Systemic mastocytosis in a 5-year-old child: successful treatment with disodium cromoglycate

Most clinical signs and symptoms of systemic mastocytosis (SM) are attributed to histamine release. We report here a 5-year-old male child with SM, who suffered from the age of 4 months from disseminated skin lesions, vomiting, diarrhoea, abdominal pain, flushing, tachycardia, hypotension, somnolence, and transient blindness, triggered by heat and egg ingestion. Oral disodium cromoglycate (DSCG) or placebo were started in a single blind trial at a dose of 100 mg/kg/day in four divided doses. The child was studied for 21 months during the administration of three courses of DSCG, each of 6 months’ duration, interspersed with three 1-month courses of placebo. During treatment with DSCG all the systemic manifestations improved, and the histaminaemia decreased. During the placebo periods the symptoms, signs, and histaminaemia recurred.     

Treatment of cutaneous mastocytosis

Therapy of cutaneous mastocytosis is directed towards skin and systemic symptoms due to mediator release and targeted on skin lesions. Symptomatic therapy of cutaneous mastocytosis involves agents that inhibit the release of mediators or antagonize H1 and H2 receptors such as antihistamines ketodifen and Aspirin. Disodium cromoglycate has no effect of the cutaneous symptoms of cutaneous mastocytosis. Skin-targeted therapies that lead to a resolution of the lesions of cutaneous mastocytosis are psoralen-photochemotherapy and topical corticosteroid therapy either by occlusion or intralesional injection for a limited number of lesions. There is no treatment that permanently cures cutaneous mastocytosis and patient selection will therefore have to be made on the basis of the clinical manifestations, onset of disease, the probability of spontaneous involution and the severity of cutaneous and systemic symptoms.     

Mixed organic brain syndrome as a manifestation of systemic mastocytosis

Systemic mastocytosis is a disease characterized by an excessive accumulation of mast cells, and associated with skin lesions, flushing, diarrhea, tachycardia, and psychiatric manifestations. In order to define more clearly the psychiatric manifestations, ten patients with this disorder underwent unstructured psychiatric interviews and a battery of psychologic testing. Both revealed a pattern of cognitive and affective changes in the majority of these patients, best categorized as an atypical or mixed organic brain syndrome. The cognitive changes consisted of diminished attention and memory, and the affective changes of anger, irritability, and, to a lesser extent, depression. These manifestations fluctuated with the level of disease activity, and appeared in some cases to respond to histamine antagonists and disodium cromoglycate, medications used to control the excessive mast cell activity. It is important for psychiatrists to be aware that mental status changes can represent psychiatric manifestations of mastocytosis, a readily treatable medical disorder.     

Clinical investigation of agents with prophylactic anti-allergic effects in bronchial asthma*

To determine the efficacy of ketotifen as an oral anti-asthmatic agent, experimental and therapeutic long-term trials were carried out. Four models were used in the experimental therapeutic trials and the antihislaminic agent clemastine and disodium cromoglycate were used as comparative substances. It was demonstrated that ketotifen provides protection against bronchospasm induced by allergens, histamine and exercise, but not against that induced by acetylcholine. In the therapeutic long-term trials, the efficacy and tolerance of ketotifen were compared with that of clemastine and disodium cromoglycate for a period of 6 months. In another study ketotifen was administered for 1 year, Ketotifen proved very effective in decreasing the frequency and duration of asthmatic attacks, concomitant medication could be reduced and the patients improved subjectively. From these trials it can be concluded that ketotifen is a safe and effective oral anti-anaphylactic agent for use in the long-term treatment of bronchial asthma.     

Disodium cromoglycate in anaphylaxis and pollinois.

Because disodium cromoglycate is being used in treating the symptoms of allergic patients and its mode of action remains uncertain, morphological experiments were conducted in an attempt to further elucidate this compound's mode of action. Rabbits with an ear chamber underwent anaphylaxis, lethal or sublethal, with microscopic observations of the microcirculation during anaphylaxis. At death or a chosen interval tissue of the ear chamber was secured for histological examination. The mast cells and the state of their granules were counted for each section. In no instance did disodium cromoglycate have any effect in preventing the gross or microscopic changes and disodium cromoglycate did not protect mast cells in passive anaphylaxis. The nasal mucosa of a subject sensitive to ragweed pollen was exposed to ragweed pollen in a non-pollen season and the gross symptoms of hay fever were noted. When the nasal mucosa was pre-treated with disodium cromoglycate, however, no symptoms were observed and biopsies of nasal mucosa showed more normal mast cells and fewer degranulated mast cells.     

