reactions to therapeutic corticosteroid (CS) preparations are rare but have been reported. Butani of the University of California, Davis Medical Center in Sacramento, CA extensively reviewed the English language literature from 1964 to 2002 for relevant reports. Excluding contact sensitivity reactions to topical CS, the author found 80 reports about this subject, mainly individual case reports. The adverse reactions described ranged from minor rashes to serious cardio-vascular collapse. The apparent underlying mechanisms varied considerably from case to case with some resembling typical IgE-mediated reactions. Diagnostic approaches used have generally been skin testing or progressive, dose-ranging therapeutic challenges. In convincing cases, one may find that the patient can tolerate another CS which differs in certain chemical aspects.

Reference - Ann Allergy Asthma Immunol 2002;89:439-45

Editor's Comments
Systemic allergic reactions to CS seem almost like a paradox because of the potent anti-allergic properties of most CS. First, one must rule out as a cause of the adverse reaction some form of reactivity to a preservative, excipient, etc. also present in the commercial CS preparation. However, there do appear to be very infrequent convincing cases of true allergic or pseudo-allergic reactions to the CS molecule itself. A practical approach is to switch to a CS preparation with a somewhat different chemical grouping.
3/12/03 re: Literature reference for effects of adding leukotriene antagonist to Advair treatment
Q. I am trying to find current literature (journal articles, etc.) that discuss trials conducted in regards to a combined therapy of Advair and Leukotriene antagonists (Singulair or Accolate) in patients. I am finding this particularly difficult. Do you have any suggestions for literature where I may find such studies?
A. First, I will briefly review some background information about the effects of adding treatment with cysteinyl leukotriene antagonists (LA) to inhaled corticosteroids (ICS) in asthma treatment. There has been some debate about whether addition of LA treatment significantly reduces the amount of ICS needed for control of moderate asthma (1,2,3,4,). There has also been conflicting findings in studies of whether addition of LA improved control of asthma not well-controlled by ICS alone (3, 5,6,). In a comparison of adding LA vs adding inhaled long-acting beta agonist therapy (LABA) to ICS, Busse et al (7) reported that added salmeterol provided better asthma control than added zafirlukast. It is well established that added LABA significantly reduces ICS dosage needed for control (8). Perhaps the most convincing evidence that addition of LA yields only modest added benefit to ICS (w/wo inhaled LABA such as salmeterol) comes from the recent meta-analysis referred to above (4, also see enclosed abstract of that report). Also, there is evidence that addition of LA to ICS is less cost-effective than addition of LABA (see enclosed abstract).

I am not aware of a report specifically comparing the effects of adding LA vs adding placebo to Advair in treatment of moderate to severe asthma. However, based on indirect evidence quoted above, I would expect that added LA treatment would not confer an impressive improvement in moderate asthma already being treated with high dose Advair.

REFERENCES
1) N Eng J Med 1999;340:197-206
2) Ann Intern Med 1997;127:472-480
3) Lancet 2001;357:2007-11
4) Cochrane Database Syst Rev 2002:CD003133
5) Am J. Resp Crit Care Med 1999;160:1862-8
6) Am J. Resp Crit Care Med 2000;162:578-85
7) JACI 199; 103:1075-80
8) JAMA 2001;285:2594-2503
_________________________________________________________________
Cochrane Database Syst Rev 2002;(1):CD003133
Update of: Cochrane Database Syst Rev. 2001;(3):CD003133.
Addition of anti-leukotriene agents to inhaled corticosteroids for chronic asthma.
Ducharme F, Hicks G, Kakuma R.
Pediatrics and Epidemiology & Biostatistics, McGill University Health Centre, Montreal Chidren's Hospital, 2300 Tupper Street, Room C-538E, Montreal, Quebec, Canada, H3H 1P3.

BACKGROUND: Anti-leukotriene (AL) agents are being considered as "add-on" therapy to inhaled corticosteroids (ICS), in chronic asthma. OBJECTIVES: To examine the safety and efficacy of daily AL plus ICS compared to ICS alone, and determine the corticosteroid-sparing effect of AL when added to ICS in chronic asthma. SEARCH STRATEGY: We searched Medline, Embase, Cinahl (until September 2001), reference lists of review articles and trials, contacted international headquarters of AL manufacturers and ATS meeting abstracts (1998-2000). SELECTION CRITERIA: Randomised placebo-controlled trials of asthmatics aged 2 years and older with at least one month intervention. DATA COLLECTION AND ANALYSIS: Two reviewers assessed quality and extracted data independently. Trials were grouped by asthma control at baseline (symptomatic or well-controlled) and dose of ICS in the control group (same or double). MAIN RESULTS: Of 438 citations, 13 (12 adult and 1 paediatric) trials met inclusion criteria. Seven were published in full-text. In symptomatic patients, addition of licensed doses of anti-leukotrienes to ICS resulted in a non-significant reduction in the risk of exacerbations requiring systemic steroids: Relative Risk (RR) 0.61; 95% Confidence Interval (CI) 0.36,1.05). A modest improvement group difference in PEF was seen (Weighted Mean Difference (WMD) 7.71 L/min; 95%CI 2.98, 12.44 L/min) together with beta2-agonist use (WMD= -0.32 puffs/day; 95%CI -0.0.08, -0.56). No trials that compared the use of licensed doses of anti-leukotrienes with doubling-dose of inhaled glucocorticoids could be pooled.

