An Enigmatic Case of Skeletal Fluorosis: Inhalant-Induced Toxicity.

ABSTRACT: Skeletal fluorosis is more common in the developing world, but is occasionally seen in the United States. We present radiographic, scintigraphic, CT, and clinical images of a 26-year-old woman with rapidly progressive, debilitating, polyostotic periostitis, and diffuse osteosclerosis typical of skeletal fluorosis. Laboratory analyses supported this diagnosis. The source of excess fluoride intake was elusive until a concurrent mental health workup revealed the patient's proclivity for inhaling air-duster cans containing difluoroethane. Difluoroethane inhalant abuse is an increasingly reported cause of skeletal fluorosis that astute clinicians should recognize. Discontinuation and sobriety from this toxic agent are essential for recovery.

Ultrasonographic Evidence of Persistent Synovitis in a Chikungunya-Infected Service Member.

Chikungunya virus (CHIKV) is an arthropod-borne alphavirus initially endemic to Central and East Africa but now spreading to Asia, Europe, and most recently the Western hemisphere. CHIKV infection initially presents as an acute, nonspecific febrile syndrome with rash and polyarthralgia, later leading to a chronic arthritis clinically similar to rheumatoid arthritis. We report a case of an active duty military member infected with CHIKV while deployed to Central America, who developed chronic arthritis. Active duty military members are at higher risk of contracting CHIKV because of deployment to countries with a high prevalence of this mosquito-borne illness. Severe chronic arthritis can result from CHIKV, resulting in serious impact on fitness for military duty.

Novel Brentuximab Vedotin Combination Therapies Show Promising Activity in Highly Refractory CD30+ Non-Hodgkin Lymphoma: A Case Series and Review of the Literature.

Non-Hodgkin lymphomas (NHLs) are a heterogeneous group of hematologic malignancies which typically respond to standard first-line chemoimmunotherapy regimens. Unfortunately, patients with refractory NHL face a poor prognosis and represent an unmet need for improved therapeutics. We present two cases of refractory CD30+ NHL who responded to novel brentuximab vedotin- (BV-) based regimens. The first is a patient with stage IV anaplastic large cell lymphoma (ALCL) with cranial nerve involvement who failed front-line treatment with cyclophosphamide, doxorubicin, vincristine, etoposide, and prednisone (CHOEP) and second line cyclophosphamide, vincristine, doxorubicin, dexamethasone alternating with high-dose methotrexate (MTX), and cytarabine (hyperCVAD) with intrathecal- (IT-) MTX and IT-cytarabine, but responded when BV was substituted for vincristine (hyperCBAD). The second patient was a man with stage IV diffuse large B-cell lymphoma (DLBCL) with leptomeningeal involvement whose disease progressed during first-line rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone (R-CHOP) and progressed despite salvage therapy with rituximab, dexamethasone, cytarabine, and cisplatin (R-DHAP) in whom addition of BV to topotecan resulted in a significant response. This report describes the first successful salvage treatments of highly aggressive, double refractory CD30+ NHL using two unreported BV-based chemoimmunotherapy regimens. Both regimens appear effective and have manageable toxicities. Further clinical trials assessing novel BV combinations are warranted.

Rapid selection of a transmissible multidrug-resistant influenza A/H3N2 virus in an immunocompromised host.

BACKGROUND: The overall impact of influenza virus infection in immunocompromised patients is largely unknown. Antigenic drift and genetic variations during prolonged influenza infection have been demonstrated. In this report we describe a multidrug-resistant H3N2 influenza virus isolated from an immunocompromised patient after 5 days of therapy. METHODS: Multiple nasal wash samples were collected from an infected patient, and viral isolates were characterized. Sensitivity to antiviral agents was evaluated. Fitness and transmissibility were assessed in ferrets and tissue culture. RESULTS: An in-frame 4-amino acid deletion emerged in the neuraminidase (NA) gene of an H3N2 virus after 5 days of oseltamivir therapy. No other changes in the NA or hemagglutinin genes were noted. Drug sensitivity assays revealed resistance to oseltamivir (>10-fold increase in 50% inhibitory concentration [IC(50)]) and reduction in sensitivity to zanamivir (3-7-fold increase in IC(50) or 50% effective concentration). No change in fitness or transmissibility was observed. CONCLUSIONS: An in-frame NA gene deletion was rapidly selected for in an immunocompromised patient, resulting in decreased sensitivity of the isolate to available NA inhibitors without a change in fitness or transmissibility. This finding has implications for our understanding of the emergence of antiviral resistance and treatment of patients with influenza A infection, especially those who are immunocompromised.

Rapid selection of oseltamivir- and peramivir-resistant pandemic H1N1 virus during therapy in 2 immunocompromised hosts.

Pandemic 2009 H1N1 virus isolates containing the neuraminidase inhibitor resistance mutation H275Y have been reported. We describe rapid selection for the H275Y resistance mutation during therapy in 2 immunocompromised individuals at 9 and 14 days of therapy, as well as the first described case of clinically significant resistance to peramivir.

