Approaches to the treatment of hypereosinophilic syndromes: a workshop summary report

Hypereosinophilic syndromes are a heterogeneous group of uncommon disorders characterized by the presence of marked peripheral blood eosinophilia, tissue eosinophilia, or both, resulting in a wide variety of clinical manifestations. Although corticosteroids are the first-line therapy for many of these disorders, approaches to the treatment of patients who do not tolerate or are unresponsive to corticosteroids are poorly standardized. A multidisciplinary group of 37 clinicians and scientists participated in a workshop held in May 2005 in Bern, Switzerland to discuss current and future approaches to therapy for 3 eosinophil-mediated disorders: hypereosinophilic syndrome, Churg-Strauss syndrome, and eosinophil-associated gastrointestinal disease. The goal of the workshop was to summarize available data regarding treatment of these disorders to identify the most promising therapies and approaches for further study. There was consensus among all of the participants that the identification of markers of disease progression to assess treatment responses is a research priority for all 3 disorders. Furthermore, the need for newer therapeutic strategies and novel drugs, as well as multicenter trials to assess all treatment modalities, was emphasized.

Contrast-enhanced transcranial Doppler ultrasound for diagnosis of patent foramen ovale

The suspected cause of clinical manifestations of patent foramen ovale (PFO) is a transient or a permanent right-to-left shunt (RLS). Contrast-enhanced transcranial Doppler ultrasound (c-TCD) is a reliable alternative to transesophageal echocardiography (TEE) for diagnosis of PFO, and enables also the detection of extracardiac RLS. The air-containing echo contrast agents are injected intravenously and do not pass the pulmonary circulation. In the presence of RLS, the contrast agents bypass the pulmonary circulation and cause microembolic signals (MES) in the basal cerebral arteries, which are detected by TCD. The two main echo contrast agents in use are agitated saline and D-galactose microparticle solutions. At least one middle cerebral artery (MCA) is insonated, and the ultrasound probe is fixed with a headframe. The monitored Doppler spectra are stored for offline analysis (e.g., videotape) of the time of occurrence and number of MES, which are used to assess the size and functional relevance of the RLS. The examination is more sensitive, if both MCAs are investigated. In the case of negative testing, the examination is repeated using the Valsalva maneuver. Compared to TEE, c-TCD is more comfortable for the patient, enables an easier assessment of the size and functional relevance of the RLS, and allows also the detection of extracardiac RLS. However, c-TCD cannot localize the site of the RLS. Therefore, TEE and TCD are complementary methods and should be applied jointly in order to increase the diagnostic accuracy for detecting PFO and other types of RLS.

Effect of Alzheimer caregiving stress and age on frailty markers interleukin-6, C-reactive protein, and D-dimer

BACKGROUND: Elevated plasma levels of interleukin (IL)-6, C-reactive protein (CRP), and D-dimer belong to the biological alterations of the "frailty syndrome," defining increased vulnerability for diseases and mortality with aging. We hypothesized that, compatible with premature frailty, chronic stress and age are related in predicting inflammation and coagulation activity in Alzheimer caregivers. METHODS: Plasma IL-6, CRP, and D-dimer levels were measured in 170 individuals (mean age 73 +/- 9 years; 116 caregivers, 54 noncaregiving controls). Demographic factors, diseases, drugs, and lifestyle variables potentially affecting inflammation and coagulation were obtained by history and adjusted for as covariates in statistical analyses. RESULTS: Caregivers had higher mean levels of IL-6 (1.38 +/- 1.42 vs 1.00 +/- 0.92 pg/mL, p =.032) and of D-dimer (723 +/- 530 vs 471 +/- 211 ng/mL, p <.001) than controls had. CRP levels were similar between groups (p =.44). The relationship between caregiver status and D-dimer was independent of covariates (p =.037) but affected by role overload. Age accounted for much of the relationship with IL-6. After controlling for covariates, the interaction between caregiver status and age was significant for D-dimer (beta =.20, p =.029) and of borderline significance for IL-6 (beta =.17, p =.090). Post hoc regression analyses indicated that, among caregivers, age was significantly correlated with both D-dimer (beta =.50, p <.001) and IL-6 (beta =.38, p =.001). Among controls, however, no significant relationship was observed between age and either D-dimer or IL-6. CONCLUSIONS: The interaction between caregiving status and age for D-dimer and IL-6 suggests the possibility that older caregivers could be at risk of a more rapid transition to the frailty syndrome and clinical manifestations of cardiovascular diseases.

