Invasive meningococcal disease due to ciprofloxacin-resistant Neisseria meningitidis sequence type 4821: The first case in Japan.

We present a 4-year-old girl who developed invasive meningococcal disease (IMD) caused by Neisseria meningitidis serogroup C sequence type (ST)-4821. She was hospitalized due to fever, vomiting, rash and altered consciousness. Serogroup C N. meningitidis was isolated from blood culture taken on admission and was confirmed by matrix-assisted laser desorption ionization time-of-flight mass spectrometry, a biochemical test, and molecular microbiological analysis. The patient was successfully treated with 50 mg/kg ceftriaxone every 12 hours for 7 days without any complications. The isolate was susceptible to a wide variety of ß-lactams and rifampin but was resistant to ciprofloxacin. The isolate harbored gyrA T91I and parC S87I mutations at the quinolone-resistance-determining regions. Multi-locus sequence typing revealed the isolates as ST-4821, which was identical to an endemic clone frequently detected in China. However, neither the patient nor her family members had traveled abroad. To our knowledge, this report is the first to describe an IMD patient caused by ciprofloxacin-resistant N. meningitidis ST-4821 in Japan, and is the first community-acquired IMD case due to this strain outside of China. The high proportion of ciprofloxacin resistance and hypervirulent features of this ST-4821 strain raise special public health concerns. We still consider ciprofloxacin is still appropriate drug for post-exposure chemoprophylaxis in Japan. However, nationwide surveillance for susceptibility of IMD isolates is necessary to establish the regional antibiogram, and thereby to avoid chemoprophylaxis failure.

Long-term follow up of hospitalized pediatric anorexia nervosa restricting type.

BACKGROUND: Information on long-term follow up of childhood-onset anorexia nervosa is scarce. This study investigated long-term (>10 years) course, outcome and prognostic factors for hospitalized childhood-onset anorexia nervosa restricting type (ANR). METHODS: Forty-one ANR girls admitted to a single regional center participated. Median age at first admission was 13.3 years (range, 8.6-15.6 years). The longitudinal clinical course was retrospectively determined for a median follow-up period of 17.1 years (range, 10.4-21.1 years). We analyzed physical, psychological, and social variables to predict partial remission (PR) and full remission (FR). RESULTS: The completion rate of follow up >10 years was high at 97%. At final evaluation (n = 38), distribution of prognosis was as follows: FR, n = 27 (71%); PR, n = 6 (16%); and non-remission, n = 5 (13%). The cumulative ratio of PR and FR increased during the first 5-6 years, and gradually reached a plateau at around 10 years. More than 10 years after the onset, one patient eventually achieved FR, and one patient died. Seven patients were rehospitalized and two died due to suicide during the entire follow up. On multivariate analysis, family disorders/problems rating score was a significant predictor of PR and FR. CONCLUSIONS: This study included hospitalized ANR children aged ≤15 years, the youngest cohort ever reported. Long-term prognosis is generally favorable, but the mortality rate was 5%. Careful long-term follow up >10 years is needed to evaluate outcome of childhood-onset ANR, and family therapy is important in high-risk patients with family disorders/problems.

Neurogenic pulmonary edema combined with febrile seizures in early childhood-A report of two cases.

Neurogenic pulmonary edema (NPE) is a clinical entity that can occur following central nervous system disorders. However, NPE occurs quite rarely in early childhood, and there has only been one report about pediatric NPE associated with febrile seizures. Two cases are reported here. One case involved a 2-year-old girl who presented with febrile seizures, which rapidly progressed to severe NPE. Since the NPE occurred in the emergency department room, the patient was able to be resuscitated via immediate endotracheal intubation. The other case involved an 11-month-old boy who developed respiratory distress following a 50-min episode of febrile status epilepticus. Both patients required respiratory management in the intensive care unit. However their conditions were dramatically improved within several days and fully recovered without any sequelae.

[Invasive Campylobacter jejuni/coli Infections: 9 Case Reports at a Single Center between 2000 and 2015, and a Review of Literature Describing Japanese Patients].

