Effect of adenoidectomy on respiratory function: a randomised prospective study.

OBJECTIVE: Risk of childhood asthma is increased in children with recurrent otitis media. This may be associated with recurrent respiratory tract infections in these children, but the role of adenoidectomy, a frequent operation during childhood, is unknown. Therefore, the role of adenoidectomy in the development of atopy and respiratory function changes characteristic of asthma was evaluated. DESIGN: Randomised controlled study. SETTING: Tertiary care centre. PATIENTS: 166 children aged 12-48 months who had recurrent or persistent otitis media and who were followed-up for 3 years after randomisation. INTERVENTION: Randomisation to undergo insertion of tympanostomy tubes with or without adenoidectomy. MAIN OUTCOME MEASURES: The primary outcome measure was exercise-induced bronchoconstriction as evaluated by impulse oscillometry. The secondary outcome measures were bronchial inflammation as evaluated by exhaled nitric oxide and atopy as evaluated by skin prick tests. During the 3-year follow-up period otitis media episodes were documented in patient diaries. RESULTS: Adenoidectomy did not significantly influence baseline lung function, exercise-induced bronchoconstriction, exhaled nitric oxide concentration, the development of positive skin prick tests, or doctor-diagnosed asthma. Adenoidectomy did not significantly prevent otitis media. Recurrent otitis media (>or=4 episodes) during the first follow-up year was associated with an abnormal exercise-induced bronchoconstriction (OR 6.62, 95% CI 1.27 to 34) and an elevated exhaled nitric oxide concentration (OR 3.26, 95% CI 0.98 to 10.8) regardless of adenoidectomy. CONCLUSIONS: Adenoidectomy did not promote asthma or allergy. Recurrent respiratory tract infections during early childhood are associated with the risk of bronchial hyper-reactivity.

Human primary adenotonsillar naïve phenotype CD45RA CD4 T lymphocytes undergo apoptosis upon stimulation with a high concentration of CD3 antibody.

Young children need to develop immune tolerance to harmless foreign antigens such as digested nutrients and various inhaled airborne antigens. Because of its anatomical location, pharyngeal adenotonsillar tissue is a potential site for the establishment of this immune tolerance. To characterize possible mechanisms of peripheral immune tolerance, we studied human primary adenotonsillar naïve phenotype CD45RA(+) CD4(+) T cells, which represent cells that have not previously encountered foreign antigens. It was found that these CD45RA(+) CD4(+) T cells expressed higher levels of the activation marker CD69 as compared with peripheral blood CD45RA(+) CD4(+) T cells. Upon stimulation with a high concentration of CD3 antibody, which mimics the encounter of a high antigen dose, adenotonsillar CD45RA(+) CD4(+) T lymphocytes, but not peripheral blood CD45RA(+) CD4(+) T cells, underwent apoptosis. After 6 h stimulation with a high concentration of CD3 antibody, over 25% of the cells were apoptotic. Interfering with the Fas-FasL interaction with recombinant Fas or an antibody against Fas-ligand partially inhibited apoptosis. Our study results suggest that high concentrations of antigens, such as various nutrients and airborne antigens, may induce peripheral immune tolerance by selectively deleting naïve phenotype CD45RA(+) CD4(+) T cells via T-cell receptor-triggered apoptosis in human adenotonsillar tissue.

Analysis of risk factors for childhood persistent middle ear effusion.

Although exposure to infectious agents and parental smoking are known to influence the overall risk of otitis media, these risk factors do not appear to be linked with the tendency to develop chronic otitis media with effusion (COME) instead of recurrent acute otitis media (RAOM). The genetic inflammatory response type of the child appears to influence the risk of persistent middle ear effusion in COME. Two different clinical presentations of childhood otitis media are encountered: RAOM; and COME, which is associated with persistent effusion in the middle ear. The objective of this study was to assess putative factors that may regulate the development of persistent middle ear effusion in COME. In total, 159 children with RAOM and their parents (n=304), and 55 children with COME and their parents (n=110) were evaluated. All the children with COME or RAOM were aged <4 years. There was no difference in the frequency of attendance at day care outside the home, number of siblings or parental smoking between children with RAOM and those with COME. The frequency of parental allergy and asthma was lower among children with COME than those with RAOM.

