Delayed cutaneous hypersensitivity: epidemiologic factors affecting and usefulness in predicting diarrheal incidence in young Peruvian children

Cell-mediated immunity, as assessed by delayed cutaneous hypersensitivity, can be diminished by malnutrition and viral infections. In turn, decreased immune functioning might lead to more frequent or more severe infectious diseases. Delayed cutaneous hypersensitivity was assessed in young Peruvian children by simultaneous application of seven standardized antigens and a negative control (Multitest CMI). Response to tuberculin was frequent and was higher in children vaccinated with Bacillus Calmette-Guérin, response to tetanus or diphtheria toxoids was also good, especially in children who had received at least two doses of diphtheria-tetanus toxoids-pertussis vaccine. Two summary assessments, the number of positive responses and the sum of indurations of all positive responses provided useful measures of delayed cutaneous hypersensitivity. Responsiveness, as assessed by these summary measures, was inversely related to the incidence of diarrhea, identified by household surveillance for the 6 months after the skin test. Undernutrition, as assessed by weight for age or length for age, was also a significant determinant of the incidence of diarrhea, but not the duration of episodes, in this group of study children. Depressed cell-mediated immunity and malnutrition may be important risk factors for diarrhea in developing country children.     

Evaluation of the delayed skin reaction in chronically ill children

The evaluation of delayed cutaneous hypersensitivity by using a standardized test system offers an assessment of cell-mediated immunity. The number and diameter of positive responses induced by seven antigens result in a score. The study included 21 healthy children, 20 children with bacterial infections as well as 20 patients with chronic renal insufficiency. In addition, 16 children with cystic fibrosis were also studied. No differences in the skin reactions was found in children with bacterial infections, showing a score of 13 +/- 6 mm. But children with cystic fibrosis or with renal insufficiency exhibited a severe impaired cell-mediated immunity. To what extent the alteration of cell-mediated immunity affects the course of the various diseases, has to be investigated by further prospective studies.     

Cell-mediated immunity in schoolchildren assessed by multitest skin testing. Normal values and proposed scoring system for healthy children

Measurement of cutaneous delayed-type hypersensitivity (DTH) to a battery of ubiquitous antigens is an accepted means of assessing cell-mediated immunity (CMI). The recently introduced Multitest CMI system consists of a plastic multiple puncture device that simultaneously applies seven standardized recall antigens in a reproducible manner. A representative population of 448 healthy US schoolchildren was tested to determine incidence and size of DTH responses to each of the seven antigens. All responded to one or more antigens, the number and size of reactions generally increasing with age. Incidence of positive DTH tests was highest for tetanus and diphtheria toxoids, intermediate for streptococcal, Candida, and Proteus antigens, and lowest for tuberculin and Trichophyton antigens. These normal values, related to age and sex, can be a foundation for immunologic evaluation and are the basis of a proposed scoring system that distinguishes between normal DTH reactivity and diminished responsiveness.     

Unintended consequences: mandatory tuberculin skin testing and severe isoniazid hepatotoxicity

After mandatory school-enrollment tuberculin skin testing, a 4-year-old girl who was at low risk for Mycobacterium tuberculosis infection had severe isoniazid hepatotoxicity that was managed with a liver transplant. Although severe isoniazid hepatotoxicity is very uncommon in children, this case emphasizes the need to limit skin testing to persons who have a risk factor for infection and to educate parents on how to monitor for adverse effects during treatment.     

Preliminary immunological studies in spinal muscular atrophy

Evidence of impaired cell-mediated immunity in children with spinal muscular atrophy was obtained using lymphocyte transformation with PHA (20 children) and skin tests with tuberculin and DNCB (35 children). Laryngological examination of 16 children demonstrated hypoplasia of lymphatic tissue in Waldeyer's ring and the cervical lymph nodes. An ectodermal defect involving both spinal cord and thymus is suggested.The study was supported by agreement No. 05-002-N, NIH Bethesda     

A study of transfer factor for opportunistic infections in cancer patients.

Although supportive care during therapy of patients with malignancies has improved, infection remains the major cause of death in these patients. The problem of "opportunistic" infections is becoming more apparent as better antibiotics are found. The control of these infections depends in part on mechanisms of cell-mediated immunity. It has been demonstrated that delayed-type hypersensitivity can be transferred from one person to another. Therefore, we used transfer factor in the treatment of 15 patients, most with leukemia, who had fungal, viral, or mycobacterial infections that were not responding to conventional therapy. Seven of ten evaluable patients had therapeutic control of their infections while receiving transfer factor. Transfer factor appears to have contributed to these clinical improvements and is a modality of treatment that deserves further investigation.     

