Successful treatment with Omalizumab of a child affected by Systemic Mastocytosis: clinical and biological implications.

BACKGROUND: Pediatric Mastocytosis is a rare and heterogeneous disease, characterized by accumulation of mast cells in the skin (Cutaneous Mastocytosis) and/or, less frequently, in other organs, mainly liver, spleen, bone marrow, lymph nodes and gastrointestinal tract (Systemic Mastocytosis). Patients affected by Systemic Mastocytosis show symptoms caused by  a massive release of mast cell mediators: itching, flushing, abdominal pain, generalized weakness, fatigue and neuropsychiatric disorders. Moreover, children with Systemic Mastocytosis are at greater risk of anaphylactic/anaphylactoid reactions, often poorly controlled by the conventional therapy with antihistamines, mast cells stabilizers and steroids. As a result, children affected by Systemic Mastocytosis have a poor quality of life and suffer the consequence of prolonged steroidal treatment. CASE PRESENTATION: A child with Systemic Mastocytosis and severe symptoms, refractory to symptomatic and steroidal therapy, has been successfully treated with Omalizumab, an anti-IgE monoclonal antibody usually employed in allergic patients with severe asthma and orticaria. The onset of clinical benefit of Omalizumab therapy was extraordinarily rapid, but proved to be strictly dependent on drug administration. The child has become completely and steadily asymptomatic. No other anaphylactic episodes have been reported. Steroid treatment could be definitively withdrawn after the second dose of Omalizumab, and all the other medications were later reduced. Twenty months after beginning, Omalizumab therapy is still ongoing with good symptomatology control; no side effects have been observed so far. CONCLUSIONS: In our experience, Omalizumab is an effective treatment for children affected by Systemic Mastocytosis not responding to conventional medical treatments. The main strengths of this therapy are its rapid and extraordinary efficacy to control the severe mast cells mediator-related symptoms, the lack of side effects and its steroid-sparing effect. However, more extensive and controlled studies in pediatric patients affected by Systemic Mastocytosis are needed to substantiate these promising findings.

Anaphylaxis in Risky Populations.

Anaphylaxis should be clinically diagnosed with immediate recognition, whereas, despite advances in the field of allergy, the symptoms of anaphylaxis remain to be under-recognized, diagnosis is often missed, and treatment is often delayed. Anaphylaxis presents with symptoms in a spectrum of severity, ranging from mild objective breathing problems to circulatory shock and/or collapse. Indeed, anaphylaxis management frequently relies on a 'one-size-fits-all approach' rather than a precision medicine care model, despite the evidence that anaphylaxis is a heterogeneous condition with differences in causative agents, clinical presentation, and host susceptibility. The key important risk factors for severe anaphylaxis and mortality are certain age groups or certain stages of life (infants, elderly and pregnant women), augmenting factors (physical exercise, alcohol consumption, menstruation, acute infections), concurrent use of some medications (beta-adrenergic blockers (ß-blockers) and angiotensin-converting enzyme (ACE) inhibitors, non-steroidal anti-inflammatory drugs (NSAIDs), and proton pump inhibitors (PPIs), and concomitant diseases (i.e. asthma, cardiovascular disease, mastocytosis). The present review aims to collectively address the patient groups who are at high risk of having anaphylaxis, those who have a more severe course, those that are difficult to diagnose, and require a special approach in treatment. Therefore, the risky populations like the elderly, pregnant women, patients receiving ß- blockers or ACE inhibitors, those with concomitant cardiovascular diseases, asthma, and mastocytosis, or those having higher baseline serum tryptase levels are discussed, including their clinical presentations and treatment strategies. Additionally, anaphylaxis during the perioperative period is addressed.

Recognition and Management of Medication Excipient Reactivity in Patients With Mast Cell Activation Syndrome.

Mast cell activation syndrome (MCAS) is a complex disorder hallmarked by chronic multisystem inflammatory, allergic and growth dystrophic phenomena caused by inappropriate mast cell activation. MCAS has been estimated to affect as many as 17% of the population with a severity ranging from mild to life-threatening. MCAS patients are more sensitive than the average person to chemicals in the environment, including the nondrug ("inactive") ingredients (excipients) in medications and supplements. Excipient reactivity may explain unusual side effects to medications health professionals often find puzzling, such as the patient who appears intolerant of prednisone, acetaminophen, levothyroxine, or a vitamin. We present a series of patients with MCAS to illustrate important points regarding excipient reactivity which may be useful in everyday practice.

