Donald A. Person

Prospective randomized double blind placebo-controlled evaluation of azithromycin for treatment of cat-scratch disease

OBJECTIVE To determine the efficacy of azithromycin in the treatment of patients with typical cat-scratch disease. DESIGN Prospective, randomized, double blind, placebo-controlled clinical trial. SETTING Large military medical center and its referring clinics. PATIENTS Active duty military members and their dependents with laboratory-confirmed, clinically typical cat-scratch disease. INTERVENTION Study participants assigned by randomization to treatment with oral azithromycin or placebo for 5 days. OUTCOME MEASURES Lymph node volume was calculated using three dimensional ultrasonography at entry and at weekly intervals. The ultrasonographer was blinded to the treatment groups. Endpoint evaluations were predetermined as time in days to 80% resolution of the initial total lymph node volume. RESULTS Demographic and clinical data showed that the azithromycin and placebo treatment groups were comparable at entry although the placebo group tended to be older. Eighty percent decrease of initial lymph node volume was documented in 7 of 14 azithromycin-treated patients compared with 1 of 15 placebo-treated controls during the first 30 days of observation (P = 0.026). After 30 days there was no significant difference in rate or degree of resolution between the two groups. CONCLUSIONS Treatment of patients with typical cat-scratch disease with oral azithromycin for five days affords significant clinical benefit as measured by total decrease in lymph node volume within the first month of treatment.

The expanding spectrum of Bartonella infections : II. Cat-scratch disease

Recent advancements and developments in molecular biotechnology have allowed more precise reclassification of many microorganisms. With the use of these new taxonomy tools, several organisms previously thought to belong to other genera have been recently described as bartonellae. Of the 11 organisms now described as Bartonella spp., only four have been shown to be pathogenic for humans. Table 1 lists the four Bartonella human pathogens along with the their known epidemiology and the scope and range of disease associated with each. All are now considered to be bacteria and can be grown on blood-enriched agar although primary isolation in some may best be achieved in cell tissue culture. B. bacilliformis infection is limited to certain geographic regions in South America where the only human reservoir and the sandfly vector(s) that spreads the disease reside together. Specific antibiotic treatment is dramatically effective in treating the highly fatal, acute intraerythrocytic hemolytic form of the disease, but their effectiveness in treating the vascular proliferative forms (verruga peruana) or the chronic asymptomatic, bacteremic, carrier state of the disease has not been effective. This disease should remain confined to its present endemic geographic areas in South American unless asymptomatic bacteremic persons from these areas migrate to areas where sandflies and humans exist that are capable of establishing this infection in new endemic areas. B. quintana and B. henselae cause a wide range of clinical diseases in humans, the type and extent of which varies significantly with the immune status of the host. In immunocompetent hosts the pathologic response is granulomatous, suppurative, extracellular and intracellular, generally self-limited and usually unresponsive to antibiotic treatment, even to those drugs to which the organism is shown to be sensitive in vitro. In contrast, in immunocompromised hosts the pathologic response is vasculoproliferative, organisms may be seen intracellularly but they are often seen in abundance in extracellular clumps and infection is usually progressive and fatal unless treated. In these patients clinical response to treatment with drugs that are effective in vitro against these organisms has usually been dramatic. Of these agents those that penetrate cells and are found in high concentrations intracellularly, such as erythromycin, clarithromycin, azithromycin, rifampin, doxycycline and gentamicin, appear to be most effective. These agents not only appear to provide the most dramatic treatment response in patients with BA, BP and PRFB and other manifestations of B. henselae (and B. quintana as well) in immunocompromised persons, they appear to be the most promising agents for treatment of persons with both typical and atypical CSD. Further studies will be necessary to more clearly elucidated the mechanisms responsible for the diverse clinical presentations of infection with these organisms in human hosts relative to their immune status. In addition clarification of the epidemiology of B. elizabethae infections in humans may be helpful in understanding the nature of infection with Bartonella organisms.