Serological and DNA-based evaluation of Chlamydia pneumoniae infection in inflammatory bowel disease

OBJECTIVES: Chlamydia has been associated with autoimmune diseases, but a link between chlamydial infection and the aetiopathogenesis of inflammatory bowel disease (IBD) remains controversial. In this study we assessed the relationship between chlamydial infection and IBD, as evidenced by serological measurement and DNA analysis of mucosal biopsy specimens. PATIENTS AND METHODS: The sera of 78 patients with Crohn's disease (CD), 24 patients with ulcerative colitis (UC), 73 healthy family members, and 20 healthy controls were tested for anti-C. pneumoniae IgG titres. A subgroup consisting of 13 UC and 39 CD patients was screened for the presence of chlamydial DNA on 42 inflamed versus 30 non-inflamed biopsy specimens and for mutations of their NOD2/CARD15 gene. RESULTS: Anti-C. pneumoniae IgG antibodies were found in the sera of 32 (41%) patients with CD, 11 (46%) patients with UC, 35 (48%) of unaffected family members, and nine (45%) unrelated healthy controls. Thirty-five percent of the control, 18% CD and 24% UC biopsy specimens contained C. pneumoniae DNA. In CD, however, C. pneumoniae DNA was significantly more frequently found in inflamed (27%) versus non-inflamed (8%) biopsy specimens (P < 0.05, Fisher's exact test). The frequencies of NOD2/CARD15 mutations were 33% for CD patients with C. pneumoniae DNA compared to 47% for CD patients without C. pneumoniae DNA. CONCLUSION: We found no marked differences in respect to anti-C. pneumoniae serum IgG or C. pneumoniae DNA between healthy controls and patients with IBD. However, in CD patients, inflamed tissue specimens contained significantly more likely C. pneumoniae DNA compared with biopsies from unaffected areas. Thus C. pneumoniae is unlikely to be of pathogenic importance in IBD while it may still influence local clinical manifestations.

Effects of genetic and environmental factors on chronic lower airway disease in horses

BACKGROUND: Environment and genetics influence the manifestation of recurrent airway obstruction (RAO), but the associations of specific factors with mild, moderate, and severe clinical signs are unknown. HYPOTHESIS: We hypothesized that sire, feed, bedding, time outdoors, sex, and age are associated with clinical manifestations of mild, moderate, and severe lower airway disease. ANIMALS: Direct offspring of 2 RAO-affected Warmblood stallions (F1S1, n = 172; F1S2, n = 135); maternal half-siblings of F1S1 (mHSS1, n = 66); and an age-matched, randomly chosen control group (CG, n = 33). METHODS: A standardized questionnaire was used to assess potential risk factors and to establish a horse owner assessed respiratory signs index (HOARSI 1-4, from healthy to severe) according to clinical signs of lower airway disease. RESULTS: More F1S1 and F1S2 horses showed moderate to severe clinical signs (HOARSI 3 and HOARSI 4 combined, 29.6 and 27.3%, respectively) compared with CG and mHSS1 horses (9.1 and 6.2%, respectively; contingency table overall test, P < .001). Sire, hay feeding, and age (in decreasing order of strength) were associated with more severe clinical signs (higher HOARSI), more frequent coughing, and nasal discharge. CONCLUSIONS AND CLINICAL RELEVANCE: There is a genetic predisposition and lesser but also marked effects of hay feeding and age on the manifestation of moderate to severe clinical signs, most markedly on coughing frequency. In contrast, mild clinical signs were not associated with sire or hay feeding in our populations.

Aussergewöhnliche Manifestation eines Magenkarzinoms mit Meningeosis carcinomatosa und spinaler Metastase

BACKGROUND: Leptomeningeal carcinomatosis is a rare complication of solid tumors, e. g., breast, lung and gastrointestinal carcinomas. Clinical manifestations are variable with radicular pains with or without neurologic deficiencies as well as headache and hallucinations. CASE REPORT: The rare case of a 57-year-old patient with neurologic symptoms caused by a leptomeningeal carcinomatosis and a spinal metastasis of an asymptomatic signet-ring cell gastric carcinoma is reported. In spite of combined radiochemotherapy the patient died already 4 weeks after discharge from hospital due to an intracerebral hemorrhage. CONCLUSION: Until today, prognosis of leptomeningeal carcinomatosis is poor with a median survival between 3-4 months independently of the primary tumor.