A study of transfer factor for opportunistic infections in cancer patients

Although supportive care during therapy of patients with malignancies has improved, infection remains the major cause of death in these patients. The problem of ?opportunistic”? infections is becoming more apparent as better antibiotics are found. The control of these infections depends in part on mechanisms of cell-mediated immunity. It has been demonstrated that delayed-type hypersensitivity can be transferred from one person to another. Therefore, we used transfer factor in the treatment of 15 patients, most with leukemia, who had fungal, viral, or mycobacterial infections that were not responding to conventional therapy. Seven of ten evaluable patients had therapeutic control of their infections while receiving transfer factor. Transfer factor appears to have contributed to these clinical improvements and is a modality of treatment that deserves further investigation.     

Thymus-dependent lymphocytes and delayed hypersensitivity in low birth weight infants.

The proportion of thymus-dependent (T) lymphocytes in the blood and the ability to mount cutaneous delayed hypersensitivity to a battery of antigens were evaluated in 50 low birth weight (LBW) infants when they were 3 months to 5 years old. There was a significant reduction in the number of T lymphocytes. Delayed hypersensitivity was impaired. The abnormalities were more pronounced in those with persistent growth retardation. It is suggested that continued postnatal depression of cell-mediated immunity in LBW infants may contribute to increased frequency of infections and immunopathological diseases.     

Tuberculosis Immunity in Sarcoidosis Studied with the Aid of Radioactive BCG Vaccine

1. The relationship between tuberculin sensitivity and tuberculosis immunity was studied in 39 cases of pulmonary sarcoidosis. The tuberculosis immunity was assessed by following the absorption of intradermslly injected BCG vaccine.
3. A depression of tuberculin sensitivity was noted chiefly in cases of generalized and/or chronic sarcoidosis.
3. Signs of enhanced tuberculosis immunity (the so-called positive anergy were not to be observed in the present series. In several grave cases of sarcoidosis, absorption of radioactive BCG vaccine was instead decidedly rapid, which suggests a decrease in tuberculosis immunity.
4. No parallelism emerged between the degree of tuberculin sensitivity and of tuberculosis immunity.     

Cell-mediated immunity assessed by Multitest CMI skin testing in infants and preschool children

Two hundred twenty-one healthy children, from 6 months to 7 years of age, were tested for delayed-type hypersensitivity (DTH) by the Multitest CMI (cell-mediated immunity) (Merieux Institute, Miami). This device permits the simultaneous application of seven standardized recall antigens and a glycerol diluent control. Younger children were tested on the back and older children on the volar surface of the forearm. Only 6.8% of the children were anergic, and most of them (11/15) were female. The DTH responses were present for one or more antigens in 93% of the infants. The DTH responses increased tremendously during the second year of life and increased slowly thereafter. A relatively high incidence of positive reactions was found for three of the tested antigens--diphtheria toxoid (79%), tetanus toxoid (62%), and Proteus (57%), in children in the preschool years, and accounted for three fourths of all positive reactions. Much lower levels were found for Streptococcus (25%), Candida (16%), Trichophyton (5%), and tuberculin (4%). Measurement of DTH by the standardized Multitest CMI system seems to be a convenient and reliable tool for assessing CMI function in infants and small children. The tool permitted us to measure patterns of DTH responses from infancy onward in a healthy population and to develop index values in a normal reference population with which any tested preschool child can be compared.     

Influence of MPR revaccination on tuberculin and sensitin skin reactions in children

ABSTRACT. Many viral diseases, as well as viral vaccines, have a transient effect in depressing cell-mediated immunity. The study group consisted of 52 children, aged 6.0–6.3 years. Thirty (57%) of them had been revaccinated against measles, parotitis and rubella (MPR vaccination). In MPR-revaceinated children, the mean skin reaction sizes were 4.7 mm, 4.1 mm, 4.3 mm and 2.1 mm to tuberculin, Mycobacterium avium, M. scrofulaceum and M. fortuitum sensitins, respectively. In non-revaceinated children ( n = 22), the respective mean skin reaction sizes were 3.0 mm, 2.8 mm, 2.9 mm and 0.8 mm. The difference between re- and non-revaccinated children was statistically significant with regard to reactions to M. fortuitum sensitin ( p <0.05). These results suggest that the influence of viral revaccination is different from natural infection or primary vaccination. The mechanism of stimulation of cell-mediated immunity—ither specific or non-specific—is unknown.     