Platelet endothelial cell adhesion molecule-1 is expressed in adenoidal crypt epithelial cells.

The adenoidal epithelial crypt is a potential site of antigen transport from pharyngeal lumen to adenoidal tissue. The base of the crypt is consistently infiltrated with leucocytes, forming a reticular lymphoepithelial structure. To evaluate mechanisms that possibly mediate leucocyte infiltration, expressions of leucocyte adhesion molecules, such as platelet endothelial cell adhesion molecule-1 (PECAM-1) (CD31), vascular cell adhesion molecule-1 (VCAM-1) (CD106) and intercellular adhesion molecule-1 (ICAM-1) (CD54), were studied in the adenoidal epithelial crypt. Epithelial cells in the outer opening of the adenoidal crypt were positive for VCAM-1, whereas epithelial cells at the base of the crypt were positive for PECAM-1. Isolated ICAM-1-expressing cells were found throughout the epithelial crypt. Double immunofluorescence staining revealed that the epithelial cells positive for PECAM-1 or VCAM-1 were positive for cytokeratin. The expression of PECAM-1 in the base and VCAM-1 at the orifice of the adenoidal epithelial crypt implies that the base and the orifice of the crypt have a distinct ability to recruit leucocytes. Epithelial cells expressing PECAM-1 may have a role in the formation of the reticular lymphoepithelial structure in the epithelial crypt.

Genoprevalence in human tissues of TT-virus genotype 6.

TT virus (TTV) is a newly discovered human virus of high genotypic diversity. TTV is widely distributed among humans, but the possible genotype-related differences in TTV biology are not well known. The prevalence and amount of TTV-DNA, especially of genotype 6, was determined by nested-PCR in various human tissues, and human parvovirus B19, another ssDNA virus, was used as a reference. TTV DNA was detected simultaneously in bile, peripheral blood mononuclear cells (PBMC) and plasma of 77% subjects, in 38% skin samples, in 38% synovial samples and in all (100%) adenoids, tonsils and liver samples. The relative concentrations of TTV-DNA did not vary significantly among the different samples. Genotype 6 TTV-DNA was detected in bile and plasma of one subject (3%), in skin and serum of one subject (8%) and in one liver (5%). The overall prevalence of TTV genotype 6 was 4% in subjects and 4% in sera. TTV genotype 6 was shown to occur in human tissues with no obvious tissue-type or symptom specificity. Parvovirus B19 DNA was detected overall in 38% subjects, and bile was the only sample type tested that did not persistently harbour B19 DNA.

High incidence of PTLD after non-T-cell-depleted allogeneic haematopoietic stem cell transplantation as a consequence of intensive immunosuppressive treatment.

The occurrence of post-transplant lymphoproliferative disorder (PTLD) in relation to immunosuppressive treatment was determined in 257 patients treated with non-T-cell-depleted allogeneic stem cell transplantation from an HLA-matched sibling (173 patients) or unrelated donor (84 patients). The conditioning consisted of total body irradiation and cyclophosphamide (myeloablative conditioning, 250 patients), or fludarabine combined with cyclophosphamide or a single 2 Gy dose of TBI (nonmyeloablative conditioning, seven patients). In transplantations from an unrelated donor, the patients also received antithymocyte globulin (ATG). The prophylaxis against graft-versus-host disease (GVHD) consisted of cyclosporine A, methotrexate, and methylprednisolone. The autopsy reports of deceased patients were systematically reviewed, and the autopsy materials of cases suggestive of PTLD were re-examined histologically for Epstein-Barr virus (EBV). Nineteen patients with EBV-positive PTLD were identified, of whom six had been transplanted from a sibling donor and 13 from an unrelated donor. All the patients who developed PTLD had been given ATG either for the treatment of steroid-resistant acute GVHD (all PTLD patients with a sibling donor and one with an unrelated donor), or as part of the conditioning (all patients with an unrelated donor). In conclusion, in transplantations from an HLA-identical donor with a non-T-cell-depleted graft, the risk of PTLD correlated strongly with the intensity of the immunosuppressive treatment.

