Targeted testing of children for tuberculosis: validation of a risk assessment questionnaire.

OBJECTIVE: Given the directive of the American Academy of Pediatrics to test children for tuberculosis (TB) only if they are at high risk for the disease, we sought to determine how well a risk assessment questionnaire can predict a positive tuberculin skin test (TST) result among children seen in a medical office setting. METHODS: In a prospective observational study, we identified 31 926 children who received well-child care in 18 pediatric offices of the Kaiser Permanente Northern California Region from August 1996 through November 1998 and who were due to receive a routine TST (Mantoux method) as part of universal screening. Parents were asked to complete a questionnaire about risk factors for TB infection that included demographic information. The TST result at 48 to 72 hours was compared with questionnaire responses to identify responses that were most highly associated with a positive TST result at both the 10-mm and 15-mm cutoffs. A concurrent study was conducted to determine whether parents can recognize induration. RESULTS: This population was diverse in age (range: 0-18 years), race/ethnicity (white: 37%; Hispanic: 26.4%; Asian: 15.0%; black: 11.8%; other: 8.4%; not stated by parent: 1.6%), and household annual income (range: $10 524-$175 282). Overall incidence of positive TST results was 1.0% at the 10-mm cutoff and 0.5% at the 15-mm cutoff. Positive predictive value of selected individual risk factors at the 10-mm cutoff were: child born outside the United States, 10.4%; history of receiving bacille Calmette-Guérin vaccine, 5.5%; and child having lived outside the United States, 5.3%. Using multivariate analysis, we selected a subset of risk factors that were independently and significantly associated with a positive TST result >/=10 mm: history of receiving bacille Calmette-Guérin vaccine (odds ratio [OR]: 2.31; 95% confidence interval [CI]: 1.70-3.13); household member with history of positive TST result or TB disease (OR: 1.53; 95% CI: 1.14-2.04); child born outside the United States (OR: 8.63; 95% CI: 6.16-12.09); child having lived outside the United States (OR: 2.06; 95% CI: 1.49-2.85); and race/ethnicity reported by parent as Asian (OR: 2.28; 95% CI: 1.59-3.27) or Hispanic (OR: 1.57; 95% CI: 1.09-2.26). Several factors were not statistically significant predictors of a positive TST result: age, sex, household annual income, household member infected with human immunodeficiency virus or who had stayed in a homeless shelter, and being an adopted or foster child. Overall sensitivity of the 9 main items on the questionnaire was 80.9%; when a subset of 4 of these questions plus the race/ethnicity questions were used, sensitivity of responses was 83.5%. Parents failed to recognize positive TST results at a rate of 9.9% (for the 10-mm cutoff) and 5.9% (at the 15-mm cutoff). CONCLUSION: A 5-question risk assessment questionnaire completed by parents can be used to accurately identify risk factors associated with TB infection in children. In our population, some risk factors suggested by the American Academy of Pediatrics could not be validated. Parents cannot be relied on to read TST results accurately. Screening for TB can be enabled by using a standardized, validated questionnaire to identify children who should be given tuberculin skin testing.

Computer-generated recall letters for underimmunized children: how cost-effective?

OBJECTIVE: To evaluate the effectiveness and cost effectiveness of computer-generated recall letters to parents of children overdue for immunizations. METHODS: This randomized controlled trial included children of two facilities in a regional health maintenance organization. Parents of 20-month-olds who had not yet received a measles-mumps-rubella (MMR) immunization were identified via a computerized immunization tracking system. One half were mailed personalized letters that included the recommended immunization schedule and a request to call for an appointment; the other half served as a control group. Receipt of the MMR between 20 and 24 months of age was evaluated with the computerized tracking system. A telephone survey was conducted with parents whose children had not received the MMR by 24 months. Decision analysis was used to project the theoretical outcomes and costs of a recall letter policy for other populations. RESULTS: Among 20-month-old children 10% had not received the MMR; 289 families were included in the analysis. Of families who were mailed letters, 54% (82 of 153) received the MMR by 24 months of age, compared with 35% (47 of 136) of those in the control group (P = 0.001). The telephone survey was completed with 110 parents of children who still did not appear on the health plan computer as having received the MMR by 24 months. Fifteen percent said the child had received an immunization at an outside provider, and of the rest 62% said they had not been aware that an immunization was due. In the cost effectiveness analysis it was projected that recall letters would increase the immunization rate for the regional population of approximately 30000 children from 86% to 90% at a total cost of $5031 annually. The cost per additional child appropriately immunized was $4.04. In sensitivity analyses this cost effectiveness ratio varied depending on the baseline population coverage rate as well as the estimated effectiveness of recall letters. CONCLUSIONS: Computer-generated letters to recall children overdue for immunizations resulted in a higher proportion of children appropriately immunized in this setting. However, the strategy was not as cost-effective as intuition might suggest. Further studies in health maintenance organization (HMO) settings should compare the cost effectiveness of letters with other low cost strategies including automated telephone reminders.

