True and false contraindications to vaccines

Nowadays, the awareness of risks related to infectious diseases has decreased, whereas THE perception of risks related to vaccination is growing. Therefore, it may be difficult for health care providers to convince people of the importance of vaccination and adherence to the immunisation schedule. Selected situations that might raise uncertainties about vaccine recommendations are discussed in order to help health care providers to identify real and perceived contraindications to vaccines, and cases to be referred to specialised pre-vaccination consultation due to an increased risk of adverse events to vaccines (AU)

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True and false contraindications to vaccines.

Nowadays, the awareness of risks related to infectious diseases has decreased, whereas THE perception of risks related to vaccination is growing. Therefore, it may be difficult for health care providers to convince people of the importance of vaccination and adherence to the immunisation schedule. Selected situations that might raise uncertainties about vaccine recommendations are discussed in order to help health care providers to identify real and perceived contraindications to vaccines, and cases to be referred to specialised pre-vaccination consultation due to an increased risk of adverse events to vaccines.

Tracking a CAD-ALK gene rearrangement in urine and blood of a colorectal cancer patient treated with an ALK inhibitor.

BACKGROUND: Monitoring response and resistance to kinase inhibitors is essential to precision cancer medicine, and is usually investigated by molecular profiling of a tissue biopsy obtained at progression. However, tumor heterogeneity and tissue sampling bias limit the effectiveness of this strategy. In addition, tissue biopsies are not always feasible and are associated with risks due to the invasiveness of the procedure. To overcome these limitations, blood-based liquid biopsy analysis has proven effective to non-invasively follow tumor clonal evolution. PATIENTS AND METHODS: We exploited urine cell-free, trans-renal DNA (tr-DNA) and matched plasma circulating tumor DNA (ctDNA) to monitor a metastatic colorectal cancer patient carrying a CAD-ALK translocation during treatment with an ALK inhibitor. RESULTS: Using a custom next generation sequencing panel we identified the genomic CAD-ALK rearrangement and a TP53 mutation in plasma ctDNA. Sensitive assays were developed to detect both alterations in urine tr-DNA. The dynamics of the CAD-ALK rearrangement in plasma and urine were concordant and paralleled the patient's clinical course. Detection of the CAD-ALK gene fusion in urine tr-DNA anticipated radiological confirmation of disease progression. Analysis of plasma ctDNA identified ALK kinase mutations that emerged during treatment with the ALK inhibitor entrectinib. CONCLUSION: We find that urine-based genetic testing allows tracing of tumor-specific oncogenic rearrangements. This strategy could be effectively applied to non-invasively monitor tumor evolution during therapy. The same approach could be exploited to monitor minimal residual disease after surgery with curative intent in patients whose tumors carry gene fusions. The latter could be implemented without the need of patient hospitalization since urine tr-DNA can be self-collected, is stable over time and can be shipped at specified time-points to central labs for testing.

Perioperative anaphylaxis: epidemiology.

The clinical diagnosis of an anesthesia-related immediate hypersensitivity reaction is a difficult task for clinicians. Anaphylaxis may present as cardiovascular collapse or airway obstruction, associated or not with cutaneous manifestations. Drug hypersensitivity reactions that occur during anesthesia are responsible for significant morbidity and mortality and socio-economic costs. Perioperative anaphylaxis is becoming more common, probably because of the more frequent use of anesthesia and the increasing complexity of the drugs used. However, despite increased awareness of anaphylactic reactions to drugs and compounds used in anesthesia, their incidence remains poorly defined. Moreover, current epidemiological data should be carefully evaluated since the various studies published concerned non-homogeneous populations and gave differing definitions of drug hypersensitivity.

Antibiotic allergy.

Antibiotics are commonly injected during the perioperative period and are responsible of 15 percent of the anaphylactic reactions. Anaphylaxis triggered by antibiotics primarily involves penicillin and cephalosporin. The management of patients with histories of allergic reactions to antibiotics is a common situation in clinical practice. The confirmation or invalidation of the allergic nature of the reported reaction is not based on in vitro tests, but on a rigorous allergological work-up based on detailed analysis of clinical history, skin tests and drug provocation test. Considering a possible cross-reactivity between penicillins, once an immediate penicillin allergy has been diagnosed, skin testing with the alternative molecule (cephalosporin, carbapenem, aztreonam) is mandatory and, if negative, the relevant drug should be given in an appropriate setting at increasing doses.

Perioperative allergy: therapy.

Perioperative allergic reactions manifest in various ways. The majority of systemic reactions occur during anesthesia within minutes of intravenous induction; however, agents which are administered via other routes may cause reactions after more than 15 minutes. Anaphylaxis during anesthesia may present in many different ways and the signs and symptoms, which do not vary from those of anaphylactic reactions in general, may be masked by hypovolemia, light, deep anesthesia or extensive regional blockade. Recommendations for treatment are based on available evidence in the literature. A treatment algorithm is suggested, with emphasis on the incremental titration of adrenaline and fluid therapy as first-line treatment. Increased focus on this subject will hopefully lead to prompt diagnosis and rapid, correct treatment.