Pancreatitis preceding acute episodes of thrombotic thrombocytopenic purpura-hemolytic uremic syndrome: report of five patients with a systematic review of published reports

BACKGROUND AND OBJECTIVES: The thrombotic thrombocytopenic purpura-hemolytic uremic syndromes (TTP-HUS) have diverse etiologies, clinical manifestations, and risk factors, but the events that may trigger acute episodes are often unclear. We describe the occurrence of TTP-HUS following pancreatitis and consider whether pancreatitis may be a triggering event for acute episodes of TTP-HUS. DESIGN AND METHODS: We report on three patients from the Oklahoma Registry and two patients from Northwestern University who had an acute episode of TTP-HUS following pancreatitis. A systematic review of published case reports was performed to identify additional patients who had TTP-HUS following pancreatitis. RESULTS. In each of our five patients there was an apparent etiology of alcoholism or common bile duct obstruction for the pancreatitis and no evidence of TTP-HUS when the pancreatitis was diagnosed. Two patients had severe ADAMTS13 deficiency with an inhibitor; in one of these patients TTP-HUS recurred following a subsequent recurrent episode of pancreatitis. The systematic review identified 16 additional patients who had TTP-HUS following pancreatitis; recurrent TTP-HUS occurred in three of these patients following a subsequent episode of recurrent pancreatitis. In all 21 patients, the interval between the diagnosis of pancreatitis and TTP-HUS was short (1-13 days; median, 3 days). The three Oklahoma patients represent approximately 1% of the 356 patients in the Registry. INTERPRETATION AND CONCLUSIONS: These observations suggest that in some patients pancreatitis, a disorder that results in an intense systemic inflammatory response, may be a triggering event for acute episodes of TTP-HUS.

Maculopapular drug eruptions

Maculopapular (exanthematous) reactions are the most common adverse drug eruptions affecting the skin. Several studies indicate that immunological mechanisms including cytotoxic T cells (CD4+ > CD8+), both type 1 (e.g. IFN- γ ) and type 2 (e.g. IL-5) cytokines and various chemokines are critically involved in the pathogenesis of these eruptions. While maculopapular exanthems can virtually be elicited by any drug, antimicrobials (e.g. Β -lactam antibiotic, sulfonamides), anticonvulsants, allopurinol, and NSAIDs are most frequently involved. Clinical manifestations are variable and range from faint macules to widespread erythematous and maculopapular lesions, which usually begin on the trunk, neck and upper extremities and subsequently spread downwards in a symmetrical fashion. Although the clinical course is often relatively mild, these exanthems may sometimes progress to erythroderma or represent the beginning of even more severe drug reactions like Stevens-Johnson syndrome, toxic epidermal necrolysis or a drug rash with eosinophilia and systemic symptoms. In most cases, management includes early withdrawal of the offending drug and usually supportive treatment with emollients, topical corticosteroids and systemic antihistamines depending on the severity of the eruption. Allergological work-up is recommended to provide the patient with appropriate information about the causative drug and possible alternatives for future use.

Pathophysiology and diagnosis of cancer drug induced cardiomyopathy

The clinical manifestations of anti-cancer drug associated cardiac side effects are diverse and can range from acutely induced cardiac arrhythmias to Q-T interval prolongation, changes in coronary vasomotion with consecutive myocardial ischemia, myocarditis, pericarditis, severe contractile dysfunction, and potentially fatal heart failure. The pathophysiology of these adverse effects is similarly heterogeneous and the identification of potential mechanisms is frequently difficult since the majority of cancer patients is not only treated with a multitude of cancer drugs but might also be exposed to potentially cardiotoxic radiation therapy. Some of the targets inhibited by new anti-cancer drugs also appear to be important for the maintenance of cellular homeostasis of normal tissue, in particular during exposure to cytotoxic chemotherapy. If acute chemotherapy-induced myocardial damage is only moderate, the process of myocardial remodeling can lead to progressive myocardial dysfunction over years and eventually induce myocardial dysfunction and heart failure. The tools for diagnosing anti-cancer drug associated cardiotoxicity and monitoring patients during chemotherapy include invasive and noninvasive techniques as well as laboratory investigations and are mostly only validated for anthracycline-induced cardiotoxicity and more recently for trastuzumab-associated cardiac dysfunction.