Basophil activation test in the diagnosis and monitoring of mastocytosis patients with wasp venom allergy on immunotherapy.

BACKGROUND: There is need for an accurate diagnostic test in mastocytosis patients with wasp venom allergy (WVA) and monitoring of these patients during immunotherapy (IT). In this study, we aimed to evaluate sensitivity and specificity of the Basophil Activation Test (BAT) as a diagnostic and monitoring test in patients with mastocytosis and WVA. METHODS: Seventeen patients with mastocytosis and WVA and six mastocytosis patients without WVA were included. BAT was performed before the start of IT (first visit) and at 6 weeks (second visit) and 1 year (third visit), after reaching the maintenance dose. Of 17 patients included, 11 completed the third visit. In mastocytosis patients with WVA, dose-dependent wasp-venom induced upregulation of CD63 and CD203c expression on basophils was observed compared with mastocytosis patients without WVA. Serum specific IgE, IgG4, and tryptase levels were measured in all patients. RESULTS: BAT had a sensitivity of 87% and specificity of 100% in diagnosing WVA in mastocytosis patients. Basophil allergen threshold sensitivity with respect to CD63 and CD203c was significantly decreased in the second visit compared with the first visit and increased significantly in the third visit compared with the second visit. Specific IgE levels increased significantly in the second visit compared with first and decreased significantly in the third visit compared with the second. Specific IgG4 levels rose significantly in the second visit compared with the first and on the third visit compared with the second. Tryptase levels did not change significantly during the study. CONCLUSIONS: BAT represents a diagnostic test with 100% specificity in allergic patients with mastocytosis and these patients are better to be monitored for a longer period during IT.

Mast cell degranulation distinctly activates trigemino-cervical and lumbosacral pain pathways and elicits widespread tactile pain hypersensitivity.

Mast cells (MCs) are tissue resident immune cells that participate in a variety of allergic and other inflammatory conditions. In most tissues, MCs are found in close proximity to nerve endings of primary afferent neurons that signal pain (i.e. nociceptors). Activation of MCs causes the release of a plethora of mediators that can activate these nociceptors and promote pain. Although MCs are ubiquitous, conditions associated with systemic MC activation give rise primarily to two major types of pain, headache and visceral pain. In this study we therefore examined the extent to which systemic MC degranulation induced by intraperitoneal administration of the MC secretagogue compound 48/80 activates pain pathways that originate in different parts of the body and studied whether this action can lead to development of behavioral pain hypersensitivity. Using c-fos expression as a marker of central nervous system neural activation, we found that intraperitoneal administration of 48/80 leads to the activation of dorsal horn neurons at two specific levels of the spinal cord; one responsible for processing cranial pain, at the medullary/C2 level, and one that processes pelvic visceral pain, at the caudal lumbar/rostral sacral level (L6-S2). Using behavioral sensory testing, we found that this nociceptive activation is associated with development of widespread tactile pain hypersensitivity within and outside the body regions corresponding to the activated spinal levels. Our data provide a neural basis for understanding the primacy of headache and visceral pain in conditions that involve systemic MC degranulation. Our data further suggest that MC activation may lead to widespread tactile pain hypersensitivity.

Pulmonary mastocytosis and enhanced lung inflammation in mice heterozygous null for the Foxf1 gene.

The Forkhead Box f1 (Foxf1) transcriptional factor (previously known as HFH-8 or Freac-1) is expressed in endothelial and smooth muscle cells in the embryonic and adult lung. To assess effects of Foxf1 during lung injury, we used CCl(4) and butylated hydroxytoluene (BHT) injury models. Foxf1(+/-) mice developed severe airway obstruction and bronchial edema, associated with increased numbers of pulmonary mast cells and increased mast cell degranulation after injury. Pulmonary inflammation in Foxf1(+/-) mice was associated with diminished expression of Foxf1, increased mast cell tryptase, and increased expression of CXCL12, the latter being essential for mast cell migration and chemotaxis. After ovalbumin (OVA) sensitization and OVA challenge, increased lung inflammation, airway hyperresponsiveness to methacholine, and elevated expression of CXCL12 were observed in Foxf1(+/-) mice. During lung development, Foxf1(+/-) embryos displayed a marked increase in pulmonary mast cells before birth, and this was associated with increased CXCL12 levels in the lung. Expression of a doxycycline-inducible Foxf1 dominant-negative transgene in primary cultures of lung endothelial cells increased CXCL12 expression in vitro. Foxf1 haploinsufficiency caused pulmonary mastocytosis and enhanced pulmonary inflammation after chemically induced or allergen-mediated lung injury, indicating an important role for Foxf1 in the pathogenesis of pulmonary inflammatory responses.

