Inhibition of aggregation of aluminum hydroxide adjuvant during freezing and drying.

Aluminum-salt adjuvants are widely used to increase immunogenicity of recombinant protein vaccines. However, when vaccines formulated with these adjuvants are frozen or lyophilized, losses of efficacy are often reported. This loss of potency is usually attributed to the aggregation of adjuvant particles during processing. In this study, we examine the aggregation behavior of Alhydrogel, a commercial aluminum hydroxide adjuvant, during freeze-thawing and freeze-drying. By cooling Alhydrogel formulations at faster rates or by the addition of sufficient amounts of a glass forming excipient such as trehalose, aggregation of Alhydrogel, can be prevented or minimized. We propose that freeze-concentration of buffer salts induces modifications in adjuvant surface chemistry and crystallinity, which in turn favor aggregation. These modifications, and the resulting aggregation of Alhydrogel particles can be minimized through choice of buffer ions, or kinetically inhibited by rapidly forming a glassy state during freezing.

Risk Factors for Targeted Fungal and Mycobacterial Infections in Patients Taking Tumor Necrosis Factor Inhibitors.

OBJECTIVE: To identify predictors of the receipt of medical care, including the receipt of pre-drug screening, for diagnostically targeted fungal or mycobacterial infections among patients prescribed a tumor necrosis factor inhibitor (TNFi). METHODS: We conducted a case-control study using deidentified patient health claims information from a data set representing a commercially insured US population of 15 million patients annually from January 1, 2007 to December 31, 2009. Descriptive statistics as well as a 2-sample t-test, chi-square test of association, Fisher's exact test, and multivariate logistic regression were used for data analysis. RESULTS: A total of 30,772 patients received a TNFi during the study period. Of these, 158 patients (0.51%) developed targeted fungal and/or mycobacterial infections (cases). The median number of infections per case was 1.0 (interquartile range 1.0-2.0). Tuberculosis was diagnosed in 61% of cases, followed by histoplasmosis in 60%, nontuberculous mycobacterial infections in 11%, coccidioidomycosis in 10%, unspecified fungal infection in 8%, blastomycosis in 4%, cryptococcal infection in 3%, and pneumocystosis in 2%. Compared to controls (n = 474), a higher proportion of cases were prescribed prednisone (55% versus 37%; P < 0.001). Patients who were prescribed prednisone during the study period were twice as likely as those not taking prednisone to seek medical care attributable to a targeted fungal or mycobacterial infection (odds ratio 2.03; P < 0.001). CONCLUSION: Development of a targeted fungal or mycobacterial infection among patients taking a TNFi is rare. Concomitant use of prednisone predicted development of such infections.

Use of Intravenous Immunoglobulin for Patients with Inflammatory Bowel Disease with Contraindications or Who Are Unresponsive to Conventional Treatments.

BACKGROUND: Managing patients with IBD who are refractory or have contraindications to standard therapies is challenging. Many will lose response, become intolerant to treatment, or develop infections with contraindication for immunosuppression. Therefore, alternative therapies, such as the use of intravenous immunoglobulin (IVIg), could be used to manage patients in these difficult cases. METHODS: Data were extracted retrospectively from the electronic medical records at Vanderbilt University on patients with IBD who received IVIg (February 2011-June 2013). Patients were treated with IVIg 0.4 g·kg·d for 3 consecutive days and then 0.4 g/kg once monthly. The dose was increased to 0.4 g/kg biweekly for loss of response or partial response. Clinical response was defined as decreasing the Harvey-Bradshaw Index ≥3 points or improvement in C-reactive protein >25%. Clinical remission was defined as Harvey-Bradshaw Index score <5, no hospitalizations or surgeries after IVIg, or symptom resolution. Statistical analysis was performed using Wilcoxon signed-rank test. RESULTS: Twenty-four patients with IBD received IVIg. Seventeen patients received IVIg for failure of standard treatment. Six patients received IVIg during active infection. Two patients had histoplasmosis, 1 patient had tuberculosis, and 2 patients had pulmonary fungal infections. One patient with ulcerative colitis was given IVIg for recurrent Clostridium difficile. Nine patients required dose escalation after median 153 days (30-360). Ninteen patients (79%) had a response or remission. Sixteen (67%) had a response and 3 (12.5%) obtained remission with IVIg. C-reactive protein decreased significantly after treatment (19 mg/dL [0.1-77] to 7.5 [0.2-20]), P < 0.05. Harvey-Bradshaw Index scores improved (8 [0-19] to 6 [0-17]), P = not significant. Of note, 62.5% had endoscopic improvement after treatment. CONCLUSIONS: IVIg is safe and effective in the short-term management of patients with IBD when standard therapies are contraindicated.