In ICS-sparing studies in patients who were well controlled at baseline, addition of anti-leukotrienes produced no overall difference in dose of inhaled glucocorticoids (WMD -44.4 mcg/d, 95%CI -147.9, 59.0 mcg/d), but it was associated with fewer withdrawals due to poor asthma control (RR= 0.56, 95%CI 0.35, 0.89). REVIEWER'S CONCLUSIONS: There is insufficient evidence to firmly support the use of licensed doses of anti-leukotrienes as add-on therapy to inhaled glucocorticoids. Addition of anti-leukotrienes to inhaled glucocorticoids may slightly improve asthma control, but the available data do not permit this strategy to be recommended as a substitute for increasing the dose of inhaled glucocorticoids. Addition of anti-leukotrienes may be Associated with superior asthma control after glucocorticoid tapering, but a glucocorticoid-sparing effect cannot be quantified at present.
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Chest 2002 Apr;121(4):1028-35
Two-year retrospective economic evaluation of three dual-controller therapies used in the treatment of asthma.
O'Connor RD, O'Donnell JC, Pinto LA, Wiener DJ, Legorreta AP.
Sharp Rees Stealy Medical Center, San Diego, CA, USA.

OBJECTIVE: To compare asthma-related health-care utilization and expenditures for patients prescribed one of three dual-controller therapies: fluticasone plus salmeterol, inhaled corticosteroids (ICS) [excluding fluticasone] plus salmeterol, and ICS plus a leukotriene modifier (LTM). MATERIALS AND METHODS: Asthma-related medical claims from two major health plans were obtained for the 12 months before and after the initiation of dual therapy. A total of 1,325 patients > or = 12 years old with no claims for COPD or respiratory tract cancer were selected from the approximately 3.5 million lives covered. Multivariable regression was used to assess differences in asthma-related expenditures. To compensate for positive skew, all cost variables were log-transformed. RESULTS: Risk-adjusted total asthma-related costs for the fluticasone-plus-salmeterol cohort (n = 121), the ICS-plus-salmeterol cohort (n = 844), and the ICS-plus-LTM cohort (n = 360) [corrected] were $975, $1,089, and $1,268, respectively. Risk-adjusted pharmacy costs were $813, $841, and $996, respectively. Generalized linear modeling, controlling for baseline covariates, indicated that compared to ICS-plus-LTM therapy, fluticasone-plus-salmeterol therapy was associated with a significant reduction in asthma-related total (p = 0.0014) and pharmacy (p = 0.001) costs. Similar results were found when the ICS-plus-salmeterol group and the ICS-plus-LTM group were compared (p = 0.0001).

The number of inpatient, outpatient, and emergency department visits and their corresponding costs were lower for the fluticasone-plus-salmeterol cohort, but were not statistically significant (p > 0.05). CONCLUSION: Results from managed-care practice suggest that treatment with fluticasone plus salmeterol, and more broadly ICS plus salmeterol, yield important cost savings when compared to treatment with ICS plus LTM.
7/15/02 re: Adverse effects of depot triamcinolone (Kenalog) injections
Q. I wonder what your response would be to why Kenalog injections should not be used vs. oral steroids for acute allergic situations such as for acute urticaria or for severe seasonal allergic rhinitis. My answer is that it has a long suppressive effect of the pituitary adrenal axis. Is there any evidence that its longer action leads to more side effects other than the suppression of the adrenal-pituitary axis? Is there any evidence that there is a cumulative effect of past steroid usage that eventually reaches a threshold to cause a steroid side effect like a cataract, etc? If so, would Kenalog cause more cumulative side effects because its half life is longer?

I need these answers to counter a local explosion of kenalog use in our community.
 
