Possible Role of Streptococcus pyogenes in Mucocutaneous Lymph Node Syndrome VII. A Weak Response to Epstein-Barr Viral Capsid Antigen in Mice Infected Neonatally with S. pyogenes

A negligible, if not entirely negative, production of antibody to Epstein-Bart virus(EBV)-associated antigens in patients with mucocutaneous lymph node syndrome(MCLS) has been a perplexing problem for investigators who are in favor of a streptococcal etiology of the disease. In the present investigations, antibody formation to EB viral capsid antigen (VCA) was assessed by the use of the indirect immunofluorescence technique in mice which had been subjected to neonatal infection with an attenuated strain of Streprococcus pyogenes or inoculation with either heat-killed streptococci or streptolysin-O, both of which were emulsified in Freund's complete adjuvant (FCA). Each mouse of these groups was inoculated 30 days or so later with EBV dilution in FCA, blood was collected about three weeks after virus infection, and antibody titers were assessed individually. According to the results of these experiments, no apparent difference was detected among the mice, irrespective of the methods of their neonatal treatment concerning their refractoriness to EB-VCA; the majority of the animals showed titers of less than 1:8, no case having a titer above 1:30. In contrast, all sera from control mice yielded positive responses showing antibody titers of 1:250 and over. Such an immunological character is an exact counterpart of that of MCLS patients. Accordingly, the recent research focus on EBV as a possible etiological agent of MCLS seems to be too restrictive.     

Possible Role of Streptococcus pyogenes in Mucocutaneous Lymph Node Syndrome. IV Immunological Tolerance Following Exposure of Neonatal Mice to Live Attenuated Strains of Streptococcus pyogenes

The absence of seroconversion to streptolysin O in convalescent patients with mucocutaneous lymph node syndrome has been a perplexing problem for investigators who are in favor of a streptococcal etiology of the disease. In the present studies, mice subjected in the newborn period to an infection with a strain of Streptococcus pyogenes, which fails to confer cellular immuno-responsiveness even in adult mice, and then reinfected four to six weeks later with another strain of the same species, which has an intrinsic ability to render mature murine hosts sensitive to streptococcal antigens, expressed an enhanced cell-mediated immunity coupled with a lack of humoral responsiveness to the same antigens. Such immunological characters are an exact counterpart of those of MCLS patients. The involvement of these immunological characters in the pathological process of the disease is discussed.     

Possible Role of Streptococcus Pyogenes in Mucocutaneous Lymph Node Syndrome

Migration inhibitory factor (M1F)-induced activity of patients with mucocutaneous lymph node syndrome (MCLS) to antigens associated with Streptococcus pyogenes infection was compared to that of control populations consisting of children with illnesses not related to streptococcal infections (group A), and of patients with streptococcal pharyngitis (group B), with the following results. 1. Though a consiaerable number of patients in the acute state of MCLS failed to respond to antigens consisting of (1) a coccus preparation of S. pyogenes (Picibanil), (2) streptococcal pyrogenic exotoxin (SPE) and (3) an extract from cells of a virally transformed human B-cell line, a complete restoration of their responsiveness was observed in parallel with the decrease of fever. 2. While almost all patients of group A were refractory not only to Picibanil and SPE but also to the extract from the transformed human cells, some children with infections due to intracellular microbes showed responsiveness to the extract from the transformed cells. 3. In group B, some patients showed a marked responsiveness and the other a complete refractoriness to these antigens throughout the observation period. These results raise the possibility that S. pyogenes may play a principal role in the pathogenesis of MCLS.     