There have been few coherent reports on extraintestinal infection or bacteremia caused by Campylobacter jejuni (C. jejuni) or C. coli in Japan. To clarify the clinical and microbiological characteristics of invasive infections caused by these two species, we retrospectively analyzed the records of patients from whom these pathogens had been isolated from sterile sites between 2000 and 2015. During this study period, we identified 9 patients. The clinical syndrome of all of these patients was bacteremia. Three patients had underlying diseases with both liver cirrhosis and malignant neoplasm, and all of these patients were aged 60 years or older. The remaining 6 patients were immunocompetent and younger than 40 years of age. All 9 patients had a fever of 38.5 degrees C or higher. The proportion of patients with gastrointestinal symptoms was lower for the 3 patients with underlying diseases, compared with the 6 patients without underlying diseases (1/3 cases vs, 4/6 cases). Of the 8 strains evaluated for antimicrobial susceptibility, all were susceptible to imipenem/cilastatin, kanamycin and erythromycin, and 2 were resistant to levofloxacin. Antimicrobial treatment was administered to 8 patients, but one spontaneously recovered without any treatment. We were able to follow the outcomes of 8 patients, and all of these patients completely recovered without relapses. We also reviewed 14 Japanese patients reported in the Japanese and English literature and found similar clinical features consisting of a high-grade fever and an association with underlying diseases and gastrointestinal symptoms. Of note, 3 agammaglobulinemic patients presented with bacteremia and extraintestinal infections and had multiple relapses. Based on the findings of our 9 cases and previous reports, the affected patients were divided into two groups according to clinical syndrome and therapeutic intervention. One group consisted of previously healthy children or young adults showing bacteremia. Most of them had enterocolitis complications but had a good prognosis. The other group consisted of patients with underlying diseases or elderly patients who presented with bacteremia alone or bacteremia with extraintestinal infections. The latter group, especially among those with humoral immunodeficiency, should be parentally treated with antimicrobial agents and requires careful monitoring for relapse. This is the largest case series study to examine invasive C. jejuni/coli infections in Japan, and it provides important epidemiological information on this rare infection.

[Invasive Infections Caused by Nontyphoidal Salmonella sp. in Childhood Clinical Features and Incidence Trends between 1994 and 2014].

Little is known about the clinical characteristics of invasive infections caused by nontyphoidal Salmonella sp. in childhood and the temporal changes of their incidence over a long period of time. In order to clarify these issues, we retrospectively analyzed the records of 17 such infected children admitted between August 1994 and December 2014 to our center. We divided the study period into the first (1994-1999), second (2000-2004), third (2005-2009), and fourth (2010-2014) periods. The ages of the 17 patients ranged from 2 days to 13 years. Clinical syndrome included bacteremia with enteritis (n = 13), followed by bacteremia or sepsis alone, (n = 2), osteomyelitis (n = 1), and meningitis (n = 1). The affected patient numbers in the first to fourth periods were 10, 5, 2, and 0, respectively, and the decreasing trend was significant (trend p < 0.001). This significant trend held up even after correction by the number of in-patients during each quarter period (trend p = 0.009). In the 14 cases of bacteremia with or without enteritis, excluding two neonatal cases and one case of osteomyelitis, most patients (n = 13, 93%) had WBC of <15,000/µL with a wide range of serum CRP levels (0.8-20.4mg/dL) on admission. Thus, it was very difficult to diagnose these bacteremia cases based on blood tests alone, and we needed to consider such risk factors of bacteremia as high fever, poor general condition, and younger age. O group serotypes of the isolates were as follows: O9 (n = 11), O7 (n = 5), and O4 (n = 1). Of the 15 strains evaluated, two strains were resistant to ampicillin and one each was resistant and intermediately resistant to fosfomycin. All strains were susceptible to cefotaxime, ofloxacin or levofloxacin, and trimethoprim-sulfamethoxazole. We were also presented with two rare cases : one involved sepsis due to vertical transmission and the other involved meningitis. The latter case had clinical relevance in that recurrence developed 3 weeks after treatment with susceptible antibiotics. In conclusion, this study is the first report on invasive infections caused by nontyphoidal Salmonella sp. in childhood in Japan, and provides important information on their clinical features and incidence trends over the last 20 years.