A. Some authors such as Sharma and colleagues in Los Angeles have promoted the use of depot triamcinolone (DT) injection as more effective than oral steroids in severe (presumably steroid-dependent) asthma, claiming less frequent acute flares/intubations with "no increase in adverse effects" (see enclosed abstracts). However, others have reported more adverse effects with the use of DT (see enclosed abstract). I long ago stopped using depot steroid injections except in very particular situations because of my concerns not only about the usual systemic adverse effects (e.g., suppression of the HPA axis) but also what appeared to more frequent incidence of atrophy in the injection site and steroid-induced myopathy. I did not look specifically at the incidence of cataracts in such DT-treated individuals. This impression has been reported by others (see enclosed abstract).

To be sure that my response to your questions was complete and balanced, I referred your questions to Prof. Brian Lipworth of the University of Dundee in the UK. As you may recall, Prof. Lipworth is an expert in the study of the systemic effects of corticosteroids and has lectured about this subject at several AAAAI annual meetings. His prompt response is also enclosed below. I suggest that you also consult Dr. Stan Szefler in Denver about your questions. Stan is not only expert in the study of steroid effects but has very good clinical sense as well, in my opinion.

Prof. Lipworth's comments:

We do not use kenalog here at all for SAR or anything else as the adverse effects are worse than low dose oral prednisone qd mane. In fact we very rarely have to resort to oral steroid in SAR where we use nasal steroid, as as add on H1 antagonist +/- LTR antagonist. I can't remember the lat time we had someone who was refractory to this cocktail. If they were at the height of the pollen season we would add in alt day prednisone 15-25 mg. The reason for greater systemic effects than prednisone is its greater glucocorticoid potency and accumulation due to depot administration.I agree there are no controlled studies comparing daily pred v kenalog,but there is question that it has worse adverse effects, especially cushingoid and proximal myopathy in the longer term.
 

Curr Opin Pulm Med 1998 Jan;4(1):31-5
Parenteral triamcinolone acetonide: an alternative corticosteroid for the treatment of asthma.
Veeraraghavan S, Sharma OP.
Division of Pulmonary and Critical Care Medicine, University of Southern California School of Medicine, Los Angeles 90033, USA.

Corticosteroids are effective in reducing the airway inflammation and controlling the symptoms of asthma. Many patients with chronic, severe asthma are steroid-dependent, requiring daily oral corticosteroids. Although corticosteroids may be effective, many patients suffer from their intolerable side effects. Various medications have been used as steroid-sparing agents in patients who suffer from the side effects of long-term high-dose steroids. While drugs like methotrexate and cyclosporine are promising, none have clearly been shown to be beneficial in most patients with asthma. The long-acting parenteral steroid triamcinolone acetonide has been tested by various investigators in these patients for over 20 years. Intramuscular triamcinolone appears to beneficial, with no significant increase in adverse effects.


Thorax 1985 Nov;40(11):840-5
Intramuscular triamcinolone acetonide in chronic severe asthma.
McLeod DT, Capewell SJ, Law J, MacLaren W, Seaton A.

Seventeen subjects with chronic severe asthma completed a 48 week prospective, double blind study with crossover of treatment at 24 weeks, in which triamcinolone acetonide 80 mg intramuscularly every four weeks was compared with oral prednisolone 10 mg daily. Spirometry, twice daily measurements of peak expiratory flow rate, and self assessment of asthma symptom scores showed significant improvement during triamcinolone treatment; less extra prednisolone was required and there was significant weight loss. Two patients withdrew, one because of dissatisfaction with prednisolone and one because of side effects while taking triamcinolone. Three were withdrawn, one with proximal muscle weakness and two because of intercurrent illness. Adrenal suppression, bruising, and hirsuitism were worse with triamcinolone, other side effects being comparable. On completion of the study 16 of the 17 patients opted to continue taking triamcinolone acetonide. This treatment is an important addition to the therapeutic options available for chronic severe asthma.
 

Postgrad Med 1986 Sep 15;80(4):159-60
Local subcutaneous atrophy after corticosteroid injection.
Jacobs MB.

Subcutaneous atrophy developed in a 36-year-old woman at the site of a triamcinolone acetonide (Kenalog) injection for subdeltoid bursitis. Occurrence
of local atrophy after corticosteroid injection is relatively frequent yet unappreciated. It is more common in young women and girls who are given preparations with a lesser degree of water solubility. Although the condition is often reversible, instances of long-term disfigurement are well documented. This complication of a useful treatment method can be avoided by following a set of precautions for local injection of corticosteroi.