Possible polyclonal B cell activation in mucocutaneous lymph node syndrome

Immunoserological studies on polyclonal B cell activation were carried out on 39 patients with mucocutaneous lymph node syndrome (MCLS) and in age-matched healthy individuals. The incidence of anti-mite, P. acnes (Kato) and EB virus antibodies, recently proposed as aetiological agents by some investigators, was increased in the patient group. Serum immunoglobulin (Ig) M level and IgM-anti-dinitrophenyl (DNP) antibodies, which are considered to be parameters of polyclonal B cell activation, were determined in MCLS cases. The level of serum IgM in MCLS was significantly elevated (0.02<P<0.05). Levels of anti-DNP antibodies in seven cases of MCLS (18%) were significantly higher than those of the controls (P<0.01). Nine of the ten pair sera in MCLS showed a stage-dependent decrease in anti-DNP antibodies. These results suggest that polyclonal B cell activation occurs in MCLS.Abbreviations MCLS mucocutaneous lymph node syndrome - P. acnes Propionibacterium acnes - EB virus Epstein-Barr virus - D. farinae Dermatophagoides farinae - PBS phosphatebuffered saline - Ig immunoglobulin - RT room temperature - FITC fluorescein isothiocyanate - DNP dinitrophenyl - BSA bovine serum albumin - OD optical density     

Possible Role of Streptococcus Pyogenes in Mucocutaneous Lymph Node Syndrome. XII. Variable Responses of Platelets in MCLS Seem to Be Explainable by Streptococcal Pyrogenic Exotoxin

As a model system for mucocutaneous lymph node syndrome (MCLS), we have advocated and used mice which had been rendered tolerant to Streptococcus pyogenes-associated antigens by neonatal infection with group A fteta-hemolytic streptococci, because these mice have shown a variety of peculiar bioimmunological characteristics bearing a striking resemblance to those of MCLS patients. The results of our current investigations reaffirmed the reliability of the animal model by indicating that mice subjected to neonatal infection with 5. pyogenes , or inoculation with streptococcal pyrogenic exotoxin (SPE) in Freund's adjuvant, were perfect counterparts of patients with MCLS on account of their platelet activation and hyperaggregability in response to provocative treatment, which are familiar findings in this disease.     

Possible Role of Streptococcus pyogenes in Mucocutaneous Lymph Node Syndrome VI. Heightened Cellular Reactivity to Streptolysin-O in Mice Infected with S. pyogenes and in MCLS Patients

The present investigations were performed to determine, by using the macro-phage migration inhibition test (MIT), whether cell-mediated hypersensitivity to streptolysin-O (SLO) was developed in mice infected with Streptococcus pyogenes as well as in patients with mucocutaneous lymph node syndrome (MCLS), with the following results: 1. The splenic lymphocytes from murine hosts infected with B-346 op strain of S. pyogenes, which fails to induce cellular immunity in infected mice, showed a complete lack of responsiveness to SLO. In contrast, the mice infected with streptococci of Sv and S-43 strains, both of which possess an intrinsic activity of eliciting enhanced cellular hypersensitivity in the same species of animals, exhibited positive responses to the hemolysin from strep-tococcal culture supernatant. 2. Although a considerable number of MCLS patients in the acute phase of the illness failed to respond to SLO, a complete restoration of their responsiveness was observed in parallel with recovery from the acute illness. Conversely, all patients in the subacute phase of the disease reacted well in vitro to SLO, followed by a gradual decline of their responsiveness over a period of 1–2 weeks. Furthermore, the implications of these findings are discussed in association with the possible role of S. pyogenes as an etiological agent for MCLS.     

Are infantile periarteritis nodosa with coronary artery involvement and fatal mucocutaneous lymph node syndrome the same? Comparison of 20 patients from North America with patients from Hawaii and Japan.

We reviewed available clinical and pathologic autopsy material from 20 patients with infantile periarteritis nodosa with coronary artery involvement (IPN) from the continental United States, two Hawaiian patients with fatal mucocutaneous lymph node syndrome (MCLS; Kawasaki disease), and three patients with classical periarteritis nodosa (CPN). Comparison of the findings in patients with IPN and in patients with MCLS from Hawaii to material from patients with fatal MCLS from Japan showed no definite clinical reason to distinguish IPN from MCLS; neither gross nor microscopic features of the vascular lesions nor their pattern of distribution appears to warrant separation of IPN from fatal MCLS. CPN differs, both clinically and pathologically, from IPN/MCLS, and may well have a different etiology.     

