Describing and expanding the clinical phenotype of anti-MDA5-associated rapidly progressive interstitial lung disease: case series of nine Canadian patients and literature review.

OBJECTIVE: To describe and expand the phenotype of anti-MDA5-associated rapidly progressive interstitial lung disease (MDA5-RPILD) in Canadian patients. METHOD: All proven cases of MDA5-RPILD hospitalized in the University of Montreal's affiliated centres from 2004 to 2015 were selected for inclusion. RESULTS: Of nine consecutive patients, RPILD was the presenting manifestation in seven, whereas two patients developed RPILD 2 years after the onset of arthritis and of chronic interstitial lung disease. In the case with arthritis, RPILD was probably triggered by initiation of tumour necrosis factor-α-inhibitor therapy. In most patients (89%), RPILD was accompanied by concomitant onset of palmar/lateral finger papules, skin ulcerations, and/or mechanic's hands. All patients experienced profound weight loss over 1-2 months (mean ± SD 10.2 ± 4.8 kg). All had arthralgias and/or arthritis. Six patients were clinically amyopathic; only one patient had creatine kinase (CK) levels > 500 U/L. Initial ferritin and transaminase levels were elevated in 86% and 67% of patients, respectively. The antinuclear antibody (ANA) test was negative for nuclear and cytoplasmic staining; antisynthetase autoantibodies were negative. Three patients died; time from initial symptoms to death ranged from 7 to 15 weeks. All six survivors received mycophenolate mofetil and/or tacrolimus as part of induction and/or maintenance therapy. CONCLUSION: In an inpatient setting, RPILD associated with characteristic skin rashes, profound weight loss, articular symptoms, normal or low CK with elevated ferritin, and absent fluorescence on ANA testing should alert the clinician to the possibility of MDA5-RPILD. T-cell-mediated therapies may play a role in this highly lethal condition.

Left heart disease: a frequent cause of early pulmonary hypertension in systemic sclerosis, unrelated to elevated NT-proBNP levels or overt cardiac fibrosis but associated with increased levels of MR-proANP and MR-proADM: retrospective analysis of a French Canadian cohort.

OBJECTIVES: Pulmonary hypertension (PH) causes mortality in systemic sclerosis (SSc). Pulmonary arterial hypertension (PAH) and left heart disease (LHD) are frequent causes of PH. Therefore, we studied PAH and LHD in early PH. METHOD: A total of 432 French Canadian SSc patients were studied retrospectively. All underwent screening for PH. We analysed clinical, serological, and radiographic data from 26 patients with early PH diagnosed by right heart catheterization (RHC). SSc patients with (n = 21) and without PH (n = 19) were prospectively re-evaluated by cardiac magnetic resonance imaging (MRI) and serial measurements of N-terminal pro-brain natriuretic peptide (NT-proBNP) and the haemodynamic biomarkers mid-regional pro-atrial natriuritic peptide (MR-proANP) and mid-regional pro-adrenomedullin (MR-proADM). RESULTS: The most frequent cause of early PH was LHD (58%). PAH was seen in 34% of patients. No association was found between the type of PH and autoantibodies. Early LHD-PH, but not early PAH, was associated with lower NT-proBNP (p = 0.024), but MR-proANP and MR-proADM levels were higher in early LHD-PH than in patients without PH (p = 0.014 and p = 0.012, respectively). Only one patient had abnormal cardiac MRI explaining LHD-PH. CONCLUSIONS: Early PH in SSc, like late PH, is heterogeneous and RHC is essential for determining its underlying cause. The most frequent cause of early PH was LHD. Levels of MR-proANP and MR-proADM, but not NT-proBNP, were increased in early LHD-PH, and may be more reliable than NT-proBNP as a biomarker of early PH in this subgroup of patients. Cardiac MRI did not explain LHD-PH. This study is the first to identify a high frequency of LHD in early PH correlating with normal NT-proBNP levels but increased MR-proANP and MR-proADM levels in SSc patients.

