Biomarkers in asthma and allergic rhinitis.

A biological marker (biomarker) is a physical sign or laboratory measurement that can serve as an indicator of biological or pathophysiological processes or as a response to a therapeutic intervention. An applicable biomarker possesses the characteristics of clinical relevance (sensitivity and specificity for the disease) and is responsive to treatment effects, in combination with simplicity, reliability and repeatability of the sampling technique. Presently, there are several biomarkers for asthma and allergic rhinitis that can be obtained by non-invasive or semi-invasive airway sampling methods meeting at least some of these criteria. In clinical practice, such biomarkers can provide complementary information to conventional disease markers, including clinical signs, spirometry and PC(20)methacholine or histamine. Consequently, biomarkers can aid to establish the diagnosis, in staging and monitoring of the disease activity/progression or in predicting or monitoring of a treatment response. Especially in (young) children, reliable, non-invasive biomarkers would be valuable. Apart from diagnostic purposes, biomarkers can also be used as (surrogate) markers to predict a (novel) drug's efficacy in target populations. Therefore, biomarkers are increasingly applied in early drug development. When implementing biomarkers in clinical practice or trials of asthma and allergic rhinitis, it is important to consider the heterogeneous nature of the inflammatory response which should direct the selection of adequate biomarkers. Some biomarker sampling techniques await further development and/or validation, and should therefore be applied as a "back up" of established biomarkers or methods. In addition, some biomarkers or sampling techniques are less suitable for (very young) children. Hence, on a case by case basis, a decision needs to be made what biomarker is adequate for the target population or purpose pursued. Future development of more sophisticated sampling methods and quantification techniques, such as--omics and biomedical imaging, will enable detection of adequate biomarkers for both clinical and research applications.

The effectiveness of calcitonin on chronic back pain and daily activities in postmenopausal women with osteoporosis.

The aim of this study was to investigate the effect of nasal calcitonin on chronic back pain and disability attributed to osteoporosis. The study design involved three groups of osteoporotic postmenopausal women suffering from chronic back pain. Group I consisted of 40 women with vertebral fractures, group II of 30 women with degenerative disorders and group III of 40 patients with non specific chronic back pain and without abnormality on plain X-rays. Pain intensity was measured using a numerical rating scale (NRS) and disability due to back pain was measured using the Oswestry disability questionnaire. The patients were randomly assigned to receive, for three months, either 200 IU intranasal salmon calcitonin and 1,000 mg of oral calcium daily (groups IA, IIA, IIIA) or 1,000 mg of oral calcium daily (groups IB, IIB, IIIB). Repeated measures ANOVA showed that there were no significant time, group or interaction effects for pain intensity and disability in any of the groups studied. Mean Oswestry and NRS scores were reduced during the follow-up period in the groups IA, IIIA, but the differences between the two time points were not statistically significant. Intranasal calcitonin has no effect on chronic back pain intensity and functional capacity of osteoporotic women regardless of the presence of fractures, degenerative disorders or chronic back pain of non-specific etiology.

Decreasing morbidity of childhood asthma by regular outpatient follow-up, in Crete.

AIM: There is evidence that the prevalence and morbidity of childhood asthma are increasing in many countries despite improvement of therapeutic regimens. We aimed to study possible changes in childhood asthma morbidity in Crete, Greece, by evaluating hospital admissions and emergency room visits for childhood asthma before and after 1-year regular follow-up at a special pediatric pulmonary out-patient clinic. METHODS: We followed-up 118 asthmatic children, aged 1-14 years, at a special pediatric pulmonary outpatient clinic. We evaluated the total number of hospital admissions due to asthma as well as asthma exacerbations during the 12 months before and 12 months after the regular follow-up care at the special pediatric pulmonary outpatient clinic. RESULTS: The total annual number of hospital admissions of the 118 children before and after the regular follow-up was 122 and 19, respectively (reduction of 84%). Similarly, the total number of asthma exacerbations was 771 before and 230 after the 1-year follow-up (reduction of 71%). CONCLUSION: These findings show that regular follow-up care of asthmatic children at a specialized pediatric pulmonary outpatient clinic considerably reduces the morbidity of childhood asthma, thus reducing hospital costs for asthma and improving the quality of life for asthmatic children and their families.