Malignancies after heart transplantation: presence of Epstein-Barr virus and cytomegalovirus.

The presence of Epstein-Barr virus (EBV), human papilloma virus (HPV), and cytomegalovirus (CMV) was studied in 20 patients who developed malignancies after heart transplantation in the Helsinki University Central Hospital. The tumors were analyzed for the presence of HPV by polymerase chain reaction and for EBV by in situ hybridization. Clinical CMV infection was verified by immunochemical quantitation of CMV antigen in peripheral blood cells. HPV was detected in one of the eight epithelial malignant tumors studied. Three of the six lymphomas were positive for EBV. Two (67%) of 3 patients with EBV-positive lymphomas and one (33%) of the other three lymphomas but only 2 (14%) of 14 patients who developed other malignancies had a history of a manifest post-transplantation CMV infection prior to the development of malignancy. These results confirm the presence of EBV in lymphomas of heart transplant recipients and suggest that CMV might have a contributory role in the development of EBV-associated lymphomas.

Causes of tonsillar disease and frequency of tonsillectomy operations.

OBJECTIVE: To characterize the factors that influence the frequency of tonsillectomy and adenoidectomy operations. DESIGN AND SETTING: Nationwide questionnaire. Analysis of patients undergoing tonsillectomy or adenoidectomy at Helsinki University Central Hospital, Helsinki, Finland. PARTICIPANTS: Four hundred eighty-three of 819 individuals randomly selected from the Finnish National Public Registry. Two thousand two hundred thirty-one individuals younger than 30 years who underwent tonsillectomy (888 patients), adenotonsillectomy (294 patients), or adenoidectomy (1049 patients) at Helsinki University Central Hospital from January 1, 1997, through December 31, 1998. MAIN OUTCOME MEASURES: Age of the individual at the time of operation. Indication for the operation. RESULTS: The frequency of adenoidectomies was 24% (116 persons) and that of tonsillectomies 8% (39 persons) among the 483 individuals who returned the questionnaire. The frequency of tonsillectomy operations by age was multimodal; the frequency of tonsillectomies increased in preschool-aged children, declined thereafter, and increased again in teenagers. Tonsillar hyperplasia was the most frequent among children younger than 10 years, peritonsillar abscesses among teenagers, and chronic tonsillitis among individuals older than 20 years. The proportion of females was higher than males among teenaged patients. However, the cause and sex distribution could not explain the multimodality in the age-specific frequency. The age-specific frequency of tonsillectomies performed because of peritonsillar abscesses still followed a multimodal distribution. CONCLUSIONS: Factors relating to respiratory tract infections, maturation of the immune system, and the onset of puberty contribute to the cause of tonsillar disease. Distinct indications for tonsillectomy should be defined for preschool-aged children, teenagers, and individuals older than 20 years.

Stimulation of adenoidal lymphocytes by Alloiococcus otitidis.

Otitis media with effusion (OME) is characterized by persistent effusion in the middle ear cavity and by chronic inflammation in the middle ear mucosa. Alloiococcus otitidis, a gram-positive aerobic bacterium, has been isolated in middle ear effusion, and by means of sensitive polymerase chain reaction detection assays it has been detected in as many as 20% of middle ear aspirates of patients with OME. Because A otitidis may freely interact with leukocytes in the middle ear effusion, it may potentially modulate the inflammatory reaction in OME. To study the nature of these interactions, we applied an in vitro assay in which killed A otitidis bacteria were incubated with peripheral blood and adenoidal mononuclear cells. The expression of the proliferation-associated surface marker CD69 was then measured in B lymphocytes and in CD4+ helper and CD8+ cytotoxic-suppressor T lymphocytes by means of multicolor flow cytometry. Alloiococcus otitidis induced the expression of CD69 in both peripheral blood and adenoidal T and B cells. Among the T cells, the cytotoxic-suppressor T lymphocytes were preferentially activated. It was also tested whether A otitidis would have an effect in another cytotoxic and immunoregulatory system, namely, the induction of natural killer cell activity in peripheral blood mononuclear cells. However, the effect was minimal compared with that of Salmonella minnesota or Staphylococcus aureus. The results show that A otitidis has a unique immunostimulatory capacity in vitro that is mainly confined to CD8+ T lymphocytes.