Activity of faropenem against resistant isolates of Streptococcus pneumoniae.

An in vitro study of the activity of 9 agents against 181 US pediatric isolates of Streptococcus pneumoniae identified imipenem and faropenem as the most active agents. Overall, faropenem was the most potent oral agent inhibiting 98% of isolates at 1 microg/mL.

Infectious hematopoietic necrosis virus antibody profiles in naturally and experimentally infected Atlantic salmon Salmo salar.

Atlantic salmon Salmo salar naturally and experimentally exposed to infectious hematopoietic necrosis virus (IHNV) in British Columbia, Canada, developed antibodies against the virus. More than 50% of the fish exposed to IHNV remained seropositive for several months after the IHN epizootic had subsided. The virus itself could not be detected in asymptomatic fish once the fish had recovered from IHN. The persistence of IHNV-specific antibodies in a large percentage of Atlantic salmon, from 4 different populations that survived an outbreak of IHN, and the lack of IHNV-specific antibodies in fish with no history of the disease, suggests that serology may be a useful tool for determining previous exposure to the virus. It may be important to determine whether Atlantic salmon have been infected with IHNV because, although the virus is difficult to detect in asymptomatic fish, an incidental finding suggests it may persist in a small number of fish after the outbreak has subsided. Furthermore, the presence of seropositive fish would be an indication that the virus may be enzootic at a farm, and such information would thus aid producers with stocking decisions.

Activity of oral agents against pediatric isolates of Streptococcus pneumoniae.

An in vitro study of the activity of 10 oral agents against 153 pediatric isolates of Streptococcus pneumoniae identified moxifloxacin and levofloxacin as the most active agents regardless of penicillin or macrolide susceptibility. Moxifloxacin inhibited all strains at 0.25 microg/ml and was 8- to 16-fold more potent than levofloxacin.

[Growth and pubertal development following pediatric heart transplantation]. / Croissance et développement pubertaire après transplantation cardiaque pédiatrique.

STUDY AIM: Prospective study of growth and pubertal development following pediatric heart transplantation in 25 children. PATIENTS AND METHOD: Twenty-five children underwent orthotopic cardiac transplantation at Ste-Justine Hospital from July 1984 to August 1996. Systematic evaluation of anthropometric parameters (weight, height, bone age), hormonal profile (LH, FSH, testosterone, oestradiol, DHEAS), and pubertal development according to Marshall and Tanner were done yearly. RESULTS: Six patients had severe growth retardation at transplantation and only one patient was obese. All patients showed normal height increment following cardiac transplantation. Only 3 patients will not reach genetic target height. The 6 children suffering from congenital cardiomyopathy and showing severe growth delay before surgery did not show any significant catch up growth. Significant weight gain was observed during the first post-operative year (113 +/- 27% ideal body weight p = 0.0002) with evolution towards normal values at 2 years (100 +/- 18%). Thirteen patients were in the prepubertal stage at the time of transplant. Since then, one girl had her menarche at 11 years of age and 3 boys started their pubertal onset at 12 years old. The elevation of blood gonadotrophins during pubertal development correlated with progression of secondary sexual characteristics in both sexes. CONCLUSION: This pediatric population showed normal growth and normal onset and progression of puberty following cardiac transplantation. However, no catch-up growth was observed. The most important factor influencing attainment of maximal growth potential following heart transplantation was the degree of staturoponderal growth retardation at the time of surgery.

Severe intrauterine herpes simplex disease with placentitis in a newborn of a mother with recurrent genital infection at delivery.

We present a case of fatal herpes simplex type 2 (HSV-2) in a premature infant born to a mother diagnosed with recurrent HSV-2, based on history and HSV serology results. It was clinically evident at delivery, and subsequently confirmed by laboratory studies that the infant was infected before delivery. There was histopathologic evidence of placentitis and chorioamnionitis upon examination of the placenta and fetal membranes. This case illustrates a relatively uncommon complication of recurrent genital herpes at delivery--intrauterine transmission to the fetus from a primary episode during pregnancy.