Successful treatment with allogenic hematopoietic stem cell transplantation of a severe congenital neutropenia patient harboring a novel ELANE mutation.

We report a 4-year-old boy with severe congenital neutropenia (SCN), who was successfully treated with hematopoietic stem cell transplantation (HSCT). The patient had frequently developed bacterial infections since 6 months of age, and showed severe neutropenia below 100/µl at 1 year and 4 months of age. The patient harbored a heterozygous missense mutation in ELANE exon 3 (p.Q73P, g.2253 A>C). This was a novel de novo mutation, and he was thus diagnosed as having SCN. Because of failure to respond to granulocyte colony-stimulating factor treatment and repeated admissions due to bacterial infections, allogeneic HSCT was performed from a serologically matched unrelated donor following the conditioning regimen: fludarabine/melphalan/anti-thymocyte globulin and a low dose of total body irradiation. Tacrolimus and a short course of methotrexate were used for graft-versus-host disease prophylaxis. Engraftment was achieved at day 12, and the patient maintained normal hematopoiesis for over 15 months after HSCT. We concluded that HSCT is a useful treatment for SCN patients, especially those who are at high risk for leukemic transformation. However, a larger number of SCN patients and longer follow-up are necessary to identify appropriate conditioning regimens and long-term prognosis.

Factors predictive of neonatal thrombocytopenia in pregnant women with immune thrombocytopenia.

To determine predictive factors for neonatal thrombocytopenia in deliveries with immune thrombocytopenia (ITP), we conducted a retrospective study at a tertiary hospital between 1997 and 2013. During this period, 30 women with ITP delivered 44 children. Neonatal thrombocytopenia (<100 × 10(9)/L) at birth was observed in seven neonates; four of these cases were severe (<50 × 10(9)/L). No cases were complicated by intracranial hemorrhage, and there was no neonatal mortality. Platelet counts at birth of neonates born to mothers, who had first been diagnosed with ITP during pregnancy were significantly higher than those born to mothers diagnosed with ITP before pregnancy. There were significant correlations between neonatal platelet counts in the first and second siblings at birth (P = 0.015) and at nadir (P = 0.035). Platelet counts of neonates born vaginally were significantly more likely to decline after birth than those delivered by cesarean section (13/16 vs. 10/23, P = 0.024). In conclusion, diagnosis of ITP before pregnancy was significantly associated with neonatal thrombocytopenia, and the platelet count of an older sibling is a strong predictor for that of the next baby. The delivery mode may be an indicator of the timing of platelet count nadir after birth.

Corynebacterium propinquum as the first cause of infective endocarditis in childhood.

We here present a 7-year-old girl with ventricular septum defect and ventriculoatrial communication, who developed infective endocarditis (IE) due to Corynebacterium propinquum in the tricuspid valve. The patient was admitted because of an 8-day history of fever. Transthoracic echocardiogram showed non-pedunculated vegetation on the septal leaflet of the tricuspid valve. Gram-positive coryneform bacteria grew from three consecutive sets of blood cultures taken on admission. C. propinquum was confirmed by 3 microbiological approaches; (i) biochemical testing using API Coryne panels, (ii) a sequence-based method using the 16S rRNA gene and partial rpoB sequencing, and (iii) matrix-assisted laser desorption ionization-time of flight mass spectrometry. The isolates were susceptible to a wide variety of ß-lactams and vancomycin. The patient was successfully treated with antimicrobial agents without surgical intervention. There have only been available of clinical details of two adult cases of invasive C. propinquum infections; one of which was presented as IE, and the other was pleuritis in a patient with lung cancer. To the best of our knowledge, this is the first report to describe C. propinquum as a cause of IE as well as that of invasive infections in a pediatric population. Multiple methods that reliably differentiated related species helped us to establish this rare organism. Our report expanded the clinical spectrum of C. propinquum infections.

[Ultra-late onset group B streptococcal disease--a report of two cases].