传染性单核细胞增多症与皮肤黏膜淋巴结综合征的实验室检测对比分析

目的　分析传染性单核细胞增多症 (IM)和皮肤黏膜淋巴结综合征 (MCLS)的实验室检测结果 ,并对比分析 ,以明确二者的鉴别诊断要点 ,指导治疗。方法　收集我院近 10年住院IM患儿 2 2 5例 ,MCLS患儿 2 80例。实验室指标包括 :EB病毒 (EBV)抗体、嗜异凝集试验、外周血白细胞总数及分类、异形淋巴细胞、血小板计数等进行对比分析。结果　IM及MCLS患儿EBV抗体阳性率均高 ,无显著差异。嗜异凝集试验及异形淋巴细胞检查 ,阳性率差异甚大 ,IM患儿中可见明显增高。外周血白细胞总数均增高 ,MCLS白细胞分类以中性粒细胞升高更明显 ,而IM则以淋巴细胞升高明显 ;而血小板计数则以MCLS增高明显 ,且当白细胞总数趋于正常时血小板持续升高。结论　IM及MCLS病因似与EBV感染有连带关系 ,在实验室检查中各有特点 ,掌握其鉴别诊断要点 ,对早期明确诊断 ,指导治疗有重要意义     

Intrahepatic cholangitis associated with mucocutaneous lymph node syndrome

Although gallbladder hydrops occurs frequently in patients with mucocutaneous lymph node syndrome (MCLS), the etiology of the gallbladder lesion is unclear. Recently we performed a liver biopsy on a child with severe MCLS and demonstrated selective invasion of biliary ductular epithelial cells by polymorphonuclear leukocytes with sparing of the hepatocytes. The possible role of the selective destruction of biliary cells in the pathogenesis of biliary disease in MCLS is discussed.     

Acute chest syndrome of sickle cell disease: radiographic and clinical analysis of 70 cases

Background. Acute chest syndrome (ACS) is a pulmonary illness with fever, chest pain, leukocytosis and new pulmonary opacity in a patient with sickle cell disease. It is a common reason for hospitalization in sickle cell patients, and a significant cause of mortality. The etiology of ACS is unclear. Lung or bone infarction and infection, among other possible causes, have been proposed. Objective. We reviewed the chest radiographs and medical records of 41 patients with 70 episodes of ACS and correlated the clinical and radiographic courses in an attempt to better characterize and understand the syndrome. Results. In 87 % of episodes, no identifiable etiology of ACS was found. This group of patients had a median age of 14 years and showed dramatic clinical and radiographic improvement within 24 h of therapy. In the remainder of episodes (13 %), an identifiable etiology was found, usually bacterial pneumonia. These patients were younger than the group without an identifiable etiology (median age 2 years) and had a prolonged radiographic course of illness. Conclusion. The chest radiographs of children with ACS without an identifiable etiology have an extremely typical appearance and evolution. Only in cases which do not have this typical pattern should infection be suspected as the underlying cause. Received: 18 December 1995 Accepted: 7 February 1997     

Possible Role of Streptococcus pyogenes in Mucocutaneous Lymph Node Syndrome. V. Further Electron Microscopic Observations on Group A Beta-Hemolytic Streptococci Inoculated into Immune Mice

In the preceding studies, protoplast-like “spherical bodies” were detected electron microscopically in mice which were challenged intramuscularly, approximately 15 days before, with an attenuated strain of Streptococcus pyogenes. The “spherical bodies” were 0.5–1.5 Mm in diameter, poor in ultra-structural preservation of the cytoplasm, devoid of cell walls, and indistinguishable from those discovered in the buffy coat of peripheral blood from patients with mucocutaneous lymph node syndrome (MCLS). The present investigation was intended to elucidate the intracellular localization of the “spherical bodies” and to understand better the mechanisms responsible for the elimination of viable streptococci from the infected sites. Accordingly, a larger amount of bacterial inoculum was injected i.m. into mice immunized, in advance, against streptococcal infection, and every biopsy specimen was obtained on day 3 postchallenge. Subsequently, ingested “spherical bodies” were detected under an electron microscope in the cytoplasm of phagocytic cells, including polymorphonuclears, eosinophils and fibroblasts, situated in the perimysium.     