Growth and pubertal development following pediatric heart transplantation: a 15-year experience at Ste-Justine Hospital.

BACKGROUND: Thirty-one children and adolescents have undergone allograft heart transplantation at Ste-Justine Hospital from July 1984 to August 1996. Twenty-five patients were followed prospectively more than 3 years to document their growth and pubertal development. METHODS: Parameters surveyed were clinical (height, weight, pubertal staging, and bone age) and biochemical (luteinizing hormone (LH), follicle-stimulating hormone (FSH), testosterone, estradiol, dehydroepiandrosterone sulphate (DHEAS), IGF-1, and fasting insulin). RESULTS: At surgery, there were 18 boys and 7 girls aged 11 months to 17 years (median 13 years); 14 had congenital heart defects (CHDs) and 11 had a cardiomyopathy (CM). Immunosuppressive therapy included cyclosporine, azathioprine, and prednisone. Eighteen patients were still growing (15 boys, 3 girls): 8 had a retarded bone age and 6 with CHD had severe growth failure. Following surgery, most patients maintained their height within one sodium dodecyl sulfate (SDS) score of that initially observed. Patients reaching their target heights do so mainly in the lower range. Three patients not reaching target height had a CHD. Weight was greatest 1 year postoperatively (113 +/- 27% ideal body weight) with normalization at 2 years (100 +/- 18%). Of the 13 prepubertal patients, menarche occurred at age 12 in 1 girl, while 3 boys began puberty at age 12 years. In both sexes, serum levels of gonadotropins and IGF-1 increased during puberty, moderate hyperinsulinism was observed, and DHEAS levels decreased. CONCLUSIONS: Our results indicate that children and adolescents grow normally following cardiac transplantation and that they attain their target height despite a lack of catch-up growth. They gain weight significantly in the first postoperative year with normalization of their weight at 2 years. Furthermore, the clinical and biochemical indices of puberty are overall within the norms. However, the severity of growth delay at the time of transplantation inherent to the cardiac pathology has a major impact on adult height.

Varicella vaccine.

Varicella vaccine is safe, effective, and cost-effective in healthy children, adolescents, and adults. Breakthrough cases of MVLS are significantly milder than wild-type varicella infection. No severe adverse events have been reported following vaccination, and the incidence of herpes zoster is less in vaccinees than in individuals who have had natural varicella infections. To date, there is no evidence waning immunity following vaccination. "New and improved" varicella vaccines that may be more effective than the current vaccine and can be stored at refrigerator temperatures may soon become available in the United States.

Activity of moxifloxacin against pathogens with decreased susceptibility to ciprofloxacin.

A panel of 279 clinical isolates of Gram-positive cocci and Gram-negative bacilli with varying levels of resistance to ciprofloxacin were analysed for susceptibility to moxifloxacin, ciprofloxacin, ofloxacin and nalidixic acid. Moxifloxacin was eight- to 32-fold more potent than ciprofloxacin and ofloxacin against staphylococci and Streptococcus pneumoniae, and equivalent to eight-fold more potent against enterococci. Although ciprofloxacin was intrinsically more potent than the other quinolones against highly susceptible Gram-negative isolates, the percentages of Gram-negative isolates susceptible to 1 mg/L of moxifloxacin or ciprofloxacin, or 2 mg/L of ofloxacin were 78%, 80% and 76%, indicating in-vitro equivalence of the agents against a collection that included isolates with diminished quinolone susceptibility. Staphylococci were analysed according to their ciprofloxacin susceptibility status. As ciprofloxacin resistance increased to high levels, all quinolone MICs increased, but moxifloxacin and ofloxacin MICs increased less than ciprofloxacin MICs. In mutational studies moxifloxacin inhibited more mutants (69%) at a concentration of 1 mg/L than did ciprofloxacin (63%) at 1 mg/L or ofloxacin at 2 mg/L (31%). The study indicated that moxifloxacin is more potent than ciprofloxacin and ofloxacin against Gram-positive pathogens, may be comparable in activity against less quinolone-susceptible Gram-negative isolates (other than Pseudomonas aeruginosa), and is less affected than ciprofloxacin by mechanisms responsible for increasing quinolone resistance in staphylococci.