Group B Streptococcus (GBS) infection in infants aged over 90 days, known as ultra-late onset disease (ULOD), is extremely rare. We present 2 cases of ULOD and investigate etiology from both the host and microbiological aspects. Case 1, 99-day-old girl born in the late preterm, had a history of 6-hour fever. Bacterial meningitis was diagnosed and the patient was treated with intravenous ampicillin for 14 days. The isolate was serotype III GBS. Case 2, a 7-month-old girl with no medically significant history had an intermittent fever for 2 weeks before admission. Serotype Ia GBS was isolated from urine and blood, leading to a diagnosis of urosepsis. Intravenous cefotaxime was administered for 7 days. Both patients were discharged without any sequelae. We examined the host risk factors for ULOD development. (i) One subject had underlying preterm birth and the other had bilateral vesicoureteral reflux. (ii) Both had extremely low serum anti-serotype specific immunoglobulin levels, an important measure of protective immunity. The anti-type Ia antibody concentration was 0.24 microg/mL and the anti-type III IgG antibody concentration was 0.25 microg/mL. We employed multilocus sequence typing (MLST) to determine the genetic background of bacterial isolates. Sequence types (STs) of isolates were ST-335 (one allele variant of ST-19) and ST-23. ST-335 is an epidemic invasive GBS disease strain in Japan and is dominantly correlated with serotype III. ST-23 is highly associated with serotype Ia and is also a common invasive type in Europe, the United States and Japan. Our findings suggest that ULOD likely develops combined with underlying host disease, immunological factors and highly virulent strains. Continuous investigation of large numbers of cases is needed to better understand ULOD etiology.

[Seasonal changes of invasive pneumococcal disease in children and association with day care attendance].

To determine seasonal changes in the incidence of invasive pneumococcal disease (IPD) in children, we retrospectively analyzed 69 children with 72 episodes of IPD, admitted to a regional center in Kobe, Japan, between July 1994 and June 2011. IPD episodes involved occult bacteremia (n = 48), pneumonia (n = 10), meningitis (n = 10), periorbital cellulitis (n = 3), and mastoiditis (n = 1), including 3 cases of two IPD recurrences. We analyzed 5 IPD-associated factors previously documented in Europe and North Amrica with inconsistent results--1) age at onset, 2) sibling number, 3) preschool sibling number, 4) subjects' day care attendance, and 5) siblings' day care attendance. We collected information on these factors by reviewing medical charts or contacting subjects' parents or guardians by telephone. IPD peaked bimodally in April and May (n = 21) and in November and December (n = 20), decreasing prominently between July and September (n = 8). Subjects with IPD attending day care formed a significantly higher propotion during April and May than did those developing IPD during other months: 12/21 [57.1%] vs. 12/51 [23.5%], odds ratio 4.3, 95% confidence interval, 1.5-12.8; p = 0.006. Combined day care attendance among subjects with IPD and/or their siblings also differed significantly between these two groups: 17/21 [80.9%] vs. 27/51 [52.9%], odds ratio 3.8, 95% confidence interval, 1.1-12.8; p = 0.027. Not significant differences were seen in age at onset, sibling number, or preschool sibling number. In contrast, however children with IPD onset during November and December showed no significant difference in association with any of the 5 factors, compared to children with IPD onset in other months. Our findings showed a bimodal peak in IPD in children, the first and highest of which occurred in April and May and was significantly associated with day care attendance by those with IPD and/or their siblings. This first peak may, however, be related to circumstances in Japan, where preschool children usually enter day care center or kindergarten in April.

Recurrent bacterial meningitis by three different pathogens in an isolated asplenic child.

Isolated congenital asplenia (ICA) is a rare condition at risk for overwhelming infection. When complicated by invasive infection, the mortality remains high, at greater than 60%. We describe a girl with ICA who developed recurrent meningitis by three different pathogens. The first, meningitis by Escherichia coli, occurred 4 days after premature birth. The other two pathogens were serotype 6B Streptococcus pneumoniae and Haemophilus influenzae type b (Hib), at 18 and 25 months of age, respectively. The patient was successfully treated with prompt antimicrobial therapy in all episodes. Serum anti-polyribosylribitol phosphate (PRP) and anti-6B-type pneumococcal antibodies were below the levels for protective activity after natural infections. Although anti-PRP antibody was significantly increased after Hib vaccination, two (6B and 19F) of seven serotype-specific pneumococcal antibodies were not elevated to protective levels after the second 7-valent pneumococcal conjugate vaccine (PCV7). We, therefore, added a third PCV7. To our knowledge, this is the first neonatal ICA patient with invasive infection and the first case of bacterial meningitis occurring three times. Our findings indicate that monitoring of immune responses after natural infections and vaccinations, and reevaluations of vaccine schedule, are important for ICA patients to prevent subsequent invasive infections.