Adenoids provide a microenvironment for the generation of CD4(+), CD45RO(+), L-selectin(-), CXCR4(+), CCR5(+) T lymphocytes, a lymphocyte phenotype found in the middle ear effusion.

Adenoidectomy in children with otitis media with effusion reduces inflammation in the middle ear by an unknown mechanism. Potentially, the adenoids of these children may serve as a site for the differentiation of lymphocytes, which after entering blood circulation eventually extravasate in the middle ear mucosa and thereby contribute to excessive inflammation. During lymphocyte extravasation various adhesion molecules and chemokines play a crucial role. To evaluate possible connections between the adenoids and middle ear inflammation, the expression of the chemokine receptors CXCR4 and CCR5 and the lymphocyte homing receptor L-selectin were analyzed in adenoidal and middle ear lymphocytes. It was found that most CD4(+) T lymphocytes in the middle ear effusion express the memory phenotype marker CD45RO and the chemokine receptors CXCR4 and CCR5, but are negative for the lymphocyte homing receptor L-selectin. This cell phenotype was rare in peripheral blood but was found much more frequently in the adenoids. The results suggest that the adenoids provide a microenvironment for the generation for CD4(+), CD45RO(+), L-selectin(-), CXCR4(+) and CCR5(+) T lymphocytes. Further, these cells may include cells that have the capacity to home to the middle ear mucosa. As the adenoidal CD4(+) memory phenotype CD45RO(+) T cells expressed the activation antigen CD69 and included cells expressing the HIV co-receptors CXCR4 and CCR5 at a high level, they may be permissive for HIV infection.

Life-threatening Mycoplasma hominis mediastinitis.

Mycoplasma hominis infections are easily missed because conventional methods for bacterial detection may fail. Here, 8 cases of septic mediastinitis due to M. hominis are reported and reviewed in the context of previously reported cases of mediastinitis, sternum wound infection, pleuritis, or pericarditis caused by M. hominis. All 8 patients had a predisposing initial condition related to poor cardiorespiratory function, aspiration, or complications related to coronary artery surgery or other thoracic surgeries. Mediastinitis was associated with purulent pleural effusion and acute septic symptoms requiring inotropic medication and ventilatory support. Later, the patients had a tendency for indolent chronic courses with pleuritis, pericarditis, or open sternal wounds that lasted for several months. M. hominis infections may also present as mild sternum wound infection or as chronic local pericarditis or pleuritis without septic mediastinitis. Treatment includes surgical drainage and debridement. Antibiotics effective against M. hominis should be considered when treating mediastinitis of unknown etiology.

Thoracic duct cyst: a case report and review of 29 cases.

Cysts of the thoracic duct are rare. We report a case of a cervical thoracic duct cyst and review 29 thoracic duct cysts reported previously (19 mediastinal, 9 cervical, and 1 abdominal). The mean age of the patients was 47.6 years (range 17 to 86 years). Fourteen (46.7%) of the patients were asymptomatic. When symptoms were present, they ranged from retrosternal pain, dysphagia, and dyspnea to respiratory insufficiency and superior vena cava compression. Diagnosis of the cyst can be made after computed tomography or ultrasonography. The cystic fluid contains T lymphocytes and triglycerides in excess. The symptoms in a patient with a thoracic duct cyst are related to compression of adjacent structures. The most profound symptoms are likely to be produced by mediastinal cysts above the aortic arch. Treatment consists of surgical removal of the cyst and ligation of all lymphatics connected to the cyst.

Familial occurrence of abdominal aortic aneurysm.