Cat-scratch disease in Hawaii: Etiology and seroepidemiology

OBJECTIVE To study the etiology and seroepidemiology of cat-scratch disease (CSD) in Hawaii. METHODS Blood and fine-needle aspirate (FNA) from the lymph nodes of 39 consecutive patients with clinical CSD were cultured for Bartonella henselae, and blood samples from index cats, stray cats, and dogs were cultured and their sera were tested by indirect fluorescence antibody test for antibodies to B. henselae and Afipia felis. Sera from age- and sex-matched human subjects without cat exposure served as controls. RESULTS Warthin-Starry staining showed positive results in only 4 of 32 FNAs, and B. henselae was isolated from only one FNA specimen. All of 38 patients who had two or more sera tested had elevated titers of antibody to B. henselae. Only 1 of 48 human control sera had antibody to B. henselae. Of 31 kittens, 21 had positive blood culture results and elevated antibody titers to B. henselae. Of three adult cats, all had negative blood culture results, but they had serologic evidence of past infection. Of 23 adult stray cats, 18 had elevated titers of antibody to B. henselae, but in only one was the blood culture result positive. Results of IFA tests were marginally positive for A. felis in 1 of 29 patients with CSD and in one adult stray cat and one dog. CONCLUSIONS This study shows that the B. henselae IFA test is both highly sensitive and specific for the detection of infection caused by B. henselae and for the laboratory diagnosis of CSD, and that FNA is seldom helpful in confirming the diagnosis. We further demonstrated that CSD in Hawaii is due to B. henselae and that infection is directly linked to the scratch or bite of a kitten. Older cats seldom have bacteremia but often have serologic evidence of past infection. Our study fails to implicate dogs in the epidemiology of CSD in Hawaii, and A. felis was not etiologically implicated in CSD in the human subjects and animals we studied.

Hypermobility of the joints in juvenile episodic arthritis/arthralgia†

It has been suggested that hypermobility of the joints may predispose children to the development of arthritis or arthralgia. To determine the normal frequency of hypermobility, 260 normal schoolchildren (5 to 17 years of age) were examined. In addition, 34 patients with juvenile rheumatoid arthritis (JRA) and 32 children with juvenile episodic arthritis/arthralgia (JEA) were tested. Any child who met at least three of the following criteria was considered to have joint hypermobility: (1) passive apposition of the thumbs to the flexor aspect of the forearms; (2) passive hyperextension of the fingers so that they lie parallel with the extensor aspect of the forearms; (3) hyperextension of the elbows greater than 10 degrees; (4) hyperextension of the knees greater than 10 degrees; (5) flexion of the trunk with knees extended so the palms rest on the floor. Thirty-two (12%) of 260 normal schoolchildren and 21 (66%) of 32 with JEA had hypermobility. Further, a significantly higher proportion (23 of 126) of normal girls than normal boys (nine of 134) had hypermobility (chi 2 = 8.0, P less than 0.005). Hypermobility was not common in children with JRA. These findings support the hypothesis that hypermobility may be an important factor in the cause of JEA.

Ibuprofen suspension in the treatment of juvenile rheumatoid arthritis

Ninety-two children with juvenile rheumatoid arthritis were randomly assigned to treatment in a multicenter, double-blind, 12-week trial designed to compare the efficacy and safety of a liquid formulation of ibuprofen at a dosage of 30 to 40 mg/kg/day versus those of aspirin at a dosage of 60 to 80 mg/kg/day. No significant intergroup differences in response rates or in the amount of improvement in articular indexes of disease activity were observed. More children treated with aspirin discontinued treatment early because of adverse reactions. After this trial, 84 additional patients with juvenile rheumatoid arthritis entered a 24-week, multidose (30, 40, and 50 mg/kg/day), open trial of ibuprofen suspension. Favorable response rates for the three groups were similar, and continued improvement was observed throughout the 24-week period. A dose-response relationship was observed with respect to adverse reactions of the upper gastrointestinal tract. We conclude that ibuprofen suspension is an effective nonsteroidal antiinflammatory drug and that its tolerability in children is acceptable.

Auranofin in the treatment of juvenile rheumatoid arthritis.