User friendliness aspects of home care telematics.

OBJECTIVES: Asthma is the most common chronic childhood disease with a high number of admissions and emergency room visits in pediatric hospitals. Treatment of asthmatic patients is best done by asthma specialists and requires the chronic use of prophylactic medications, additional treatment for acute exacerbations and regular check-ups. In Crete, a Greek island, there are many children with asthma who are not receiving care by an asthma specialist. The only specialty clinic for asthmatic children in Crete is in Heraklion, a city in the center of the island. We attempted to use telemedicine in order to reach and follow children with asthma who live in distant areas in Crete. METHODS: We set up a pilot telemedicine program with 10 asthmatic children already followed at the Specialty Clinic. Using teleconferencing techniques, we were able to obtain the medical history, examine the patients, educate them about the disease and adjust the treatment. RESULTS: The parents of patients accepted the telemedicine service with a percentage of 90% and showed a special interest in this new service. CONCLUSIONS: We conclude that telemedicine for asthmatic children performed by their specialist is feasible and accepted by the majority of patients.

Polyomyositis and myocarditis associated with acquired toxoplasmosis in an immunocompetent girl.

BACKGROUND: Acquired toxoplasmosis more frequently goes unrecognized. Immunocompetent adults and adolescents with primary infection are generally asymptomatic, but symptoms may include malaise, fever, and lymphadenopathy. By contrast, immunocompromised patients may experience severe manifestations including encephalitis and multisystem organ failure. CASE PRESENTATION: We report a case of polymyositis and myocarditis in a 13-year old immunocompetent girl with toxoplasmosis. The patient presented with proximal muscle weakness, dysphagia, palms and soles rash and elevated serum levels of muscle enzymes, with liver and myocardial involvement. The diagnosis of toxoplasmosis was confirmed by serology. The patient was treated with prednisolone and had an excellent outcome. During a follow-up period of four years no relapses occurred and antibody levels to the T. gondii significantly decreased. CONCLUSIONS: Although several previous cases of toxoplasmosis occuring in association with polymyositis have been described in the literature such a wide spectrum of acute toxoplasmosis is rather unusual in immunocompetent adolescents. The relationship between T. gondii and polymyositis remains obscure. Appropriate investigation should be performed in every case of polymyositis not only for the appropriate treatment but also for further elucidation of this relationship.

Viral infections in children undergoing hematopoietic stem cell transplant.

BACKGROUND: Although viral infection is a major clinical problem for hematopoietic stem cell transplant recipients, there are few large series reporting on these infections in the pediatric population. We performed a retrospective analysis of the impact of viral infections in this patient population in our center, managed by a uniform antiviral prophylaxis protocol. METHOD: We reviewed the medical records of consecutive children and adolescents who received hematopoietic stem cell transplantation at the Division of Pediatrics, The University of Texas M. D. Anderson Cancer Center in Houston, TX, from July, 1992 to August, 1996. RESULTS: During the study period there were 70 episodes of viral infections in 96 transplants. The viruses most commonly encountered were cytomegalovirus (24), varicella-zoster (21) and herpes simplex (10). Fifty of these episodes resulted in clinically apparent diseases, affecting 39 patients. The Kaplan-Meier estimated probability for the development of viral diseases was 62%. Ten percent of these patients died as a direct result of the infectious process, all within 4 months of transplant. Significant factors for development of viral disease were the development of acute graft-vs.-host disease and the duration of preengraftment neutropenia. CONCLUSIONS: Viruses are common pathogens after hematopoietic stem cell transplantation in the pediatric population. Despite routine antiviral prophylaxis the morbidity and mortality of viral infections remain high. Enhancement of immune recovery after hematopoietic stem cell transplantation together with the development of new classes of antiviral agents may impact the incidence and prognosis of viral infections in this setting.