BACKGROUND: A family history of abdominal aortic aneurysm has been reported to increase the risk for developing the disease. OBJECTIVE: To determine the risk for abdominal aortic aneurysm in first-degree relatives of patients with the disease. DESIGN: Cross-sectional ultrasonographic screening study. SETTING: University Central Hospital, Helsinki, Finland. PATIENTS: 238 of 325 living first-degree relatives of patients having surgery for abdominal aortic aneurysm (age > 50 years; 98 men and 110 women) and 281 controls (135 men and 149 women) without a family history of abdominal aortic aneurysm. MEASUREMENTS: Ultrasonography was used to measure aortic diameter in 101 male relatives and 140 female relatives (241 of the 325 persons at risk [74%]) and in 281 controls. RESULTS: Three siblings had already undergone surgery for abdominal aortic aneurysm. Eleven siblings (all brothers) (11 of 101 [10.9%]) had ultrasonographic evidence of abdominal aortic aneurysm (aortic diameter > 30 mm). In the control group, 2 men (1.5%) and 2 women (1.3%) had an aneurysm. Thirty siblings and no controls had dilatation of the abdominal aorta (aortic diameter, 20 to 29 mm). Neither the age nor the sex of the proband affected risk for developing abdominal aortic aneurysm among first-degree relatives. Family history increased the risk for an aneurysm by 4.33-fold (95% CI, 1.32-fold to 14.23-fold), male sex increased the risk by 12.21-fold (CI, 2.63-fold to 56.64-fold), and age (by decade) increased the risk by 1.93-fold (CI, 1.15-fold to 3.25-fold). CONCLUSION: Aging brothers of patients with known abdominal aortic aneurysm have the highest risk for developing the disease; the prevalence of the disease in siblings older than 60 years of age is 18%.

Differentiation of T lymphocytes in the human adenoid as measured by the expression of CD45 isoforms.

Encounter of antigen by T lymphocyte on antigen-presenting cells results in changes in the expression of several cell surface molecules, including the abundant cell surface glycoprotein CD45. We have characterized the expression of the CD45 isoforms CD45RA and CD45RO in CD4+ and CD8+ T lymphocytes in the adenoids and peripheral blood of young children. We found that the relative proportions of CD45RA-,CD45RO+ antigen-experienced T cells was higher in the adenoids than in peripheral blood, and that the proportion of naive or resting CD45RA+,CD45RO- T cells was lower in the adenoids than in peripheral blood. The frequency of bright double-positive CD45RA+,CD45RO+ T cells, which represent cells in transition from the CD45RA+ to CD45RO+ phenotype, was higher in the adenoids than in peripheral blood. The frequency of another double-positive cell population, but with unknown ontogeny, expressing both CD45RA and CD45RO at a low level, was higher in peripheral blood than in adenoidal T cells. It was found that the frequency of adenoidal antigen-experienced CD45RA-,CD45RO+ T lymphocytes increased with increasing age of the child. These results are consistent with the model that the adenoids serve as a site for conversion of CD45RA+ to CD45RO+ T lymphocytes, and that the maturation of the immune system in young children is associated with phenotypic changes in T lymphocytes residing in secondary lymphoid organs.

Age-associated changes in the cellular composition of the human adenoid.

Histological investigations suggest that the size and number of lymphoid follicles of the adenoids and tonsils decrease during ageing. The mechanisms underlying the histological changes are unknown. The authors have analysed the frequency of lymphocyte subpopulations in the adenoids by flow cytometry. The proportion of B lymphocytes decreased and the proportion of T lymphocytes of all mononuclear cells increased with age. Of all B lymphocytes the proportion of CD38+, surface IgD- B lymphocytes representing the germinal centre cell phenotype, decreased and the proportion of CD38-, IgD- B lymphocytes representing the mature B lymphocyte phenotype, increased with age. The expression of CD23, a cell surface molecule associated with activation of follicular mantle IgD+ B lymphocytes, did not change with increasing age. The results imply that the involution of the adenoid is associated with a decreased germinal centre reaction and relative accumulation of mature B cells in the adenoidal tissue, as analysed by three-colour flow cytometry.

B- and T-lymphocyte subpopulations in the adenoids of children with otitis media.