Muscle relaxants allergy.

The most common agents that are responsible for intraoperative anaphylaxis are muscle relaxants. In fact, neuromuscular blocking agents (NMBAs) contribute to 50-70 percent of allergic reactions during anaesthesia. The main mechanism of hypersensitivity reactions to NMBAs is represented by acute type I allergic reactions and the most severe form is anaphylaxis. The rate of non IgE mediated immediate hypersensitivity reactions usually varies between 20 percent and 35 percent of the reported cases in most large series. In a recent report, non allergic suspected reactions to NMBAs occurred with almost the same frequency as did those with an allergic component. Although the precise mechanisms of these reactions remain difficult to ascertain, they usually result from direct non specific mast cell and basophil activation. After diagnostic procedures, regardless of the specific IgE results, NMBAs are contraindicated if the skin tests were positive. In view of the constantly evolving anesthesiologic practices, and of the complexity of allergy investigation, an active policy to identify patients at risk and to provide any necessary support to anaesthetists and allergologists should be promoted. The high frequency of IgE anaphylactic reactions and the feasibility of skin tests in children justify systematic allergy testing whenever hypersensitivity reaction occurs during general anaesthesia.

Anesthesia in children with asthma and rhinitis.

The incidence of asthma is increasing worldwide, but morbidity and mortality are decreasing, because of improvements in medical care. Although the incidence of severe perioperative bronchospasm is relatively low in asthmatics undergoing anaesthesia, when it does occur it may be life-threatening. Preoperative assessment of asthma should include a specialized medical hystory and physical examination as well as pulmonary function testing. Potential trigger agents should be identified and avoided. In many asthmatic patients treatment with systemic corticosteroids and bronchodilators is indicated to prevent the inflammation and bronchocostriction associated with endotracheal intubation. Nonetheless, acute bronchospasm can still occur, especially at induction and emergence, and should be promptly and methodically managed.

Prevention of allergic reactions in anesthetized patients.

Hypersensitivity reactions during perioperative period are increasing and may be potentially life-threatening. Therefore, major emphasis is given to prevention. We perform a review to examine which measures should be taken to prevent reactions to products used in elective and emergency surgery. Any patient with a history of previous anaphylaxis or severe reaction during anaesthesia should be referred to allergist for detection of the offending compound. However, the identification of the triggering agent is not always feasible because of the low accuracy of diagnostic tests. In these cases and when emergency surgery is required, it should be considered to replace all drugs administered before the onset of the reaction with alternatives. Furthermore, any cross-reacting agent and latex, especially in patients belonging to populations at-risk for latex allergy should be avoided. In susceptible patients, premedication with antihistamines and corticosteroids might reduce the severity of reaction to drugs or contrast material while it is unclear whether pre-treatment decreases incidence of anaphylactic reactions. There is no evidence that premedication prevents allergic reactions to latex. Overall, physicians should not rely on the efficacy of premedication.

Perioperative allergy: uncommon agents.

Anesthesia may often be considered as a high-risk procedure and anaphylaxis remains a major cause of concern for anesthetists who routinely administer many potentially allergenic agents. Neuromuscular blocking agents, latex and antibiotics are the substances involved in most of the reported reactions. Besides these three agents, a wide variety of substances may cause an anaphylactic reaction during anesthesia. Basically all the administered drugs or substances may be potential causes of anaphylaxis. Among them, those reported the most in literature include hypnotics, opioids, local anesthetics, colloids, dye, Non-Steroidal Anti-Inflammatory Drugs (NSAIDs), Iodinated Contrast Media (ICM), antiseptics, aprotinin, ethylene oxyde and formaldehyde, and protamine and heparins. No premedication can effectively prevent an allergic reaction and a systematic preoperative screening is not justified for all patients; nevertheless, an allergy specialist should evaluate those patients with a history of anesthesia-related allergy. Patients must be fully informed of investigation results, and advised to provide a detailed report prior to future anesthesia.

Long-term auxological and pubertal outcome of patients with hereditary insulin-like growth factor-I deficiency (Laron and growth hormone-gene deletion syndrome) treated with recombinant human insulin-like growth factor-I.