Dapsone for Pneumocystis carinii prophylaxis in children undergoing bone marrow transplantation.

Children who undergo bone marrow transplantation (BMT) are at risk for Pneumocystis carinii pneumonia (PCP). Prophylaxis using trimethoprim/sulfamethoxazole (TMP/SMX) is highly effective but the incidence of adverse drug reactions is significant. We retrospectively reviewed 33 pediatric BMT (25 allogeneic and eight autologous) in whom dapsone was used for PCP prophylaxis because patients were unable to receive TMP/SMX. Dapsone was administered at 50 mg/m2 p.o. once a week from engraftment to 180 days post-autologous BMT, and to 1 year or throughout the duration of immunosuppressive treatment post-allogeneic BMT. With a total of 7268 patient days of dapsone prophylaxis and a median follow-up of 353 days post-BMT, no proven PCP was diagnosed. Sixteen cases of chest radiograph abnormalities were noted in this patient population but none was attributed to PCP. Dapsone was well tolerated by all children with no serious adverse effects; however, one patient developed Toxoplasma gondii encephalitis during dapsone prophylaxis. Dapsone warrants further evaluation as an alternative for PCP prophylaxis in pediatric BMT patients intolerant of TMP/SMX. Additional prophylaxis should be considered for patients at high risk for T. gondii encephalitis.

Reticuloendothelial clearance in cystic fibrosis and other inflammatory lung diseases.

To examine the possible pathophysiologic role of circulating immune complexes in patients with cystic fibrosis and other inflammatory lung diseases, we studied the reticuloendothelial clearance of IgG-sensitized autologous erythrocytes in 15 patients with cystic fibrosis, 6 with chronic obstructive lung disease not related to cystic fibrosis, 7 with immunodeficiencies, 5 with systemic lupus erythematosus, 4 who had previously undergone a splenectomy, and 10 normal subjects. Patients with chronic inflammation and recurrent infections (i.e., those with cystic fibrosis, chronic obstructive lung disease, and immunodeficiencies) had significantly faster clearance rates (P less than 0.05, less than 0.01, and less than 0.005, respectively) than normal subjects. In contrast, patients with systemic lupus erythematosus (a classic immune complex-mediated disease) and those who had undergone a splenectomy had delayed clearance. The accelerated reticuloendothelial clearance in patients with chronic inflammatory pulmonary disease associated with cystic fibrosis was similar to that observed in stimulated laboratory animals. The rapid clearance rate may account for the rareness of septicemia in such patients despite chronic, persistent local bacterial infection.

Human serum amyloid P component. cDNA isolation, complete sequence of pre-serum amyloid P component, and localization of the gene to chromosome 1.

Complementary DNA clones corresponding to the human serum amyloid P component (SAP) were isolated, and the complete nucleotide and derived amino acid sequence of preSAP was determined. PreSAP biosynthesis is directed by a 1.1-kilobase mRNA. Synthesis and postsynthetic processing of preSAP in Xenopus oocytes result in secretion of a protein with mobility similar to native purified SAP when analyzed by sodium dodecyl sulfate gel electrophoresis. The human SAP gene is on chromosome 1, probably closely linked to the gene for C-reactive protein which encodes the related acute phase reactant found in human plasma.

Syrian hamster female protein: analysis of female protein primary structure and gene expression.

The concentration in plasma of the female protein (FP) of the golden Syrian hamster is regulated by sex steroids and by mediators of the acute-phase response to tissue injury or inflammation. A complementary DNA (cDNA) clone corresponding to FP was isolated from a hamster liver cDNA library and used to determine the nucleotide sequence and derived amino acid sequence of native FP. The primary sequence of FP is 69 percent identical to human serum amyloid P component and 50 percent identical to human C-reactive protein. Evidence showed that sex-limited and acute-phase control of the FP gene is pretranslational. The FP protein is thus a useful model for investigating dual regulation of expression of a single gene.