Acute pancreatitis and thrombotic thrombocytopenic purpura

Thrombotic thrombocytopenic purpura (TTP) has multiple clinical manifestations and risk factors, but the events that actually trigger acute episodes of TTP are often unclear. We describe the case of a 56-year-old woman who presented with clinical signs and symptoms of TTP and acute pancreatitis. We discuss whether pancreatitis was due to ischemic pancreatic damage caused by microvascular platelet clumping in the frame of TTP, or whether acute pancreatitis, a disorder that results in an intense systemic inflammatory response, may be a triggering event for acute episodes of TTP.

Sex differences in cryptogenic stroke with patent foramen ovale

BACKGROUND: Sex differences in patients with patent foramen ovale (PFO) and cryptogenic stroke have not been systematically analyzed. We aimed to determine sex influences on demographics, vascular risk factors, clinical manifestations, stroke location, and clinical outcome. METHODS: One thousand two hundred eighty-eight consecutive patients with ischemic stroke or transient ischemic attack (TIA) were admitted to a single stroke center. All patients underwent a complete stroke workup including clinical examination, standard blood tests, cerebral and vascular imaging, transesophageal echocardiography, and 24-hour electrocardiography. In 500 patients, no definite etiology could be established (cryptogenic stroke/TIA). Of them, 167 patients (107 men and 60 women, mean age 52 +/- 13 years) had an PFO. RESULTS: The prevalence of PFO in patients with cryptogenic stroke or TIA was higher in men than in women (38% vs 28%, P = .014). Stroke severity and the prevalence of risk factors did not differ between the 2 sexes. There was an independent association between male sex and stroke location in the posterior cerebral circulation (OR 3.0, 95% CI 1.4-6.5, P = .006). Men and women did not differ in respect to PFO grade, prevalence of right-to-left shunt at rest, or coexistence of atrial septal aneurysm. Clinical outcome at 3 months was similar in both sexes. CONCLUSION: Patent foramen ovale was more prevalent in men than in women with cryptogenic stroke. There were no sex influences on age, risk factors, echocardiographic characteristics of PFO, or clinical outcome. Male sex was independently associated with stroke in the posterior cerebral circulation.

Diversity of the basic defect of homozygous CFTR mutation genotypes in humans

BACKGROUND: Knowledge of how CFTR mutations other than F508del translate into the basic defect in cystic fibrosis (CF) is scarce due to the low incidence of homozygous index cases. METHODS: 17 individuals who are homozygous for deletions, missense, stop or splice site mutations in the CFTR gene were investigated for clinical symptoms of CF and assessed in CFTR function by sweat test, nasal potential difference and intestinal current measurement. RESULTS: CFTR activity in sweat gland, upper airways and distal intestine was normal for homozygous carriers of G314E or L997F and in the range of F508del homozygotes for homozygous carriers of E92K, W1098L, R553X, R1162X, CFTRdele2(ins186) or CFTRdele2,3(21 kb). Homozygotes for M1101K, 1898+3 A-G or 3849+10 kb C-T were not consistent CF or non-CF in the three bioassays. 14 individuals exhibited some chloride conductance in the airways and/or in the intestine which was identified by the differential response to cAMP and DIDS as being caused by CFTR or at least two other chloride conductances. DISCUSSION: CFTR mutations may lead to unusual electrophysiological or clinical manifestations. In vivo and ex vivo functional assessment of CFTR function and in-depth clinical examination of the index cases are indicated to classify yet uncharacterised CFTR mutations as either disease-causing lesions, risk factors, modifiers or neutral variants.

Recent advances in understanding Marfan syndrome: should we now treat surgical patients with losartan?