Safety and immunogenicity of Chiron/Biocine recombinant acellular pertussis-diphtheria-tetanus vaccine in infants and toddlers.

OBJECTIVE: To evaluate the safety and immunogenicity of the recombinant acellular pertussis-diphtheria-tetanus (aPDT) vaccine (C-aPDT, Chiron/Biocine). STUDY DESIGN: This is a randomized blinded trial evaluating the safety and immunogenicity of the recombinant aPDT vaccine (C-aPDT, Chiron/Biocine) in 2000 infant recipients compared with 498 controls who received whole cell diphtheria-pertussis-tetanus (wDPT; Connaught) vaccine at 2, 4 and 6 months of age. In addition the safety and immunogenicity of the same C-aPDT vaccine were evaluated as a booster dose in a subset of the same population when given at 15 to 18 months of age and compared with licensed Lederle aPDT vaccine. RESULTS: The C-aPDT vaccine was associated with very few local or systemic reactions when compared with wDPT. In toddlers the local and systemic side effects observed were similar after either acellular vaccine. When the immunogenicity of the C-aPDT vaccine was compared with the wDPT (Connaught) in infancy, the vaccines were equivalent for anti-diphtheria response, the wDPT developed higher anti-tetanus response and the C-aPDT vaccine was significantly more immunogenic for all other antigens tested. In toddlers the C-aPDT acellular vaccine exhibited equal or improved immunogenicity for antigens tested as compared with Lederle aPDT except for a higher anti-filamentous hemagglutinin response with the Lederle aPDT vaccine. CONCLUSION: The Chiron/Biocine aPDT vaccine offers an improved safety profile as well as improved immunogenicity when compared with a licensed wDPT product.

Immunostimulation with muramyl dipeptide and its desmethyl analogue: Studies of non-specific resistance to pulmonary blastomycosis in inbred mouse strains.

N-acetyl-muramyl-L-alanyl-D-isoglutamine (MDP) protected against pulmonary blastomycosis when given prophylactically to BALB/c mice. Its desmethyl analogue (DM-MDP) had a similar effect. In C3H/HeJ, the effect was less marked. Early treatment after infection, with MDP and DM-MDP, had a modest effect in C3H/HeJ and BALB/c respectively, whereas late treatment had no effect in any mouse strain. No effect could be demonstrated with challenge sizes producing too lethal a model or minimal lethality, or in DBA/2J or young BALB/c mice. The effects in various strains do not correlate with differing effects on nonspecific immunostimulation in these strains. Immunostimulation with glycopeptides deserves further study in prophylaxis or therapy of fungal infection.

Protection against pulmonary blastomycosis: correlation with cellular and humoral immunity in mice after subcutaneous nonlethal infection.

A model of pulmonary blastomycosis in the mouse, in which the portal of entry is the same as natural human infection, was used to study resistance to challenge after subcutaneous infection. One week after subcutaneous infection, mice were partially resistant to pulmonary challenge, and mice challenged two weeks after infection were resistant. Measurement of cellular and humoral immune responses to Blastomyces dermatitidis antigens after subcutaneous infection showed the following. (i) Delayed-type hypersensitivity appeared 1 week after infection, and responses increased for 3 weeks thereafter. (ii) Proliferative responses in vitro appeared in spleen cells at 1 week and in contralateral lymph node cells at 3 weeks, (iii) Serum antibody, detected by an enzyme-linked immunosorbent assay, appeared 1 week after infection and then increased in titer. (iv) Peritoneal macrophages were activated to inhibit replication of B. dermatitidis in vitro by the first week after infection. Prior subcutaneous infection also resulted in rapid clearing of a second subcutaneous challenge, as well as resistance to a lethal intraperitoneal challenge. This resistance was associated with the development of cell-mediated and humoral immune responses. These data provide a chronological framework for selective transfer experiments.

Laboratory evaluation of an outbreak of nocardiosis in immunocompromised hosts.