Tubuloreticular structures and parallel tubular arrays in the lymphocytes of children with aplastic anemia and acute febrile mucocutaneous lymph node syndrome: Electron microscopic observations

Tubuloreticular structure was found in 3 and 30% of the lymphoid cells from two consecutive cases of MCLS and in 10 and 15% of the lymphoid cells from two consecutive cases of aplastic anemia. Parallel tubular array was found in 8 and 24% of the lymphoid cells from the cases of MCLS and in 3% of the lymphoid cells from the cases of aplastic anemia. The possibility of the viral etiology of the both diseases was discussed. eases was discussed.     

The changes of interleukin-2, tumour necrotic factor and gamma-interferon production among patients with Kawasaki disease

Included in this study were 43 cases of mucocutaneous lymph node syndrome (MCLS or Kawasaki disease) treated solely with aspirin. Of these, 19 developed coronary aneurysm. Mononuclear cells (MNC) of these MCLS patients were collected weekly and stimulated either with phytohaemagglutinin (PHA) or PHA plus phorbol myristic acetate. The production of interleukin-2 (IL-2), tumour necrotic factor (TNF) and gamma-interferon (IFN-r) was determined. In addition, IL-2, TNF, IFN-r from serial collections of serum samples of these patients were also measured. The results show that serum IL-2 and TNF were detected in the 1st week, reached maximal plateau in the 2nd and 3rd week and decreased 1 month later. The production of IL-2, TNF and IFN-r from MCLS patients' MNC increased from the 1st to the 3rd week, persisted at a high level for 1 month and then decreased. During the 2nd and 3rd weeks, there were significantly higher serum IL-2 levels and IL-2 production in patients with than in patients without coronary lesions. These observations suggest that the serum IL-2 level and IL-2 production during the 2nd week may serve as a predictive parameter for coronary aneurysm formation. It also suggests that the production of TNF, IL-2 and IFN-r from MNC may contribute to the development of vascular injury in acute MCLS.     

Possible Role of Streptococcus pyogenes in Mucocutaneous Lymph Node Syndrome. XV. Potential Utility of Streptococcal Pyrogenic Exotoxin Toxoid for the Prophylaxis and Treatment of MCLS

Mice made tolerant to streptococcal pyrogenic exotoxin (SPE) by neonatal inoculation with SPE emulsified in incomplete Freund's adjuvant demonstrated early thrombocytopenia followed by thrombocytosis. This state is the perfect counterpart of patients with mucocutaneous lymph node syndrome (MCLS). We have hypothesized that by inducing tolerance to SPE, the biological activities of the toxin might play leading roles in the pathogenesis of MCLS. In the present investigations, the efficacy of SPE on the prophylaxis and treatment of diseases caused by Streptococcus pyogenes (including MCLS) were monitored using the murine model system accompanied with a platelet-counting technique. The mice, rendered tolerant due to neonatal SPE inoculation and followed by immunization with SPE toxoid about 1 month prior to the provocative injections with SPE, demonstrated an almost complete lack of response to the provocation, keeping platelet counts within the normal range of values (except for a marginally significant thrombocytosis 7 days postprovocation). Moreover, anti-SPE titers of the sera from the mice sacrificed on day 35, at which point the observation was terminated, were proved to be markedly elevated when compared with controls. These findings seem to suggest that immunization with the toxoid could overcome tolerance, resulting in the production of an antitoxin. In a second experiment that examined the effect of administration with rabbit antiserum raised against the toxoid, the antiserum-treated mice demonstrated a transitory thrombocytosis on 7 days postprovocation with SPE, followed by an abrupt decrease in the number of platelets from day 10 onward. Such a finding was in complete agreement with that observed in tolerant mice administered with antiserum specific for SPE, suggesting a strong neutralizing activity against SPE of the antitoxoid serum. A third experiment evaluated the effect of F(ab')₂ fragments of the rabbit antiserum to the toxoid on platelet activity. The tolerant mice passively administered i.v. with the F(ab')2 fractions demonstrated a complete lack of responsiveness, except for a small thrombocytosis on days 7 and 10.     