 
4/14/02 re: Steroid withdrawal after long-term therapy
Q. I recently saw a 49 yr. old WMF for chronic urticaria. Her history is remarkable for being on 5 mgm of prednisone for 14 years. My first charge is to wean her off the steroids. Her 8 am cortisol level is 4.4 mcg./dl with normal of 4.3-22.0. I know there are often many symptoms that arise during steroid withdrawal and I have not done this for years or for anyone on such long term treatment. Helen Morris at National Jewish used to teach us to triple the dose to alternate day in patients with asthma and then taper slowly. With such small doses I may have to resort to a liquid preparation. She is to get a slit lamp exam and a bone density was ordered by her PCM. It does not appear that her urticaria will not respond to medications now in vogue or doxepin. Any information you may have to share with me would be most appreciated.
A. As you likely know, the major problem in individuals on long-term systemic steroids is not so much the depression in baseline cortisol levels (as assessed by 8 AM cortisol levels) as a reduced increased secretion of cortisol in response to stress, etc. Therefore, the adrenal response in a cosyntropin test may be a more sensitive measure of adrenocorticol reserve (see enclosed review written for our In the News section by me of a lecture in the 3/02 AAAAI meeting given by Dr. Lipworth, an expert in this area). There have been a number of different approaches to tapering off long-standing steroid therapy, including the one you attributed to Helen Morris. My personal approach has been to total the amount of corticosteroids currently taken by the patient over a 48 hour period (which I will call "total dose"). I then write out a schedule such as this (all dosing at 8 AM):
  1. Week #1 - 3/4 of total dose taken on 1st day and 1/4 of total dose on alternate day. Repeat this pattern for rest of the week
  2. Week #2 - take 7/8 of dose on 1st day and 1/8 of dose on alternate day. Repeat this pattern for rest of the week
  3. Week #3 - take all of total dose on 1st day and none on alternate day. Repeat this pattern for rest of the week.
  4. Week #4 - take 3/4 of total dose every other morning. Repeat this pattern for rest of the week
  5. Week #5 - take 1/2 of total dose every other morning. Repeat this pattern for rest of the week
  6. Week #6 - take 1/4 of total dose every other morning. Repeat this pattern for rest of the week

Stop steroid therapy.

Some experts recommend obtaining a cosyntropin test at this time, tapering the steroid dosage over a longer period of time if there is still evidence of HPA axis suppression and/or the patient exhibits clinical signs of adrenal suppression.


Effects of inhaled corticosteroids (ICS) on hypothalamus-pituitary-adrenal (HPA) function

Summary
There have been increasing concerns about the potential for suppression of the HPA axis function with the extensive use of chronic ICS therapy in asthma. Lipworth et al of the University of Dundee in Scotland has reviewed this subject at the Annual Meeting of the AAAAI in March 2002. Cushingoid changes are unusual during usual dosage ICS therapy. He pointed out that while a single dose of ICS may suppress basal adrenocortical function, repeated dosing for several weeks is needed to induce adrenocortical atrophy and impair the reserve to respond to stress. A very sensitive, practical way of assessing adrenocortical reserve is a one microgram bolus infusion of ACTH (cosyntropin test) assessing the ratio of cortisol to creatinine in an overnight urine collection (as sensitive as the 24 hour urine collection, and less subject to compliance problems in collection). There is an increasingly steep curve for systemic absorption of ICS at doses above 800 microg/day for adults and 400 microg/day for children for most ICS . Highly lipophilic ICS such as fluticasone present particular risks when used in high doses. Therefore, some investigators use 400 microg/day of fluticasone as equivalent to 800 microg/day of other ICS in this regard. However, there is considerable inter-patient variability.

Editor's Comments
Dr. Lipworth, a highly experienced investigator of ICS effects, stressed that individuals receiving high doses of ICS are rarely clinically hypo adrenal but may have decreased adrenocortical reserve. The latter may be a major problem in case of prominent stress or following sudden cessation of ICS therapy. The ICS effects on the HPA axis generally parallel other systemic adverse reactions of ICS such as decreasing bone density. Perhaps most important, it is generally accepted that ICS dose response for beneficial effects of ICS in asthma flattens out considerably above 800 microg/day in adults (400-500 microg/day in children) while the systemic adverse effects increase steeply when such doses are exceeded. Although the highly lipophilic ICS agent fluticasone binds avidly to adrenocortical receptors in the airways, once absorbed into the systemic circulation, fluticasone binds more avidly than most other ICS to adrenocortical receptors in other tissues, possibly leading to greater potential for HPA suppression.
9/4/01 re: Safety of periodic steroid injections
Q. I am a Family Practice doctor who recently relocated to a small town in Portland, Oregon. I have been drilled that I.M. steroid injections should not be used for the control of seasonal allergies. In my new clinic Kenalog 40mg IM is used for this purpose. In your opinion are these injections safe? If not, please site specific reasons so I can respond to my associates.
A. I agree with you that treatment with intramuscular injections of depo-steroids preparations (which I believe the Kenalog preparation to be) should not be used for treatment of seasonal allergic rhinitis (SAR) unless there are extenuating circumstances. The reasons for my thinking are these:

1) There is always a potential for decreased resistance to infection during the 4-6 weeks after the injection of a depo-steroid although this is an unusual complication if the depo-steroid injection is given on only 1-2 occasions per year.