BACKGROUND: GH-IGF-I axis is mainly involved in the complex process of somatic growth but emerging evidence suggests that it also influences hypothalamic-pituitary-gonadal (HPG) function. SUBJECTS: We report some data regarding long-term auxological and pubertal outcome of five female patients with hereditary forms of GH-IGF-I deficiency (Laron and GH-gene deletion syndrome) and a mean age of 23.4±5.3 yr (range 19-32). METHODS: All the patients received recombinant human IGF-I (rhIGF-I, Pharmacia and Upjohn, Stockholm, Sweden, and rhIGF-I, Genentech, San Francisco, CA, USA) from a mean age of 8.6 yr (range 3.2-14.2) up to the final height. RESULTS: Final height was very disappointing (≤ -5.0 SD scores) and lower than target height in all the patients. Pubertal onset was delayed in most of them but menarche occurred spontaneously in all the patients. Median age at menarche was 15.1 yr. Menstrual cycles were regular for several years. Median duration of gynecological follow- up was 8.3 yr with the longest span of 17.2 yr. CONCLUSION: We can assert that GH-IGF-I axis has an essential role in promoting linear growth in humans and its physiological action cannot be replaced by pharmacological treatment in most patients with hereditary forms of IGF-I insufficiency as demonstrated by their subnormal final height. Our clinical observations can also support an essential role of IGF-I in genitalia growth but not in the function of HPG axis as demonstrated by the maintenance of regular menstrual cycles in the presence of subnormal levels of IGF-I after treatment discontinuation.

Salt-wasting congenital adrenal hyperplasia: genotypical peculiarities in a Sicilian ethnic group.

Here we report for the first time the results of the molecular study of 17 unrelated patients with salt-wasting (SW) congenital adrenal hyperplasia (CAH) belonging to a Sicilian ethnic group, as corroborated by patients' pedigree taken to include 2 generations in the paternal and maternal lineage. The aim of this report was to confirm that genetic basis of CAH may be characterized by population differences. In our series, the overall predominant mutation was IVS2A/C>G, that was detected in 50% of alleles and in 58.8% of patients. The allelic and homozygous frequencies of IVS2A/C>G, Del8bpE3, and R356W mutations were significantly higher in our series than in other populations. Our study population included 2 cases with 2 different mutations that have been recently reported for the first time, 3 cases with a double mutation on the same allele, and 1 case with homozygous de novo mutation. We concluded that: a) in a Sicilian ethnic group the most frequent genotype in SW CAH is IVS2A/C>G homozygocity; b) surprisingly Del8bpE3 and R256W homozygocity are also well represented.

In the Italian population sexual dimorphism affects pre-natal thyroid migration but not biochemical severity of gland ectopia and pre-natal bone maturation.

UNLABELLED: The aim of the present study was to retrospectively re-evaluate a population of selected infants with congenital hypothyroidism (CH), in order to investigate whether sexual dimorphism affects: a) CH etiology; b) its biochemical severity at the time of screening and recall; c) patients' biochemical response to replacement treatment during the 1st yr of life; d) their bone maturation (BM) at birth; e) their psychomotor status at 1 yr. This retrospective study covers 192 infants (116 females) with persistent CH who were selected from a larger population of CH patients identified during a 10-yr period (1990-1999) by the screening programs of 5 northern, central, and southern regions of Italy. Thirty boys (39.5%) and 66 girls (56.9%) were found to have ectopia, whereas the remaining 46 boys and 50 girls exhibited the other causes of CH. When compared with the prevalence of the remaining causes that of ectopia was significantly higher in girls than in boys (66/116 vs 30/76; chi2=5.57, p<0.025), and sex ratio in ectopia was significantly different also compared with the orthotopic gland group only (66/84 vs 30/51; chi2=6.02, p<0.025). No differences between males and females were detected in the groups with either athyreosis or orthotopic gland. In no groups were there differences between sexes for gestational age, birth auxological data, percentage of newborns with bone retardation or developmental quotient at 1 yr. Thyroid tests at birth, age at TSH normalization and average thyroid tests under L-T4 treatment during the 1st yr did not differ between sexes in any of the groups. CONCLUSIONS: a) in the Italian population sexual dimorphism affects pre-natal thyroid migration but neither biochemical severity of ectopia, nor pre-natal bone maturation and psychomotor development; b) girls with CH do not require higher doses of initial therapy in order to achieve TSH normalization; c) future developmental and molecular studies on ectopia etiology in CH need to take into account the effect of sexual dimorphism.

Subclinical hypothyroidism: the state of the art.

Subclinical hypothyroidism (SH) is a common clinical problem, particularly in adulthood and the elderly. Its prevalence is conditioned by several etiological and risk factors. The highest age- and sex-specific rates are in women over 60. SH may be associated with manifestations of mild thyroid failure, which may reverse under levothyroxine (L-T4) therapy. The risk of progression to overt hypothyroidism is distinctly higher in cases with underlying thyroid disease. A population routine screening is not generally recommended, but screening is encouraged in high-risk groups. L-T4 therapy may be indicated in subjects with TSH levels which are repeatedly and consistently elevated (>10 microIU/ml) and may be considered in those with TSH ranging between 4.5-5.5 and 10 microIU/ml, particularly if anti-thyroid antibodies are positive and/or hypothyroid symptoms are present. Treatment should be based, at least initially, on L-T4 low doses.