Clinical spectrum of acute abdominal pain in Turkish pediatric patients: A prospective study

Abstract Background : The aim of the present study was to determine the prevalence, associated symptoms, and clinical outcomes of children with acute abdominal pain who had been admitted to an emergency department. Methods : Children aged between 2 and 16 years who presented to the emergency department of Cerrahpa?a Medical School, Istanbul University between July 2001 and August 2002 with acute abdominal pain were enrolled in this study. A questionnaire was completed each patient admitted to our pediatric emergency unit for acute abdominal pain. Data collected included presenting signs and symptoms, the hospital follow up for all children who returned within 10 days, test results, and telephone follow up. Results : The number of children referred to the emergency department was 7442, with 399 (5.4%) of these having acute abdominal pain. The mean age of the study population was 6.9 ± 3.5 years, and 201 of the patients were male. The five most prevalent diagnoses were: (i) upper respiratory tract infection and/or complicated with otitis media or sinusitis (23.7%); (ii) abdominal pain with uncertain etiology (15.4%); (iii) gastroenteritis (15.4%); (iv) constipation (9.4%); and (v) urinary tract infection (8%). The most common associated symptoms were decreased appetite, fever and emesis. Because of follow‐up deficiency the progress of 28 patients was not obtained. Eighty‐two children were referred to the department of pediatric surgery, but only 17 of 82 (20.7%) required surgical intervention (15 of these 17 for appendicitis). Eleven patients returned within 10 days for re‐evaluation, but the initial diagnosis was not changed. The complaints of 57 patients with uncertain etiology were resolved within 2 days. Conclusions : An acute complaint of abdominal pain was usually attributed to a self‐limited disease. However, the percentage of surgical etiology is not negligible.     

Prevalence of Chlamydia pneumoniae in acute lower respiratory infection in the pediatric population in Japan

Chlamydia pneumoniae has been established as an important etiologic agent of acute respiratory tract infection in humans, especially in adults. However, there is little information available on C. pneumoniae infection in the pediatric age group. The microimmunofluorescence test and Chlamydia pneumoniae-specific polymerase chain reaction (PCR) method were applied to reveal the role of C. pneumoniae as an etiologic agent of acute lower respiratory tract infection in children in Japan. Among 136 patients aged between 2 months and 15 years with acute lower respiratory tract infection, five patients with pneumonia were found to have recent C. pneumoniae infection by the microimmunofluorescence test. C. pneumoniae-specific PCR products were detected from specimens of four patients among these five. Neither C. trachomatis nor C. psittaci infection was found in this population. These results suggest that C. pneumoniae is an important causative agent of acute childhood pneumonia and may be the most prevalent pathogen among the genus Chlamydia that causes acute lower respiratory disease in this age group in Japan.     

The Effect of Immunoglobulin on Immune Complexes in Patients with Kawasaki Disease (MCLS)

In mucocutaneous lymphnode syndrome (MCLS) IgG and IgM class immune complex (IC) showed peak levels on day 10 to 20 after the onset of the disease respectively, and a transient decrease in IgM class IC was detected at the beginning of intravenous high dose γ-globulin therapy (IHDGT). In in vitro examination, when γ-globulin was added to the serum samples of MCLS patients, IgG class IC increased while IgM class IC decreased. Consumption of complements was also observed in these samples. Disposition of IC in the reticuloendothelial system seemed easier by both binding of γ-globulin to IC and increasing complement bound to IC resulting in increasing complement-binding site. These results suggest that IHDGT is effective for the treatment of IC in MCLS. Sodium dodecyl sulfate-polyacrylamide gel electrophoresis (SDS-PAGE) revealed 14 bands from 300 K.D. to 42 K.D. in IC of MCLS patients in the acute phase of the disease and prior to treatment. The immunoblotting method revealed that IC contains IgG, IgM, IgE, IgA, Clq, C3, and C4.     