2) What is a more likely adverse effect of depo-steroid injections is on bone density, There is evidence that such effects can be cumulative over the years, further increasing the likelihood that osteoporosis will develop. If it is truly necessary to use systemic steroid therapy, one can reduce the adverse effects of corticosteroids on bone density by simultaneously treating with one of the bisphosphonate agents s plus exogenous calcium and Vitamin D (see enclosed abstract)

3) However, there are really effective intra-nasal steroid agents for the treatment of most of the symptoms of SAR (e.g., Nasonex, Rhinocort, Nasocort, Flonase) with little if any chance of systemic adverse effect. Therefore, it would be most unusual to require depo-steroids for treatment of SAR. However, it should be noted that intranasal steroids may not be that helpful if started when there is already marked nasal congestion, the topical steroid just does not get back into the nasal cavity enough. In such cases, I have instructed the patient to use a nasal decongestant spray (e.g., oxymetazoline), 2 sprays in each nostril, then "sniffing" the medicine back into the nose, about 30 minutes prior to use of the nasal steroid spray. After 3 days, the decongestant spray is discontinued but the steroid spray is continued throughout the relevant pollinating season.

Arthritis Rheum 2001 Jul; 44(7): 1496-1503
Recommendations for the prevention and treatment of glucocorticoid-induced osteoporosis: 2001 update. 
American College of Rheumatology Ad Hoc Committee on Glucocoritcoid-Induced Osteoporosis.

Glucocorticoid-induced bone loss should be prevented, and if present, should be treated (Table 2). Supplementation with calcium and vitamin D at a dosage of 800 IU/day, or an activated form of vitamin D (e.g., alfacalcidiol at 1 microg/day or calcitriol at 0.5 microg/day), should be offered to all patients receiving glucocorticoids, to restore normal calcium balance. This combination has been shown to maintain bone mass in-patients receiving long-term low-to-medium-dose glucocorticoid therapy who have normal levels of gonadal hormones. However, while supplementation with calcium and vitamin D alone generally will not prevent bone loss in-patients in whom medium-to-high-dose glucocorticoid therapy is being initiated, supplementation with calcium and an activated form of vitamin D will prevent bone loss. There are no data available to support any conclusion about the antifracture efficacy of the combination of calcium supplementation plus an activated form of vitamin D. Antiresorptive agents are effective in the treatment of glucocorticoid-induced bone loss. All of these agents either prevent bone loss or modestly increase lumbar spine bone mass and maintain hipbone mass. While there are no randomized controlled trials of prevention of glucocorticoid-induced bone loss or radiographic vertebral fracture outcomes with HRT or testosterone, patients receiving long-term glucocorticoid therapy who are hypogonadal should be offered HRT. The bisphosphonates are effective for both the prevention and the treatment of glucocorticoid-induced bone loss. Large studies have demonstrated that bisphosphonates also reduce the incidence of radiographic vertebral fractures in postmenopausal women with glucocorticoid-induced osteoporosis. Treatment with a bisphosphonate is recommended to prevent bone loss in all men and postmenopausal women in whom long-term glucocorticoid treatment at > or =5 mg/day is being initiated, as well as in men and postmenopausal women receiving long-term glucocorticoids in whom the BMD T-score at either the lumbar spine or the hip is below normal. While there is little information on the prevention or treatment of bone loss in premenopausal women, these women, too, may lose bone mass if they are being treated with glucocorticoids, so prevention of bone loss with antiresorptive agents should be considered. If bisphosphonate therapy is being considered for a premenopausal woman, she must be counseled regarding use of appropriate contraception. The therapies to prevent or treat glucocorticoid-induced bone loss should be continued as long as the patient is receiving glucocorticoids. Data from large studies of anabolic agents (e.g., PTH) and further studies of combination therapy in patients receiving glucocorticoids are eagerly awaited so additional options will be available for the prevention of this serious complication of glucocorticoid treatment.
4/20/01 re: Are steroids given at 4 PM less suppressive on the HPA?
Q. In the last several months pediatricians in my area have been prescribing oral corticosteroids for asthma exacerbations to be given at 4 p.m. instead of first thing in the morning. When I asked about the rationale They said that recent research shows that this minimizes HPA suppression. I cannot find any documentation that supports that statement (and goes against my understanding of the HPA). Can you guide me to the literature and/or explain the physiology?
A. I am not aware of any studies in adults showing that corticosteroids given in the latter part of the afternoon have less suppressive effects on the HPA. Because I have not been involved in the care of children for many years, I consulted Dr. Susan Schuval, a highly experienced Pediatric Allergist. Her response is enclosed below. I suggest that you ask the pediatricians involved to provide you with the reference(s) for the reports of the studies to which they refer. I would appreciate receiving such references to review if you obtain them.