Mastocytosis and adverse reactions to biogenic amines and histamine-releasing foods: what is the evidence?

BACKGROUND: It has been suggested that normal concentrations of biogenic amines and 'histamine-releasing foods' may exacerbate symptoms in mastocytosis. The purpose of this study was to look for scientific evidence in the literature on diets restricted in biogenic amines and histamine-releasing foods in the treatment of mastocytosis. METHODS: Medline (1966 to 2004), Cinahl (1982 to 2004) and the Cochraine Library were searched for double-blind placebo-controlled food challenge (DBPCFC) studies with biogenic amines and/or histamine-releasing foods in mastocytosis. RESULTS: No studies employing DBPCFC with dietary biogenic amines or histamine-releasing foods in mastocytosis were found. Only a few in vitro studies in other diseases, animal studies and studies in humans in which histamine-releasing agents were incubated directly with duodenal tissues were found. One case was reported of severe adverse reactions to alcohol in mastocytosis, objectified by an open challenge. CONCLUSION: Despite the widespread belief that biogenic amines and histamine-releasing foods may cause allergy-like, non-IgE-mediated symptoms in certain patients, the role of diets restricted in biogenic amines and histamine-releasing foods in the treatment of mastosytosis remains hypothetical but worthy of further investigation. There is some evidence for adverse reactions to alcohol in mastocytosis.

Indomethacin-induced morphologic changes in the rat urinary bladder epithelium.

OBJECTIVES: To evaluate the morphologic changes in rat urothelium induced by indomethacin. Nonsteroidal anti-inflammatory drug-induced cystitis is a poorly recognized and under-reported condition. In addition to tiaprofenic acid, indomethacin has been reported to be associated with this condition. METHODS: Three groups were established: a control group (n = 10), a high-dose group (n = 10), treated with one intraperitoneal injection of indomethacin 20 mg/kg, and a therapeutic dose group (n = 10) in which oral indomethacin was administered 3.25 mg/kg body weight daily for 3 weeks. The animals were then killed and the bladders removed for light and electron microscopic studies. RESULTS: The light microscopic findings showed some focal epithelial degeneration that was more prominent in the high-dose group. When compared with the control group, both indomethacin groups revealed statistically increased numbers of mast cells in the mucosa (P <0.0001) and penetration of lanthanum nitrate through intercellular areas of the epithelium. Furthermore, the difference in mast cell counts between the high and therapeutic dose groups was also statistically significant (P <0.0001). CONCLUSIONS: Indomethacin resulted in histopathologic findings typical of interstitial cystitis, such as leaky bladder epithelium and mucosal mastocytosis. The true incidence of nonsteroidal anti-inflammatory drug-induced cystitis in humans must be clarified by prospective clinical trials.

Pulmonary infiltrates with masto- and lymphocytosis in BALF associated with arechine.

Pulmonary infiltrates developed in a 40-year-old man while receiving arechine. The hyperplasia of mast cells, hyperlymphocytosis, a predominance of cytotoxic T-cells of the CD8 type with the very low CD4/CD8 ratio in BAL were observed. The chest roentgenogram findings resolved within a month after discontinuing arechine therapy. A hypersensitivity reaction with the onset of lung fibrosis due to arechine seemed to be the likely cause.

Induction of intestinal mastocytosis in nude mice by repeated injection of interleukin-3.

The number of mast cells in various tissues of nude mice was examined after daily injection of Interleukin-3 (IL-3), which was purified from the media conditioned by WEHI-3B cell line. Repeated intraperitoneal injection of IL-3 caused a significant increase in the number of mucosal mast cells (MMC) in the epithelium of small intestine more than 30-fold and also to a lesser extent in the villous lamina propria of small intestine and caecum. The number of mast cells in the spleen, approximately 60% of which were formalin-resistant and were assumed as connective tissue type mast cells (CTMC), increased 3-fold by IL-3 treatment. Although statistically not significant, the number of mast cells in the ear skin also slightly increased.