Anti-T cell antibody in juvenile rheumatoid arthritis.

One hundred-and-seven patients with juvenile rheumatoid arthritis (JRA) were studied for the presence or absence of an autoantibody in their sera directed against T cells. Using an indirect immunofluorescence technique on a fluorescence activated cell sorter, 71% of all patients were found to be positive on at least one sample. When studied according to the mode of onset of disease 75% of those with systemic onset, 70% with a pauciarticular, and 68% of those with a polyarticular onset were positive. Longitudinal studies appeared to suggest a correlation with disease activity, particularly in individual patients who were positive, while remission was almost invariably associated with negative testing for anti-T cell antibodies. These findings suggest that the anti-T cell antibody may be a useful diagnostic test in JRA and of benefit in monitoring disease activity and remission of disease.

Systemic lupus erythematosus in childhood: clinical manifestations and improved survival in fifty-five patients.

A retrospective review of 55 patients with systemic lupus erythematosus (SLE) (45 girls and 10 boys) under age 18 (median age of onset; 12.2 years) seen at the Children's Hospital Medical Center (Boston, Mass.) over the past 20 years was done. Clinical presentation was similar to previous series, but atypical presentation was common. Certain unusual presentations (such as isolated hematopoietic abnormalities) often occurred and delayed diagnosis for years in some cases. The frequency of ARA clinical classification of SLE was different in children as compared to adults. We observed depression of lymphocyte count in many patients and encountered elevations of hepatic enzyme levels in others. Of the 55 patients reviewed, 9 have died and 8 have been lost to follow-up. Of the rest, 21 have mild to moderate disease and 17 have inactive or minimally active SLE, after a median length of follow-up of 8.8 years. In severe cases, using either corticosteroids and/or cytotoxic agents, a favorable prognosis was obtained. Our cumulative 5- and 10-year survival of 92 and 85%, respectively, equals or exceeds that of previous reports of childhood SLE.

Autoantibody to an immunoregulatory inducer population in patients with juvenile rheumatoid arthritis.

The human inducer (T4(+)) and reciprocal cytotoxic/suppressor (T5(+)/T8(+)) subsets have been defined by monoclonal antibodies. In the present study, we examined the relationship of naturally occurring anti-T cell autoantibodies found in patients with active juvenile rheumatoid arthritis (JRA) to these subsets. In one approach, normal T cells were treated with anti-T4 or anti-T8 to eliminate the corresponding subset of cells and then analyzed for reactivity with JRA sera. It was found that JRA sera were reactive with only 15% of an enriched cytotoxic/suppressor population, whereas they reacted with 37% of an enriched inducer population. In reciprocal studies, JRA(+) T cells were eliminated with JRA sera and complement and the residual T cells (JRA(-)) reacted with monoclonal antibodies and indirect immunofluorescence on a fluorescence-activated cell sorter. As expected, the JRA sera and complement treatment of unfractionated T cells markedly diminished the T4(+) subset, whereas there was a concomitant increase in T cells reactive with anti-T5 and anti-T8. A similar diminution in T4(+) T cells was found in the circulating peripheral T cell compartment of patients with active JRA who possessed the JRA antibody. Functional studies demonstrated that removal of the JRA(+) population of T cells diminished phytohemagglutinin and soluble antigen proliferative responses, both of which were previously shown to be functions of T4(+) T cells. More importantly, in the absence of JRA(+) T cells, pokeweed mitogen-stimulated immunoglobulin production was markedly enhanced, despite the concomitant increase in T5(+)/T8(+) cytotoxic/suppressor cells. These results suggest that the JRA serum may define a Qal-like antigen found predominantly on the human inducer population which could activate suppressor and/or other feedback regulatory cells.