Shunt revision in hydrocephalus

Objective : A retrospective analysis of 50 hydrocephalic children having a minimum follow-up of 6 months was carried out to see their etiology, clinical features, complications, incidence of shunt revisions, outcome and the variation from their Western counterparts.Methods : Clinical features, image findings and treatment of all the cases were recorded from their discharge summaries. Record of shunt revision complications and outcome was maintained by the principal author. The data of all the cases were analyzed.Results : The age of children varied from 1 month to 12 yr (mean 2.2 yr). The most common etiology of hydrocephalus was aqueductal stenosis in 18 (36%) children. Post infective hydrocephalus, either of post-tubercular meningitis (TBM) or following bacterial meningitis, remained the cause in 15 children (30%). Congenital TORCH infection was responsible for 3 cases of hydrocephalus making infective etiology as the cause in 18 (36%) cases. Intra 4^th ventricular neurocysticercus cyst caused blockade of CSF pathway in 2 children. 15 out of 50 children required shunt revision, either due to infection (8,16%) or shunt obstruction (7, 14%). Multiple shunt revisions were required in 2 children only. These revisions were required due to infection, obstruction or malfunction of the shunt.Conclusions : Infective etiology is responsible for hydrocephalus in significant number of children (36%). The possibility of TORCH infection, as a cause of hydrocephalus should be considered even amongst the children of screened mothers during antenatal check-up. Pure intra 4^th ventricular neurocysticercus cysts (without intraparenchymal cyst), though rare, can manifest with outlet obstruction. Incidence of shunt revision using Chhabra’s medium pressure shunt is very high in children at an average follow up of 1.6 yr. Post infective hydrocephalus is a major cause of delayed milestones, contributing to mental retardation.     

An Immunological Study on Mucocutaneous Lymph Node Syndrome: Activation of Tg Suppressor Cells

We analyzed the lymphocyte function of MCLS in pokeweed mitogen-induced immunoglobulin production. T cell suppressor activity was activated in the acute phase adn normalized in convalescence. T cells showing suppressor activity in this system were identified to be Tg cells, and they seemed to be activated as suppressor by a certain factor in the serum. the sera of patients whose T cells showed suppressor activity could induce the suppresoor activity of normal control Tg cells. The suppressor inducing factor in sera is likely to be circulating immune complexes, since T_g cells usually show suppressor activity when they interact with immune complexes. The induction of the suppressor activity of Tg cells by immune complexes may provide a kind of negative feedback suppression mechanism feedback mechanism on the antibody formation and it may be related to the self-limiting characteristics of MCLS. MCLS is different from collagen diseases such as rheumatoid arthritis in that Tg cells do not usually work as suppressor cells in the later diseases.     

Ascites in ventriculoperitoneal shunt

Objective : To fetch out the factors responsible for ascites, following shunt CSF diversion in cases of intracarnial lesions. Four children developing ascites/abdominal psuedocyst following ventriculoperitoneal shunt were analyzed to see the factors responsible for such complication.Methods : Records of 4 cases developing ascites were studied retrospectively. These children developed ascites at 8 months, 6 months, 1 year and 1 year 2 months interval following their shunt installation.Resuts ;The primary etiology of hydrocephalus was demonstrated as thalamic glioblastoma, choroid plexus papillomas of third ventricle, post tubercular meningitis hydrocephalus and suprasellar craniopharyngioma.Conclusion: The proposed etiology of ascites in these cases was peritoneal metastasis from thalamic glioblastoma through ventriculoperitoneal shunt in first case, excessive production of CSF by choroid plexus papilloma in second, infection in the third case and craniopharyngioma causing excessive production of CSF in the fourth child. All the children were treated by reasonable laparotomy and fenestration of cyst along with the repositioning of shunt tip at another site.