Seven patients in a renal unit were proved to have nocardiosis in an interval of nine months. Six of these patients had received renal transplants. Serologic investigation suggested that two additional cases of undiagnosed pulmonary disease were also nocardial, and that there were no subclinical cases in patients or staff. Clinical-serologic correlations indicate that serologic evaluation may be a useful adjunct in diagnosis of nocardiosis, if used early and repeatedly, and to follow response to therapy. Epidemiologic investigations yielded cultures of Nocardia asteroides from air and dust inside the unit and elsewhere in the hospital. Biochemical, metabolic, physical and immunologic characterization of the isolates indicated that those from patients and those from the unit environment were identical, whereas some from outside the unit could be differentiated from these. The "epidemic strain" had type III antigen, which surveys indicated is not the most common type in human nocardiosis (it occurs in association with a minority of human cases). The isolates were of subgroup B, which has been associated with virulence. The characterization methods employed could be useful in studies of nocardial epidemiology. The laboratory studies indicate epidemic spread within the unit of a single organism, and current epidemiologic guidelines, which do not recommend respiratory isolation of cases of pulmonary nocardiosis, may need reconsideration particularly when there are immunocompromised hosts in the environment.

Strain differences in resistance to infection reversed by route of challenge: studies in blastomycosis.

The inbred mouse strains C3H/HeJ and DBA/1J have been shown to represent the extremes of susceptibility and resistance, respectively, to pulmonary blastomycosis. This pattern was completely reversed when challenge was performed by the intraperitoneal route, whether a virulent or an attenuated strain of Blastomyces dermatitidis was utilized. By a third route (subcutaneous), the differences were insignificant. Inhibition of replication of blastomyces in vitro by macrophages from both strains, before or after activation by subcutaneous infection, was similar.

Virulence of fungi: correlation of virulence of Blastomyces dermatitidis in vivo with escape from macrophage inhibition of replication in vitro.

Strains of Blastomyces dermatitidis which are virulent (V), attenuated (A), or avirulent (AV) in mice have been identified. Virulence of V has been reported to be associated with its ability to replicate in vivo, causing lethal infections in the lungs or in the peritoneal cavity. We report here that V, but not A or AV, has the ability to replicate in vivo in nonlethal subcutaneous lesions. The possibility that V was able to replicate in vivo by evading primary host defenses was investigated. We studied the interaction of macrophages and strains of B. dermatitidis in vitro. In 24-h cocultures, the replication of all three strains of B. dermatitidis was inhibited by macrophages from: (i) untreated mice (20 to 40%), (ii) mice that had recovered from nonlethal blastomycosis (40 to 60%), (iii) concanavalin A-treated mice (50 to 70%), or (iv) peritoneal exudates elicited by thioglycolate (65 to 80%). However, at 72 h in the first three types of cocultures A and AV remained inhibited, whereas V was not inhibited (0 to 4%). Only the most inhibitory macrophages, those induced by thioglycollate, inhibited V at 72 h, though V was again less inhibited than A or AV at that time. Thus, we show a correlation between virulence of V in vivo and its ability to escape from macrophage inhibition of replication in vitro.

Susceptibility differences of inbred strains of mice to blastomycosis.

The susceptibility of inbred strains of mice to pulmonary blastomycosis was studied to derive information relevant to host resistance and genetic background. Initial studies with eight strains with various H-2 backgrounds revealed the C3H/HeJ strain to be highly susceptible and DBA/1J mice to be resistant. These observations were confirmed with various challenge inocula. These differences were not dependent on the size of the challenge, the strain of Blastomyces dermatitidis, host age, or ability of the challenge to penetrate to the lower airways. Differences between the susceptible and resistant strains in lymphocyte proliferation in vitro and delayed-type hypersensitivity in vivo after nonlethal subcutaneous infection were not demonstrated; the susceptible strain made a significantly greater antibody response to blastomyces antigens as determined by an enzyme-linked immunosorbent assay. The resistance of the C3H/HeN strain of mice, which differs from the C3H/HeJ in sensitivity to lipopolysaccharide and lacks the macrophage cytotoxicity defect of the latter, suggests that the susceptibility of C3H/HeJ mice is not related to their C3H background or the H-2 locus. As the A/HeJ strain, which also has a macrophage cytotoxicity defect, was found in this study to be the second most susceptible strain, this also suggests macrophages as the subject for further study with respect to the mechanism of genetic resistance to this infection.

Atypical mycobacterial cervical adenitis: clinical presentation.

Atypical mycobacterium cervical adenitis (AMCA) is a disease primarily of childhood and usually presents as a unilateral mass or draining sinus. The pathogens are mycobacteria which are distinct from Mycobacteria tuberculosis, leprae and bovis (the typical mycobacteria). The atypical mycobacteria are readily recovered from the environment and are generally of low virulence. They are increasingly being recognized as pathogen for man though they are probably not transmissible from human contact. Most commonly these organisms are implicated in either pulmonary disease or lymphadenopathy. Fourteen cases of AMCA occurring in childhood are presented. A review of the bacteriology of the atypical mycobacteria is included. The clinical presentation, differential diagnosis, chemotherapeutic management and role of surgical intervention are discussed.