I agree with you. The current issue of the textbook by Middleton et al states that oral corticosteroids should be given to asthmatics as a single morning dose (1). Similarly, the NHBLI guidelines state that if needed, oral corticosteroids should be given either as a single morning dose (preferred) or in divided doses if necessary (2). Other studies have reported increased efficacy of steroids for asthma if given as a single 3:00 PM dose but this has no relation to HPA suppression (3,4).

REFERENCES:

1. Schleimer RP. Glucocorticosteroids-Their Mechanism of Action and Use in Allergic Diseases. in Middleton EM Jr, Reed CE, Ellis EF, Adkinson NF, Yunginger JW, Busse WW, editors: Allergy: principles and practice, St Louis, 1998, Mosby, p653.

2. National Heart, Lung, and Blood Institute. Guidelines for the diagnosis and management of asthma. Expert Panel Report 2. National Institutes of Health Pub. no 97-4051. Bethesda, MD, 1997.

3. Beam WR, Weiner DE, Martin RJ. Timing of prednisone and alterations of airways inflammation in nocturnal asthma. Am Rev Resp Dis 1992;146(6):1524-30.

4. Reinberg A, Halberg F, Falliers CJ. Circadian timing of methylprednisone effects in asthmatic boys. Chrononbiolgia 1974;1:333.
8/8/00 re: Avoidance of hoarseness secondary to inhaled steroid use
Q. Occasional patients with asthma, develop marked hoarseness as soon as they are placed on an inhaled steroids. Despite changing brands and methods of inhalation (e.g. both MDIs and dry powdered inhaler) the hoarseness and loss of voice occurs within a few days of starting inhaled steroids.

Does your "expert' have any hints on avoidance of hoarseness and voice loss from inhaled steroids in those few patients who are particularly susceptible to this side effect?.
A. Please pardon the delay in response to your question, occasioned by the departure of a key staff member for this program in the AAAAI Executive Office. Therefore, your question was just forwarded to me. As you know, hoarseness is an unusual, but frequently very troublesome complication of inhaled steroid treatment. Although dysfunction of the vocal cords is the most likely cause of this hoarseness, it is worth having a careful laryngeal exam by an ENT consultant to rule out the occasional instance of fungal overgrowth in the larynx or even a nodule/tumor. The latter is particularly relevant if the hoarseness persists well after the inhaled steroid therapy has been stopped. 

Although there is no simple way of avoiding hoarseness or reducing its likelihood, other than avoiding inhaled steroid therapy, the suggestions below may be helpful.

1) Use of a large volume spacer attached to the MDI. With this approach, there is a reduction in the amount of larger aerosol particles reaching the larynx and lower airways. It is the larger particles which tend more to deposit on the mucosal surfaces in and around the larynx.

2) Since some studies suggest that the hoarseness side-effect is dependant on the cumulative dose of inhaled steroids, use a lower dose of inhaled steroids plus inhaled salmeterol (Serevent) 2 puffs q 12 hours. Several extensive studies have shown that addition of inhaled salmeterol will improve control of mild-moderate asthma as well as doubling the dose of inhaled steroids (see the review I wrote for our Current Literature section "Addition of salmeterol to fluticasone for asthma").

I have also enclosed an abstract of a relevant article about evaluation of hoarseness in this setting.
9/14/99 re: Safety of inhaled steroids in children
Q. I would like to know how safe is to use inhaled steroids in children less 5 years who have allergic rhinitis.
A. The safety of inhaled steroids in children has been discussed extensively in recent years, with particular emphasis on effects on growth velocity. Most of the studies have involved use of inhaled steroids for asthma. However, there have been some studies of the effects of nasal steroids. I am enclosing below a brief summary of some of these reports which I wrote recently for the Academy News publication of the American Academy of Allergy, Asthma and Immunology. I suggest that you also consult these items in this AADMC website.
  1. News section - ICS/Growth/Pro-con
  2. Current Literature section - reviews of several articles about inhaled steroid side-effects

Adverse effects of inhaled steroids - the saga continues!
There has been a tremendous recent interest in possible adverse systemic effects of the inhaled steroids (Inh St) which have become a staple of asthma treatment. Concerns have been raised about the inhibition of growth velocity in asthmatic children on Inh St treatment (see Headline item in this AADMC web site). Yet varying conclusions have been drawn
about such adverse systemic effects in different studies, some of which have been reviewed in this Current Literature section of the AADMC.