Clinical study of the time course of clinical symptoms of Pandemic (H1N1) 2009 influenza observed in young adults during an initial epidemic in Kobe, Japan.

OBJECTIVE: Although the rates of reported symptoms of Pandemic (H1N1) 2009 influenza virus infection are well studied, the course of progression of these symptoms is not clear. In this study, we carefully reviewed the progress of each patient after hospitalization and clarified the clinical course of the symptoms. METHODS: We retrospectively examined the clinical data of 16 consecutive patients who had been hospitalized during the early stages of an influenza epidemic and observed the clinical progression of their symptoms. RESULTS: Each symptom had a different time of onset and progression pattern. In roughly one-third of our patients, symptoms appeared before the onset of high fever. Acute respiratory symptoms tended to last longer than other symptoms; similarly, sore throat and cough lasted longer than rhinorrhea. The SpO(2) of the patients with influenza showed a declining trend. The point at which minimum SpO(2) levels were noted was approximately 1.5 days after onset of fever. CONCLUSION: In this H1N1 epidemic, patients typically tended to experience general fatigue, sore throat, and cough before the onset of fever, with sore throat and cough lasting longer than the other symptoms. Most patients showed decreased SpO(2) levels at -1.5 days after onset of fever.

Parvovirus B19-associated hemophagocytic lymphohistiocytosis in a child with precursor B-cell acute lymphoblastic leukemia under maintenance chemotherapy.

Development of hemophagocytic lymphohistiocytosis (HLH) is quite rare among acute lymphoblastic leukemia (ALL) patients. We present a 3-year-old boy with precursor B-cell ALL, who was complicated by HLH because of parvovirus B19 infection during maintenance chemotherapy. Remarkable erythroid hypoplasia, giant normoblasts, and hemophagocytosed macrophages in bone marrow were important clues for the diagnosis. The patient was successfully treated with high-dose steroids and intravenous immunoglobulins. To our knowledge, this is the first report describing parvovirus B19-associated HLH in ALL. Our case highlights that parvovirus B19 can cause HLH, a potentially fatal disorder, and prolonged unexpected cytopenia in childhood ALL.

Spinal cord compression by epidural involvement over 21 vertebral levels in acute lymphoblastic leukemia.

Spinal cord compression is a rare complication of acute lymphoblastic leukemia (ALL). We report a 13-year-old boy with B-precursor ALL, presenting with restriction of breathing and back pain. Cerebrospinal fluid examination showed extremely high protein levels. Radiologic examination indicated that leukemia extended from the thoracic to sacral epidural spaces over 21 vertebral lengths in a band-shaped form, threatening to induce compressive spinal cord neuropathy. Prompt initiation of systemic chemotherapy relieved the obstruction of cerebrospinal fluid flow without local irradiation or surgical intervention. To our knowledge, this patient has shown the most extensive epidural involvement among ALL patients previously reported.

Reversible splenial lesion associated with novel influenza A (H1N1) viral infection.

We describe clinically mild encephalopathy with a reversible lesion in the splenium of the corpus callosum associated with the novel swine-origin influenza A (H1N1) virus. A 14-year-old Japanese boy was hospitalized because of dysarthria and dysphagia 5 days after the onset of fever. He had been receiving zanamivir for 4 days before admission. Diffusion-weighted magnetic resonance imaging on clinical day 6 revealed lesions in the splenium of the corpus callosum and bilateral frontoparietal white matter. With continued zanamivir treatment, his signs completely resolved within 24 hours, and the abnormal radiologic signals resolved 3 days later. Neurologic signs were limited to pseudobulbar palsy, without impairment of consciousness or seizures. This presentation is, to our knowledge, the first among patients with mild encephalopathy with a reversible lesion in the splenium of the corpus callosum, expanding the clinical spectrum of this condition. Our findings indicate that pandemic 2009 influenza A (H1N1) infection can cause mild encephalopathy with a reversible lesion in the splenium of the corpus callosum.