In-vitro activity of levofloxacin against Streptococcus pneumoniae with various levels of penicillin resistance.

This in-vitro study was designed to compare the activity of levofloxacin with that of ciprofloxacin, ofloxacin, erythromycin, penicillin, amoxycillin, loracarbef, cefaclor, cefpodoxime, ceftriaxone, trimethoprim-sulphamethoxazole, clindamycin and vancomycin against a collection of 202 Streptococcus pneumoniae isolates (56% susceptible to penicillin, 34% intermediate, 10% resistant). The isolates (60% nasopharyngeal, 40% middle ear) were obtained from otherwise healthy children at child care centres in urban and rural Nebraska, and at a paediatric clinic in rural Kentucky. MICs were determined by NCCLS agar dilution methodology using an inoculum of 10(4) cfu/spot. Using NCCLS breakpoints, the percentage of penicillin-intermediate and -resistant strains susceptible to the evaluable agents were, respectively, as follows: levofloxacin (99%, 100%), ofloxacin (87%, 100%), erythromycin (52%, 65%), ceftriaxone (93%, 25%), trimethoprim-sulphamethoxazole (7%, 0%), clindamycin (93%, 100%) and vancomycin (100%, 100%). Without NCCLS interpretive criteria, no conclusions could be made concerning the susceptibility of penicillin-intermediate and -resistant strains to the other study drugs. All beta-lactam antibiotics, erythromycin and trimethoprim-sulphamethoxazole were less active against penicillin-resistant strains, indicating that these may be suboptimal agents for empirical therapy for suspected S. pneumoniae infections in these patient populations. However, levofloxacin, ofloxacin, clindamycin and vancomycin were equally active against penicillin-susceptible and -resistant strains. These data suggest that the efficacy of levofloxacin should be examined in both adult and paediatric S. pneumoniae infections involving body sites where levofloxacin concentrations > 2 mg/L can be achieved safely.

Rationale behind high-dose amoxicillin therapy for acute otitis media due to penicillin-nonsusceptible pneumococci: support from in vitro pharmacodynamic studies.

To evaluate whether increased doses of amoxicillin should be used to treat acute pneumococcal otitis media, an in vitro pharmacokinetic model was used to evaluate the killing of pneumococci by amoxicillin when middle ear pharmacokinetics were simulated. Logarithmic-phase cultures were exposed to peak concentrations of 3, 6, and 9 microg of amoxicillin per ml every 12 h, and an elimination half-life of 1.6 h was simulated. Changes in viable bacterial counts were measured over 36 h. All three doses rapidly decreased the viable bacterial counts of penicillin-susceptible strains below the 10-CFU/ml limit of detection by 6 to 10 h and maintained counts below this limit through 36 h. The 3-microg/ml peak dose was much less effective against two of three strains with intermediate penicillin resistance and all three penicillin-resistant strains, with bacterial counts approaching those in drug-free control cultures by 12 h. The 6-microg/ml peak dose completely eliminated two of three strains with intermediate penicillin resistance and maintained viable counts of the other nonsusceptible strains at 1.5 to 2 logs below the initial inoculum through 36 h. The 9-microg/ml peak dose was most effective, completely eliminating all three strains with intermediate penicillin resistance and maintaining the viable counts of the resistant strains at 3 to 4 logs below the original inoculum. The pharmacodynamics observed in this study suggest that peak concentrations of amoxicillin of 6 to 9 microg/ml may be sufficient for the elimination of penicillin-nonsusceptible pneumococcal strains causing otitis media, especially those with intermediate resistance to amoxicillin. In vivo pharmacokinetic studies are needed to determine if these levels can be achieved in middle ear fluid with amoxicillin at 70 to 90 mg/kg/day divided into two daily doses. If these levels are reliably achieved, then clinical studies are warranted.