Asthma due to inhaled chemical fumes—amino-ethyl ethanolamine in aluminium soldering flux

Three patients with asthma due to the fumes of aluminium soldering flux containing amino-ethyl ethanolamine were tested by occupational type exposures to the fumes of the flux and the amino-ethyl ethanoiamine. Typical late asthmatic reactions not inhibited by disodium cromoglycate were produced, one patient also giving an immediate asthmatic reaction which was inhibited by disodium cromoglycate.     

The effect of disodium cromoglycate on pulmonary function in extrinsic bronchial asthma over 12 months

Fourteen patients with extrinsic type bronchial asthma had pulmonary ventilation, lung volume and gas transfer measurements at rest and on exercise, carried out during a control period and again at 2 weeks and 12 months whilst on disodium cromoglycate. A significant improvement in forced expiratory volume, vital capacity and the ratio of residual volume to total lung capacity and in the exercise gas transfer, was observed at 12 months. The improved pulmonary function measurements agree with the clinical assessment of the improvement obtained in these patients whilst on disodium cromoglycate.     

KIT D816V-associated systemic mastocytosis with eosinophilia and FIP1L1/PDGFRA-associated chronic eosinophilic leukemia are distinct entities

BACKGROUND: The broad and overlapping clinical manifestations of D816V KIT-associated systemic mastocytosis with eosinophilia and FIP1L1/PDGFRA-associated chronic eosinophilic leukemia (CEL), coupled with the increase in activated eosinophils and mast cells seen in both disorders, have led to confusion in the nomenclature. It is of paramount importance, however, to distinguish between these 2 groups of patients because of differences in clinical sequelae, prognoses, and selection of treatment. OBJECTIVE: We thus sought to identify clinical and laboratory features that could be used to distinguish these 2 diagnoses. METHODS: We compared 12 patients with D816V-positive systemic mastocytosis with eosinophilia with 17 patients with FIP1L1/PDGFRA-positive CEL. Distinguishing features were used to create a risk factor scoring system. RESULTS: This system correctly classified 16 of 17 FIP1L1/PDGFRA-positive patients with CEL and all 12 patients with systemic mastocytosis with eosinophilia. Thirty-four FIP1L1/PDGFRA-positive patients described in the literature were also classified using this system, and although a complete set of data was not available for any of the historical patients, 21 were correctly classified. CONCLUSION: These results reinforce the hypothesis that the FIP1L1/PDGFRA gene fusion and D816V-KIT mutation cause distinct clinical syndromes. CLINICAL IMPLICATIONS: This novel diagnostic approach should prove helpful in clinical practice in the evaluation of patients with increased mast cells and peripheral eosinophilia.     

Efficacy, cost-effectiveness, and tolerability of mometasone furoate, levocabastine, and disodium cromoglycate nasal sprays in the treatment of seasonal allergic rhinitis.

BACKGROUND: Current guidelines recommend intranasal glucocorticosteroids as first-line therapy for seasonal allergic rhinitis. OBJECTIVE: To compare the efficacy, cost-effectiveness, and tolerability of the topical glucocorticosteroid mometasone furoate, the topical antihistamine levocabastine hydrochloride, and the cromone disodium cromoglycate in seasonal allergic rhinitis. METHODS: This study was performed during the 2003 grass pollen season as an open, randomized, parallel-group, single-center study of 123 patients assigned to receive mometasone furoate (200 microg once daily), levocabastine hydrochloride (200 microg twice daily), or disodium cromoglycate (5.6 mg 4 times daily). Symptom scores and nasal inspiratory peak flow measurements were recorded in a patient diary. The global efficacy of the study medication was evaluated by patients after treatment. Eosinophil cationic protein concentrations were measured in nasal secretions before and after treatment. Cost-effectiveness was evaluated as medication cost per treatment success. RESULTS: Mometasone furoate therapy was significantly superior to the use of levocabastine or disodium cromoglycate with respect to all nasal symptoms, the global evaluation of efficacy, and eosinophil cationic protein concentration. Furthermore, mometasone furoate therapy was significantly superior to disodium cromoglycate therapy with respect to nasal inspiratory peak flow. Medication cost per treatment success was lowest with mometasone furoate use and highest with levocabastine use. CONCLUSION: This is the first study to compare mometasone furoate nasal spray with nonsteroidal topical treatments for seasonal allergic rhinitis. Mometasone furoate nasal spray was confirmed as a first-choice topical treatment option for seasonal allergic rhinitis.     