Methylprednisolone pulse therapy for refractory Mycoplasma pneumoniae pneumonia in children.

OBJECTIVES: To determine the efficacy of methylprednisolone pulse therapy for children with Mycoplasma pneumoniae pneumonia (MP) that is refractory to antibiotic treatment. METHODS: Refractory patients were defined as cases showing clinical and radiological deterioration despite appropriate antibiotic therapy for 7 days or more. We identified 6 such children (male/female: 3/3) aged 3-9 years who were treated between 1998 and 2006. During the same period, 190 children with MP were admitted to our institution. RESULTS: Common laboratory findings of the patients included cytopenia, elevated serum lactate dehydrogenase and ferritin levels, and elevated urine beta(2)-microglobulin levels, suggesting complication of hypercytokinemic condition. We initiated intravenous methylprednisolone at a dose of 30 mg/kg on 10.2+/-2.8 clinical days and administered it once daily for 3 consecutive days. Fever subsided 4-14 h after initiation of steroid pulse therapy in all patients. This dramatic effect was accompanied by rapid improvement of radiological abnormalities including infiltrates and pleural effusion, followed by improvement of laboratory abnormalities. There were no adverse events of steroid therapy. CONCLUSIONS: This is the first case-series study showing an effect of 3-day methylprednisolone pulse therapy on refractory MP in children. This therapy is apparently an efficacious and well-tolerated treatment for refractory MP.

[ATIC-ALK-positive anaplastic large cell lymphoma: a case report and review of the literature].

We report a 10-year-old girl with ATIC-anaplastic lymphoma kinase (ALK)-positive anaplastic large cell lymphoma (ALCL). She presented with inguinal, axillary, and paraaortic lymph node swellings that showed spontaneous regression over a 3-month period, followed by recurrence after an interval of 8 months. Radiological and clinical findings indicated Ann Arbor stage IIIA. Pathological findings showed that staining of ALK was restricted to the cytoplasm of ALCL cells. ATIC-ALK chimeric transcripts were detected by reverse transcriptase polymerase chain reaction. The patient was assigned to the standard risk group proposed by the international multicenter study for pediatric ALCL, ALCL99. The patient responded well to the treatment and remained in complete remission for more than 26 months. To date, 7 genes have been identified as a fusion partner of ALK, with the highest frequency in nucleophosmin (NPM). Little is known about the clinical implications of subtypes of ALCL harboring each of the 7 fusion genes, especially those of variant fusion genes other than NPM-ALK. In this paper, we review 9 patients with ATIC-ALK-positive ALCL in the literature in addition to discussing our patient. In eight of these 10 cases, disease occurred within the first three decades. Five of 6 cases that were followed continuously remained in complete remission.

Reversible splenial lesion in influenza virus encephalopathy.

We describe a rare case of clinically mild, influenza-associated encephalopathy with a reversible splenial lesion. A 12-year-old Japanese girl presented with fever and headache, followed by muscle weakness and somnolence. Magnetic resonance imaging on day 4 of her illness showed a solitary lesion of the splenium of the corpus callosum that was most prominently visualized on diffusion-weighted images. The patient was diagnosed with influenza B-associated encephalopathy. Her neurologic signs had completely recovered by day 6, and the splenial abnormalities disappeared on day 11. A review of the literature identified four additional pediatric cases of this type of influenza-associated encephalopathy: three and one were caused by influenza A and B viruses, respectively. Common features include prompt and complete recovery from clinical and radiologic abnormalities, a relatively older age (> or = 5 years), and a higher incidence among the Japanese. To better understand the pathophysiology of this encephalopathy, we examined interleukin-6, tumor necrosis factor-alpha, and soluble tumor necrosis factor receptor 1 levels in serum and cerebrospinal fluid from this patient. The results did not reveal any elevations of these cytokines in the sera or cerebrospinal fluid, suggesting that this condition is not mediated by augmented cytokine responses.