A practical influenza neutralization assay to simultaneously quantify hemagglutinin and neuraminidase-inhibiting antibody responses.

Influenza vaccine immunogenicity is commonly assessed by determining hemagglutination inhibition (HAI) titers in serum samples. HAI titers have been used to predict vaccine efficacy, but this often fails when live attenuated vaccines are evaluated, because it does not encompass all immune mediators of protection. Although antibodies that inhibit viral neuraminidase (NA) also contribute to protection against disease, there is currently no routine assessment of NA inhibition titers. A serological method with the capacity to measure functional inhibition of both HA and NA would be valuable. We developed a high-throughput virus neutralization assay that uses viral NA activity to quantify influenza replication (the AVINA assay), and showed its capacity to identify antivirals with a broad range of target specificities. In this report we demonstrate that antibodies with specificity for either HA or NA are detected in this assay, whereas a commonly used virus neutralization assay only detects those with HA-specificity. We also compared human responses to seasonal influenza vaccines measured by HAI, micro-neutralization, NA inhibition and AVINA assays. The response rates to both trivalent inactivated and live attenuated vaccines were greater when measured by the AVINA than the other assays, reflecting the dual antigen reactivity and increased sensitivity of the assay. The potential of this single assay to predict protection against influenza-induced tachypnea was demonstrated in vaccinated cotton rats. The AVINA assay is therefore a practical, comprehensive method to determine influenza vaccine immunogenicity and potential efficacy.

Comparison of airway measurements during influenza-induced tachypnea in infant and adult cotton rats.

BACKGROUND: Increased respiratory rate (tachypnea) is frequently observed as a clinical sign of influenza pneumonia in pediatric patients admitted to the hospital. We previously demonstrated that influenza infection of adult cotton rats (Sigmodon hispidus) also results in tachypnea and wanted to establish whether this clinical sign was observed in infected infant cotton rats. We hypothesized that age-dependent differences in lung mechanics result in differences in ventilatory characteristics following influenza infection. METHODS: Lung tidal volume, dynamic elastance, resistance, and pleural pressure were measured in a resistance and compliance system on mechanically-ventilated anesthestized young (14-28 day old) and adult (6-12 week old) cotton rats. Animals at the same age were infected with influenza virus, and breathing rates and other respiratory measurements were recorded using a whole body flow plethysmograph. RESULTS: Adult cotton rats had significantly greater tidal volume (TV), and lower resistance and elastance than young animals. To evaluate the impact of this increased lung capacity and stiffening on respiratory disease, young and adult animals were infected intra-nasally with influenza A/Wuhan/359/95. Both age groups had increased respiratory rate and enhanced pause (Penh) during infection, suggesting lower airway obstruction. However, in spite of significant tachypnea, the infant (unlike the adult) cotton rats maintained the same tidal volume, resulting in an increased minute volume. In addition, the parameters that contribute to Penh were different: while relaxation time between breaths and time of expiration was decreased in both age groups, a disproportionate increase in peak inspiratory and expiratory flow contributed to the increase in Penh in infant animals. CONCLUSION: While respiratory rate is increased in both adult and infant influenza-infected cotton rats, the volume of air exchanged per minute (minute volume) is increased in the infant animals only. This is likely to be a consequence of greater lung elastance in the very young animals. This model replicates many respiratory features of humans and consequently may be a useful tool to investigate new strategies to treat respiratory disease in influenza-infected infants.

Neuraminidase activity provides a practical read-out for a high throughput influenza antiviral screening assay.

BACKGROUND: The emergence of influenza strains that are resistant to commonly used antivirals has highlighted the need to develop new compounds that target viral gene products or host mechanisms that are essential for effective virus replication. Existing assays to identify potential antiviral compounds often use high throughput screening assays that target specific viral replication steps. To broaden the search for antivirals, cell-based replication assays can be performed, but these are often labor intensive and have limited throughput. RESULTS: We have adapted a traditional virus neutralization assay to develop a practical, cell-based, high throughput screening assay. This assay uses viral neuraminidase (NA) as a read-out to quantify influenza replication, thereby offering an assay that is both rapid and sensitive. In addition to identification of inhibitors that target either viral or host factors, the assay allows simultaneous evaluation of drug toxicity. Antiviral activity was demonstrated for a number of known influenza inhibitors including amantadine that targets the M2 ion channel, zanamivir that targets NA, ribavirin that targets IMP dehydrogenase, and bis-indolyl maleimide that targets protein kinase A/C. Amantadine-resistant strains were identified by comparing IC50 with that of the wild-type virus. CONCLUSION: Antivirals with specificity for a broad range of targets are easily identified in an accelerated viral inhibition assay that uses NA as a read-out of replication. This assay is suitable for high throughput screening to identify potential antivirals or can be used to identify drug-resistant influenza strains.