Increased urinary methylimidazoleacetic acid (MelmAA) as an indicator of systemic mastocytosis

The urinary excretion of histamine and its main metabolite, methylimidazoleacetic acid (MelmAA), was determined in 25 adult patients with the clinical diagnosis of urticaria pigmentosa (UP). Extensive clinical and laboratory investigation, including skin histology, bone marrow examination and scintigraphy of skeleton, liver and spleen, implied systemic manifestations in 16 cases. All patients with systemic mastocytosis (SM) excreted abnormal amounts of MelmAA (>4.1 mg/24 h) and most of them 8.0 mg or more per day, while histamine excretion was increased in only nine (>40 g/24 h). Thus, the urine content of MelmAA, but not histamine, could differentiate between UP and SM. Severe pruritus was found concomitant with increased urinary MelmAA and indicated systemic mastocytosis.     

Intestinal permeability in irritable bowel syndrome. Effect of diet and sodium cromoglycate administration

We studied 14 patients with irritable bowel syndrome for the presence of increased intestinal permeability to food antigens and their responses to diet with and without disodium cromoglycate. After a standardized oral challenge with cow milk, serum beta-lactoglobulin was increased above control values in three patients. This finding did not correlate with response to hypoallergenic diet or treatment with disodium cromoglycate for 3 weeks. However over 50% of patients improved after diet with and without DSCG (2/5 on diet only and 5/7 with disodium cromoglycate of 12 evaluable cases). Since only two patients had elevated serum IgE levels, our results suggest that intolerance rather than hypersensitivity to foods may play a role in the disease. The tests we used to identify immunologic mechanisms could not predict which patients would do better on the diet and/or the drug.     

Comparison of ketotifen, disodium cromoglycate and placebo in the treatment of adult patients with mild extrinsic asthma

Sixty-four patients with mild or moderate extrinsic asthma were treated with placebo for i month and thereafter with ketotifen (1 mg twice daily, orally), disodium cromoglycate (inhalation of 20 mg, four times daily), or placebo for 2 subsequent months. The trial was performed at four different centres and the treatments were compared using double-blind technique. We found no difference between the effect of ketotifen, disodium cromoglycate and placebo on the patients' daily measurements of evening peak expiratory flow, daily score values for respiratory symptoms or the number of salbutamol puffs required to control symptoms. There was no difference between the treatment groups with regard to the patients' estimates of changes in airway sensitivity to different non-specific stimuli: fumes, tobacco smoke, cold air, and exercise. The only significant effect of DSCG was a minor (4%) increase in the mean morning value for peak expiratory flow. The findings suggest that the addition of ketotifen or disodium cromoglycate to the regimen is unlikely to give further benefit in asthmatic patients, whose symptoms are reasonably well controlled by small doses of bronchodilating drugs.     

Cutaneous manifestations in Hymenoptera and Diptera anaphylaxis: relationship with basal serum tryptase

Objectives To compare the clinical presentation of systemic anaphylaxis to Hymenoptera and Diptera with regard to basal serum tryptase (BT) and to evaluate mastocytosis in patients with elevated tryptase.
Patients and Methods The medical records of 140 patients with a history of a systemic reaction to venom were retrospectively reviewed. Symptoms and severity of anaphylaxis and BT were recorded. Most patients with elevated tryptase were screened for mastocytosis: a dermatological examination with a skin biopsy was performed in 19 cases and a bone marrow biopsy in 14 cases.
Results Tryptase was elevated in 23 patients. These patients reported fewer usual skin reactions (urticaria in 26.1% of cases with raised tryptase vs. 76.1% of cases with normal tryptase), more flushing (52.2% vs. 4.3%) and frequently did not present skin reaction (26.1% vs. 9.4%). They presented a more severe reaction (mean grade of severity: 3.48 vs. 2.69). Mastocytosis was diagnosed in seven patients with elevated tryptase: indolent systemic mastocytosis in six cases and cutaneous mastocytosis without systemic involvement in one case. In five cases, mastocytosis was previously undiagnosed. Lesions of cutaneous mastocytosis, diagnosed in five patients, consisted of urticaria pigmentosa in all cases and were often inconspicuous.
Conclusion These results demonstrate particular clinical features of the allergic reaction in patients with elevated BT and the higher frequency of mastocytosis in this population. In patients with a severe anaphylactic reaction without urticaria, but with flushing, tryptase should be assayed and an underlying mastocytosis should be considered.     