Adenoid hyperplasia is connected with the pathogenesis of otitis media in children, as implicated by the residence of pathogens causing otitis media in adenoids, and by the beneficial effect of adenoidectomy. We have quantitated the proportions of certain T- and B-lymphocyte subsets in the adenoids by three-color flow cytometry. Three groups were studied: 1) children with persistent effusion in the middle ear (pOME), 2) children with recurrent otitis media with no effusion in the middle ear at the time of surgery (rAOM), and 3) children with adenoid hyperplasia without otitis media (AH) presenting either with snoring or upper respiratory tract infections. B lymphocytes comprised on average 64, 66 and 58% of all mononuclear cells in the respective patient groups. The majority of the B lymphocytes were of the follicular mantle zone phenotype expressing surface IgD (on average 69, 67 and 70% of all B lymphocytes in the respective patient groups). Almost one third of the B lymphocytes were of the germinal center cell phenotype, expressing CD38 but negative for surface IgD (on average 29, 30 and 25% in the respective patient groups). CD3+ T lymphocytes comprised 33, 33 and 40%, respectively, of all mononuclear cells, and the average CD4+/CD8+ ratio was 5.2, 4.9 and 5.7, respectively. No statistically significant differences between the patient groups were seen in these T- and B-lymphocyte subpopulations. These results suggest that the relative sizes of the germinal center, follicular mantle and interfollicular compartments of the adenoids do not correlate with the disease status of the middle ear cavity.

Extensive allelic sequence variation in the J region of the human immunoglobulin heavy chain gene locus.

During the initial stages of B lymphocyte differentiation heavy chain variable (VH), diversity (DH) and joining (JH) gene segments recombine to form a functional heavy chain variable region (VDJ) gene. Evidence for genetic polymorphism of the human JH gene segments has been obtained from mature rearranged VDJ sequences. We conducted an analysis of the published rearranged JH gene sequences and found that the JH alleles present in the two published germ-line JH region sequences were rare (approx. 2%) in the rearranged sequences. As an attempt to explain this discrepancy a 2.5-kb strech of DNA containing all the six heavy chain JH region genes and the most 3' DH gene segment, DHQ52, was amplified by the polymerase chain reaction from 39 individuals and analyzed for restriction fragment length polymorphism. Five new JH region haplotypes were found and sequenced. These new haplotypes contained the coding segment alleles that were frequent in antibody genes. Surprisingly, a high number of interallelic differencies in the non-coding sequence was found between the new and the two previously published haplotypes implying that the haplotypes had been separated early in evolution. In this respect the JH locus resembles HLA loci.

Down-regulation of monocytic VLA-4 leads to a decreased adhesion to VCAM-1.

The alpha 4 beta 1 integrin VLA-4 is expressed on practically all leukocytes, except on mature granulocytes. Here we show that in vitro treatment of monocytic cells with phorbol-12-myristate-13-acetate (PMA) leads to a selective decrease in the VLA-4 alpha-chain expression, both at the RNA and protein level. Meanwhile the expression of beta 1 and that of alpha 5, another alpha-chain associating with beta 1, was seen to increase. The decrease of alpha 4 expression was restricted to monocytic cells, and was not observed on other VLA-4-positive cells tested (MOLT-4 T cells and HOS sarcoma cells). The down-regulation of the VLA-4 alpha-chain was followed by a decreased binding capacity of the cells to recombinant VCAM-1. This data indicates that while previous findings show that the integrin-dependent adhesion may rapidly be regulated by altering the avidity of the interacting molecules, their quantitative modulation also has a clear impact on adhesion.

TNF alpha-induced expression of endothelial adhesion molecules, ICAM-1 and VCAM-1, is linked to protein kinase C activation.

The role of protein kinase C (PKC) in TNF alpha-induced activation of endothelial adhesion molecules ICAM-1 and VCAM-1 was analysed. Phorbol myristate acetate, which is known to activate PKC, was able to mimic TNF alpha-induced up-regulation of ICAM-1 and partly also VCAM-1 expression. Similarly a PKC inhibitor, H7, but not another kinase inhibitor, HA1004, inhibited TNF alpha-induced enhancement of ICAM-1 expression at both the mRNA and the protein level. Moreover we were able to measure a transient PKC activation peak at 16 min after TNF alpha induction in endothelial cells analysed by phorbol-dibutyrate binding. These results indicate that the TNF alpha-induced effect on the regulation of endothelial adhesion molecule expression is at least partly mediated by PKC activation.