A 6-month double-blind, parallel, randomized, placebo-controlled multicenter trial of auranofin (0.15-0.20 mg/kg/day) was conducted in 231 children with juvenile rheumatoid arthritis (JRA) in the United States and in the Union of Soviet Socialist Republics. Approximately 80% of the children had polyarticular disease. The auranofin-treated patients showed greater mean decreases from baseline in 11 of the 12 articular disease indices measured than did the placebo-treated subjects after 3 months of therapy, and in 9 of the 12 indices after 6 months. However, the actual intergroup mean differences were relatively small and were not statistically significant. According to the physicians global assessment, 69% of the auranofin-treated patients and 61% of the placebo-treated patients demonstrated clinically significant improvement from baseline after 6 months (P = 0.24). Children whose disease onset occurred less than 2 years prior to entry improved more than did those who had arthritis for a longer period. In addition, those with polyarticular involvement at baseline improved more than did patients with mild disease. However, these relationships were observed in both the auranofin- and placebo-treated groups, and again, there were no significant intergroup differences. Diarrhea was the most common adverse effect of auranofin. We conclude that the clinical efficacy of auranofin is modestly higher than that of placebo in the treatment of JRA, as evidenced by the consistent trends observed in the data. However, the magnitude of the individual intergroup differences is not statistically significant. Auranofin appears to be very safe in children with JRA.

Cell-mediated immunity in rheumatoid arthritis.

Cell-mediated immunity in rheumatoid arthritis (RA) was assessed by skin testing with six antigens in 107 patients, 94 of whom were age, sex, and race-matched with healthy individuals or patients with diseases unrelated to immunological abnormalities. 20% of RA patients were anergic. Impaired cell-mediated immunity in the RA patients was manifested by a decrease in the magnitude of skin reactivity as well as a decrease in the incidence of positive reactions to multiple antigens. Depression in cell-mediated immunity was related to age but not to sex, duration of disease, or disease activity. A slight correlation was found between absolute peripheral lymphocyte counts and the number of positive skin tests, and was confirmed by finding an association between lymphocyte counts and the size of skin reactions. A correlation was also found between lymphocyte counts and disease activity. Four explanations of the observed depression in cell-mediated immunity in RA were considered: (1) a preoccupation of the immune mechanism of the host with cell-mediated immunity reactions related to the pathogenesis of the disease; (2) a depression of cell-mediated immune reactivity by a virus infection; (3) depression of cell-mediated immunity by therapy; and (4) immune complex suppression of cell-mediated immunity. No effect of gold therapy was found. The near universal use of salicylates or other anti-inflammatory drugs did not permit investigation of the effect of these drugs on cell-mediated immunity.

The Pacific Asynchronous TeleHealth (PATH) system: review of 1,000 pediatric teleconsultations.

OBJECTIVE The aim of this study was to evaluate the impact on pediatric care of the Pacific Asynchronous TeleHealth (PATH) system, a provider-to-provider teleconsultation platform utilized by military medical facilities throughout the Pacific Region. This review focuses on access to care, quality of care, and cost savings for the Department of Defense as a result of ongoing development of the PATH system from 2006 to 2009. METHODS This is a retrospective review of 1,000 consecutive teleconsultations occurring from January 2006 to March 2009. Three pediatric subspecialists reviewed the characteristics of each teleconsultation and the ultimate outcome. RESULTS The PATH system processed > 300 pediatric teleconsultations in 2009 from 20 hospitals and clinics throughout the Pacific Region. The number of teleconsultations has grown significantly since 2006. Median teleconsultation response time was 14.5 h with 97% of teleconsultations answered within 1 week. The majority (75%) of teleconsultations came from areas without host nation pediatric subspecialty resources. Most teleconsultations (72%) involved diagnostic questions, whereas 21% were primarily for treatment issues. Teleconsultations originated predominantly from outpatient clinics (90%), with question resolution in 60% of cases without a face-to-face subspecialty evaluation. Fifteen percent of teleconsultations resulted in patient transfer to our center for definitive diagnosis and treatment. The diagnostic and/or treatment plan was modified in 74% of teleconsultations. PATH precluded patient transfer in 12%-43% of teleconsultations (annual savings:

Plasma exchange in selected patients with juvenile rheumatoid arthritis

208,283-

Lavage administration of dilute recombinant surfactant in acute lung injury in piglets.

746,348 per year) and generated an average of 1.7 relative value units per teleconsultation. CONCLUSIONS PATH provided patient access to pediatric subspecialty expertise via provider-to-provider asynchronous teleconsultation. Internet-based pediatric subspecialty teleconsultation provides fast, convenient, cost-effective, quality pediatric care to populations of patients who might otherwise require transfer to a distant medical facility for more advanced care. PATH serves as a model for future asynchronous teleconsultation platforms in both the military and civilian healthcare arenas.