Lipworth of the University of Dundee in Scotland has recently reported a meta-analysis of studies investigating possible adverse systemic effects of various Inh St preparations1. He concluded that both prominent HPA axis suppression and reduction in bone density is more common during chronic therapy with >750 mcg/day of fluticasone and >1500 mcg/day of
other Inh St. Medium-term growth velocity studies showed evidence of suppression at doses of >400 mcg/d for some Inh St although there has not yet been any evidence of significant reduction of final adult height. Long-term Inh St treatment increases the risk for posterior subscapular abstract, and to a much lesser degree, the risk for ocular hypertension
and glaucoma. In another report2, Li et al of the Mayo Clinic in Rochester, MN have
reported suppression of the HPA by prednisone 10 mgm/day but not by fluticasone in doses up to 400 mcg/day.

REFERENCES
1. Arch Intern Med 1999;159:941-955
2. J Allergy Clin Immunol 1999;103:622-28

EDITOR'S COMMENTS
The findings in these reports add to the burgeoning body of information about possible systemic effects of Inh St. Taken together with information previously reviewed here (including J Resp Dis 1998;19:1023-1036; J Asthma 1998;36:307-311; News Section coverage of the Symposium on Inh St in the AAAAI meeting of 3/99) one can draw some
tentative conclusions:

  1. Most data indicate that Inh St. in doses up to 400 mcg/day (perhaps 200 mcg/day for fluticasone) induce little if any adverse systemic effects.
  2. The frequency of such adverse effects during higher dose therapy will vary with the study (population, outcome measurements, etc.). As speakers in the AAAAI symposium noted, the HPA axis suppression may be subtle and not recognized clinically but could represent a threat during any major stressful event such as severe infection, trauma or surgery.
  3. Fluticasone may have greater anti-asthma efficacy on a mcg/mcg basis but possibly at the price of lower dose threshold for adverse effects.

These findings are particularly important because:

  1. There is a much less prominent dose-dependency for anti-asthma efficacy of Inh St above certain doses (generally about 800 mcg/day) while the adverse effects are much more dose dependent at those levels.
  2. Some authors strongly recommend "high dose" (over 1500 mcg/day) Inh St. as a "safe alternative" to low dose oral steroids in asthma.
  3. Adding approaches such as inhaled salmeterol bid and possibly leukotriene antagonists (not yet proven) may help asthma control without increasing the daily doses of Inh St. above 400 mcg/day
  4. There is often insufficient attention placed on controlling allergic factors in asthma pathogenesis even though such allergic reactivity has been shown clearly to be a major risk factor in many asthmatics. Such treatment approaches to the allergic component may help avoid going to higher doses of Inh. St. to control asthma
  5. A recent report, also from the Univ. of Dundee, suggests greater systemic bioavailability of fluticasone delivered by an MDI with spacer than by a dry powder inhaler (Lancet 1999;353:2128)

It may take longer follow up of sizable patient study groups to draw firmer conclusions about the best approach to the treatment of asthmatics not well controlled on Inh St. doses of up to 400 mcg/day.
3/25/99 re
Q. I, have a severe asthmatic patient with allergies. I wish to consider a regiment of antioxidant quercetin plus the B vitamin pantothenic acid along with organic sulfur (MSM) , but I will first consider if this patient is sensitive to any forms of sulfides, she is still not controlled with therapeutic index of accolate, theophylline, albutrol treatments. Has there been any further research or information on such treatment?
A. When you described your asthmatic patient as not being controlled with your existent therapy, you did not mention using inhaled corticosteroids (ICS), now considered a major part of chronic asthma management. If you have not used ICS, I suggest first starting with the more potent ICS preparations such as budesonide (Pulmocort) or fluticasone (Flovent), at least 800 micrograms/day to start, monitoring FEV1 as well as clinical symptomatology (with peak flow {PEFR} measurements by the patients in the morning and evening, using an inexpensive portable peak flow meter, for supplemental information). If the asthma is severe, you may have to first give a short tapered course of oral steroids before switching to inhaled steroids.

When the patient has improved symptomatically and the FEV is ¦70% of predicted one can try tapering the dosage of inhaled steroids to 400 micrograms/day or less (a level found to have no associated systemic steroid effects), continuing the Accolate all along. Continuous monitoring of FEV1/PEFR should be carried out. Other approaches such as avoidance of relevant allergens and irritants and possible allergy injection immuno-therapy should be considered where appropriate.