Disodium cromoglycate in ragweed-allergic rhinitis.

This study was designed to test the effectiveness of disodium cromoglycate when compared to placebo in a double-blind study in patients with ragweed allergic rhinitis. Patients were selected on the basis of a clinical history and a 4+ reaction to the intradermal injection of water-soluble ragweed, 0.02 c.c. of 500 PNU/c.c. Active agent/placebo groups were selected at random and were on the drug for approximately 8 wk, commencing 1 wk prior to the onset of the ragweed pollen season. Patient response was evaluated using patient diary cards, number of antihistamine tablets taken, and patient interviews. In the Toronto study, of 17 patients on the active drug, 15 were graded as improved, compared to only 6 of 21 placebo-treated patients who were improved. However, in the Hamilton study, results were less impressive. Nonetheless, it appears that intranasal insufflation of disodium cromoglycate was more effective in reducing ragweed hay fever symptoms than placebo.     

Improvement with disodium cromoglycate of neutrophil phagocytosis and respiratory burst activity in a patient with hyperimmunoglobulin E syndrome

We report a case of hyperimmunoglobulin E syndrome (HIE) complicated by neutrophil deficiency which was successfully treated with oral administration of disodium cromoglycate. A 48-year-old Japanese man with HIE developed Streptococcus pneumoniae meningitis. Laboratory tests after the meningitis revealed persistent neutropenia (300-800/mm³) and defects of phagocytosis and bacterial killing by neutrophils. Administration of disodium cromoglycate was started, and neutrophil counts gradually increased to 1200-1600/mm³ TTie impaired neutrophil activities returned to normal. The patient improved clinically; during the 2-year treatment, he had only two brief episodes of the common cold. Disodium cromoglycate may have potential clinical use in the treatment of cases of HIE even with neutrophil deficiency.     

Interest of interferon alpha in systemic mastocytosis. The French experience and review of the literature.

Systemic mastocytosis (SM) are defined by an abnormal growth and accumulation of mast cells in bone marrow and/or other extracutaneous organs. There is currently no cure for this disease. Because of similarities and/or association of mastocytosis with myeloproliferative disorders, interferon alpha has been tested but with contradictory reported results. A first prospective multicenter phase II trial was then started in France. From 1994 to 1997, 20 adult patients with confirmed bone marrow involvement received interferon alpha-2b for at least 6 months, (from 1 million U per day up to 5 million U/m(2)/day). Thirteen patients who presented systemic and/or specific cutaneous manifestations, demonstrated objective responses: seven (35%) were partial, six (30%) minor but no complete response could be observed at the time of analysis. The bone marrow remained unchanged in 12/13. Thus, interferon should be offered to patients with severe systemic manifestations, who have not responded to symptomatic therapies, even in case of non-aggressive mastocytosis, with or without corticosteroids the first weeks. Long-term therapy should be offered to patients with initial positive response. To control more aggressive SM or mastocytosis associated with clonal hematologic non-mast cell lineage or leukaemia mast cell, other chemotherapeutic regimens should be proposed like Cladribine (2-chlorodeoxyadenosine, 2-CDA) or polychemotherapies including interferon as it is being tested in France in a new multicentric protocol, coordinated by the association AFIRMM, with interferon and oral cytarabine.     

Observations on the safety of disodium cromoglycate in long-term use in children

A group of eighty-two children aged 6–18 years were investigated specifically for evidence of toxic or allergic effects from the use of disodium cromoglycate (‘Intal’) for 3 years or more by:

• 1 Radiological examination of the lungs.
• 2 Records of growth.
• 3 Haemoglobin estimations.
• 4 White blood counts.
• 5 Serum transaminase estimations.
• 6 Urine examinations.
• 7 Skin tests by the prick method.
• 8 Inhalation tests with disodium cromoglycate and lactose powder.

There was no evidence of drug-induced toxic or allergic effects. Random urine samples from 186 patients on treatment with disodium cromoglycate were examined for the quantity of the drug excreted. These suggested that 13·4% were not taking the treatment as instructed and another 16% may not have been using the spinhaler effectively. The failure to take the treatment properly has been noted in other conditions requiring long continued treatment, such as tuberculosis, and must affect both the results and, to some extent, the possibility of toxic effects. It is concluded that disodium cromoglycate treatment is remarkably free of toxic or allergic effects but that an important problem in long-term management is supervision of the patient's use of the treatment prescribed.     