OBJECTIVE: Marfan syndrome is a systemic connective tissue disorder caused by mutations in the fibrillin-1 gene. It was originally believed that Marfan syndrome results exclusively from the production of abnormal fibrillin-1 that leads to structurally weaker connective tissue when incorporated into the extracellular matrix. This effect seemed to explain many of the clinical features of Marfan syndrome, including aortic root dilatation and acute aortic dissection, which represent the main causes of morbidity and mortality in Marfan syndrome. METHODS: Recent molecular studies, most based on genetically defined mouse models of Marfan syndrome, have challenged this paradigm. These studies established the critical contribution of fibrillin-1 haploinsufficiency and dysregulated transforming growth factor-beta signaling to disease progression. RESULTS: It seems that many manifestations of Marfan syndrome are less related to a primary structural deficiency of the tissues than to altered morphogenetic and homeostatic programs that are induced by altered transforming growth factor-beta signaling. Most important, transforming growth factor-beta antagonism, through transforming growth factor-beta neutralizing antibodies or losartan (an angiotensin II type 1 receptor antagonist), has been shown to prevent and possibly reverse aortic root dilatation, mitral valve prolapse, lung disease, and skeletal muscle dysfunction in a mouse model of Marfan syndrome. CONCLUSION: There are indicators that losartan, a drug widely used to treat arterial hypertension in humans, offers the first potential for primary prevention of clinical manifestations in Marfan syndrome.

Triple and quadruple spontaneous cervical artery dissection: presenting characteristics and long-term outcome

BACKGROUND: Spontaneous cervicocephalic artery dissection (sCAD) of more than two cervical arteries is rare. PATIENTS AND METHODS: Vascular and potential sCAD risk factors, triggering events, clinical and neuroimaging findings, and outcome of patients with multiple sCAD were studied. Patients were drawn from prospective hospital-based sCAD registries. RESULTS: Of 740 consecutive patients with sCAD, 11 (1.5%) had three, and one had four (0.1%) sCAD. Eight of these 12 patients were women. One patient had additional dissections of the celiac trunk and hepatic artery. Vascular risk factors included hypertension (n = 1), hypercholesterolaemia (n = 6), current smoking (n = 5) and migraine (n = 6). No patient had a family history of sCAD, fibromuscular dysplasia (FMD) or connective tissue disease. SCAD was preceded by a minor trauma in five and infection in four patients. Clinical manifestations included ischaemic stroke (n = 8), transient ischaemic attack (n = 3), headache (n = 9), neck pain (n = 4), Horner syndrome (n = 5), pulsatile tinnitus (n = 2) and dysgeusia (n = 1). Brain MRI revealed ischaemic infarcts that affected one vessel territory in seven and two territories in two patients. The 3-month outcome was favourable (modified Rankin scale score 0-1) in 10 patients (83%). No new recurrent stroke or sCAD occurred during a mean follow-up of 50 (SD 29) months. CONCLUSION: Multiple sCAD occurred preferentially in women and caused clinical symptoms and signs mainly in one vascular territory. In none of the patients was FMD or any other underlying arteriopathy apparent. The majority of multiple sCAD was preceded by a minor trauma or infection. Clinical outcome was favourable in most patients, and long-term prognosis benign. The data suggest that transient vasculopathy may be a major mechanism for multiple sCAD.

Prevalence and time course of acute mountain sickness in older children and adolescents after rapid ascent to 3450 meters

OBJECTIVE: Acute mountain sickness is a frequent and debilitating complication of high-altitude exposure, but there is little information on the prevalence and time course of acute mountain sickness in children and adolescents after rapid ascent by mechanical transportation to 3500 m, an altitude at which major tourist destinations are located throughout the world. METHODS: We performed serial assessments of acute mountain sickness (Lake Louise scores) in 48 healthy nonacclimatized children and adolescents (mean +/- SD age: 13.7 +/- 0.3 years; 20 girls and 28 boys), with no previous high-altitude experience, 6, 18, and 42 hours after arrival at the Jungfraujoch high-altitude research station (3450 m), which was reached through a 2.5-hour train ascent. RESULTS: We found that the overall prevalence of acute mountain sickness during the first 3 days at high altitude was 37.5%. Rates were similar for the 2 genders and decreased progressively during the stay (25% at 6 hours, 21% at 18 hours, and 8% at 42 hours). None of the subjects needed to be evacuated to lower altitude. Five subjects needed symptomatic treatment and responded well. CONCLUSION: After rapid ascent to high altitude, the prevalence of acute mountain sickness in children and adolescents was relatively low; the clinical manifestations were benign and resolved rapidly. These findings suggest that, for the majority of healthy nonacclimatized children and adolescents, travel to 3500 m is safe and pharmacologic prophylaxis for acute mountain sickness is not needed.