Insofar as the possible use of anti-oxidants in asthma, this approach is still investigational and controversial. Flavonoids such as quescetin have been shown to exert anti-inflammatory effects in in vitro and animal models. However, their efficacy in human asthma is not clear. You referred to the possible use of organic sulfur compounds (did you mean sulfides or sufites?). In some asthmatics, ingestion of foods containing sulfites as an anti-oxidant preservative will lead to worsening of the asthma, likely due to SO2 formation from the sulfites.
3/31/98 re: cellular immunodeficiency
Q. A recently hospitalized steroid dependent asthmatic with a total IgG level of 500 underwent a complete immune work-up which revealed she had a decreased T-helper population of 363 per cu. mm. and all pneumococcal titers were low. In addition, mitogens were severely depressed at 5 to 12 % of control across the board.

She also had very poor lymphocyte antigen responses to tetanus and candida (approximately .6 to .9, with 3.0 or greater being normal).

My question is: does this patient have suppressive factors in her serum from her infection or can she really have such poor cellular responses and still have a decent total IgG level? Am I witnessing the onset of a common variable patient? Can you have such dreadful cellular responses at age 51? I have an HIV titer pending."
A. It is difficult to give a clear-cut response to the questions posed based upon the limited information provided. It sounds as if there may be a cellular immune deficiency with borderline low serum IgG levels (500 mg/dl).
  1. First, one must establish how much steroids this steroid-dependent asthmatic was taking at the time the blood specimens were obtained. Sizable steroid doses within 24 hours can lead to a prominent lymphopenia (predominantly in the CD4 "helper" subset), as well as decreased blood monocyte levels. These effects can lead to a decreased mitogen-induced in vitro proliferative response.
  2. Moderate to high dose steroid treatment for at least 10-14 days can suppress in vivo expression of delayed (cell-mediated) hypersensitivity.
  3. Continuous high dose steroid therapy for months may lead to decreased serum IgG levels.
  4. Assuming that corticosteroids or other drugs were not affecting the blood studies mentioned, one has to consider an immune defect:
  1. The questioner did not describe the pattern of recurrent infections, if any, experienced by this patient. The types of infection may help point to which defect predominates.
  2. One has to know whether there is evidence for a systemic disease (lymphoma, sarcoid, AIDS, intestinal lymphangiectasia) that may lead to lymphopenia and/or lymphocyte dysfunction.
  3. One has to know whether the subject makes adequate IgG anti-protein (e.g. tetanus toxoid) responses before considering the diagnosis of CVI.

I suggest that the viewer look for more details in the "Approach to Immuno-Deficiency Disorders" under the Practice Guidelines portion of the Current Literature Section of this AADMC web site.
6/9/97 re: corticosteroids
Q. A 25 old year old female has been diagnosed with Sarcoid. She has a very steroid sensitive illness. However, every use of Prednisone has resulted in extreme weakness with swelling of all joints and pain in the joints. One episode needed hospitalization. MTX is controlling the disease process. Question came from the PCP if it is possible to desensitize or increase her tolerance for prednisone. I have not examined the swelling so cannot comment if this is angioedema. History does not suggest a Type I IgE based reaction. Type III reaction may be occurring here, but I have no blood work to prove or disprove until next episode or challenge. Q: Is there a protocol for the "desensitization", I was planning to switch the steroids to a mineralocorticoid in slow incremental challenge amount. Any input? Please help...
A. The picture you describe is atypical. Muscular pain and weakness and joint pain are not unusual during tapering of steroid doses (particularly when done rapidly) but true multiple joint swelling during maintenance prednisone therapy would be very unusual. My suggestions:
  1. Try another oral steroid (e.g. dexamethasone) on the possibility that a reaction to either the prednisone molecule or one of the excipients in the prednisone tablet may be the cause. I would not use a pure mineral corticoid because such agents have much less anti-inflammatory effects and will be more likely to retain fluid.
  2. I know of no reliable methods of desensitization to prednisone nor could I find reference to such a method in a Medline search.
  3. If methotrexate treatment is no longer effective or limited by side-effects, another option may be chlorambucil, used successfully in many patients by Dr. Harold Israel, one of the pioneers in the care of sarcoid patients.
5/17/97 re: treatment for hay fever
Q. Are steroids appropriate for Hay Fever?
A. In my experience, systemic steroid therapy is rarely indicated in uncomplicated seasonal allergic rhinitis (hay fever). However, appropriately used nasal steroid sprays are a valuable component of therapy, provided that they are used before nasal congestion becomes so pronounced that the spray does not penetrate adequately into the nasal cavity. The incidence of side-effects from nasal steroid spray therapy is quite low.

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