Mode of action of disodium cromoglycate, studies on immediate type hypersensitivity reactions using `double sensitization'' with two antigenetically distinct rat reagins

The mode of action of disodium cromoglycate has been investigated to determine at what stage in immediate type hypersensitivity reactions the compound is effective. In vitro studies using rat subcutaneous connective tissue sensitized with rat reagin revealed that the compound inhibited the allergic release of histamine if present during antigen challenge. The presence of the compound during sensitization had no effect on antigen-induced release of histamine provided the compound was removed prior to antigen challenge. Tissues which had undergone a primary antigen challenge in the presence of disodium cromoglycate did not release histamine when the compound was removed and the tissues rechallenged. These findings indicated that antigen/antibody interaction occurred in the presence of the compound resulting in desensitization to a subsequent antigen challenge. To corroborate the evidence of the in vitro studies in vivo passive cutaneous anaphylactic reactions (PCA) were undertaken using tissue sites sensitized with two reaginic antibodies which permitted a sequence of antigen challenges. Results from these in vivo reactions demonstrated that it was possible to desensitize tissue, without the release of the mediators of anaphylaxis, by an antigen challenge and disodium cromoglycate treatment. In these sites sensitized with two antibodies the immunological reactivity was maintained following a primary antigen challenge and disodium cromoglycate treatment, as a subsequent challenge with the dissimilar antigen produced a good PCA reaction. It would appear that disodium cromoglycate acts either directly or indirectly at a stage following antigen/antibody reaction but prior to the release of the mediators of anaphylaxis.     

Occurrence of platelet-activating factor (PAF) and an endogenous inhibitor of platelet aggregation in diffuse cutaneous mastocytosis.

We have identified PAF in the blister fluid from a patient with bullous mastocytosis, a rare form of mast-cell disease. We have found a novel endogenous inhibitor of platelet aggregation which obscured the presence of the PAF in unprocessed blister fluid and in ethanol or lipid extracts. The PAF was characterized by the demonstration of chromatographic, mass spectral and biological properties identical to those of authentic PAF. Thus this is the first demonstration of PAF in biological fluid from a patient with mastocytosis. High levels of immunoreactive prostaglandin D2 (PGD2) and histamine were also present in the blister fluid. The interaction between PAF and the inhibitor of platelet aggregation in patients with systemic mastocytosis may provide an explanation for some of the manifestations of the disease, in particular the episodic hypotension, cutaneous flushing and pallor.     

Prevention of pollen rhinitis symptoms: comparison of fluticasone propionate aqueous nasal spray and disodium cromoglycate aqueous nasal spray

Fluticasone propionate aqueous spray, a new intranasal corticosteroid preparation, and disodium eromoglyeate 2% aqueous nasal spray, an established preventive treatment for seasonal allergic rhinitis, were compared in a double-blind, double-dummy, parallel-group, multicentric study in France. A total of 218 patients with seasonal allergic rhinitis caused by grass pollen (verified by positive skin prick test) were preventively treated before the onset of the grass pollen season with either fluticasone propionate 200 μg once daily or disodium cromoglycate 5.2 mg four times daily. Half of these doses was given in each nostril. Treatment started before the onset of the pollen season in most patients (178/218). Diary cards, including symptoms of rhinitis and usage of nasal sprays, were filled in twice daily for 5 weeks.
Terfenadine in 60-mg tablets and eye-drops could be used as rescue medications. We treated 110 patients with fluticasone propionate and 108 patients with disodium cromoglycate. Patients treated with flutieasone propionate had significantly more days free of primary efficacy symptoms of sneezing ( P < 0.001) and nasal discharge during the day ( P = 0.002), as well as free of all the other nasal symptoms ( P < 0.0l), and significantly lower median scores ( P < 0.05) for all nasal symptoms except nasal discharge than patients treated with disodium cromoglycate. There was no difference in eye symptoms or in rescue medication use between the two groups. Compliance with the treatment was assessed. Eleven patients recorded incorrect use of both nasal sprays for over 25% of days, and 55 patients recorded incorrect use of four-times-daily spray only; no patient recorded incorrect use of morning spray only. Both treatments were generally well tolerated.