Exposition d’une cohorte de nouveau-nés à une tuberculose bacillifère dans un service de néonatalogie

IntroductionA nursery nurse that was working in the neonatology service had been diagnosed with tuberculosis. As a consequence, the newborn infants were in danger of a possible contamination during a 4-month period.MethodologyOne hundred and thirty kids that had been in touch with the nurse were given attention. Prophylactic treatment for three months with isoniazid and rifampicin has been proposed to all families. Each of them was screened with a tuberculin sensitivity test and was given chest radiography initially and after three months.ResultsNone of the children was initially suspected for tuberculosis. Among the chest radiographies, 97.6% were normal and all the intradermal tuberculin were either negative or in the norm following a vaccination by the Bacillus Calmette-Guerin. In most cases, the treatment tolerance was high.ConclusionA 4-year-long surveillance ensured that no infant was infected. This procedure has established that the risk of transmission by a nurse is low, should it be for newborn babies, as long as guidelines are strictly adhered to.     

Exposure to open tuberculosis on a neonatal unit

The mother of a baby on the neonatal intensive care unit was found to have untreated open pulmonary tuberculosis. Tuberculin skin testing and chemoprophylaxis was offered to selected mothers and babies, depending on level of exposure. One of 3 mothers sharing a room with the index mother and 2 of 20 mothers whose babies were on the neonatal unit subsequently converted to tuberculin and were given isoniazid chemoprophylaxis. Isoniazid chemoprophylaxis was given to 13 exposed babies, none of whom tuberculin converted. Two babies were treated empirically for tuberculosis.     

Dissociation between tuberculin skin test and in vitro IFN-gamma responses following neonatal BCG vaccination

The in vitro IFN-gamma response to tuberculin was recently proposed as a correlate of vaccine-induced immunity to tuberculosis. IFN-gamma also plays a central role in the tuberculin skin test (TST), commonly used as a marker of mycobacterial infection. However, the use of TST as a marker of immunity to tuberculosis is limited for reasons ascribed mainly to interference by environmental mycobacteria. We prospectively investigated the relationship between the TST and cytokine responses to BCG in early infancy, a cohort with relatively low exposure to environmental mycobacteria. Neonatal BCG vaccination induced positive TST responses and predominant IFN-gamma responses to tuberculin in most newborns. However, the production of IFN-gamma, IL-5 and IL-13 was similar in TST responders and non-responders, and there was no significant correlation between the size of TST response and cytokine production. These results indicate that the IFN-gamma assay provides different information than TST in BCG-vaccinated newborns and could be a better marker of vaccine-induced immunity.     

Possible Role of Streptococcus pyogenes in Mucocutaneous Lymph Node Syndrome VI. Heightened Cellular Reactivity to Streptolysin-O in Mice Infected with S. pyogenes and in MCLS Patients

The present investigations were performed to determine, by using the macro-phage migration inhibition test (MIT), whether cell-mediated hypersensitivity to streptolysin-O (SLO) was developed in mice infected with Streptococcus pyogenes as well as in patients with mucocutaneous lymph node syndrome (MCLS), with the following results: 1. The splenic lymphocytes from murine hosts infected with B-346 op strain of S. pyogenes, which fails to induce cellular immunity in infected mice, showed a complete lack of responsiveness to SLO. In contrast, the mice infected with streptococci of Sv and S-43 strains, both of which possess an intrinsic activity of eliciting enhanced cellular hypersensitivity in the same species of animals, exhibited positive responses to the hemolysin from strep-tococcal culture supernatant. 2. Although a considerable number of MCLS patients in the acute phase of the illness failed to respond to SLO, a complete restoration of their responsiveness was observed in parallel with recovery from the acute illness. Conversely, all patients in the subacute phase of the disease reacted well in vitro to SLO, followed by a gradual decline of their responsiveness over a period of 1–2 weeks. Furthermore, the implications of these findings are discussed in association with the possible role of S. pyogenes as an etiological agent for MCLS.     

Immunologic aspects of phenobarbital hypersensitivity

Seven patients with hypersensitivity reactions to phenobarbital are described. Clinical manifestations consisted of fever and pruritic skin rash, often associated with adenopathy and conjunctivitis. Reexposure to phenobarbital or other anticonvulsants resulted in redevelopment of symptoms. In vitro lymphocyte stimulation studies with anticonvulsant drugs suggested a cell-mediated hypersensitivity reaction to phenobarbital.     

Cellular immunity in children with coeliac disease

The experimental evidence implicating defective cell-mediated immunity in coeliac disease, a condition where symptomatology is believed to be due to immunological reaction to wheat gluten, is often inconsistent and sometimes controversial.Studies of certain parameters of cellular immunity in four groups of pediatric patients were performed: coeliac patients on normal diet; coeliac patients consuming gluten-free diet; children with cow's milk allergy and a control group consisting of children with gastrointestinal complaints not due to gluten or cow's milk sensitivity.In all these assays no significant differences were found between treated or untreated coeliac children, infants with milk allergy or the gastro-intestinal control groups. On the basis of this study we could find no evidence of impairment of cell-mediated immunity in coeliac children. This conclusion is compatible with the hypothesis that intestinal damage may be due to a subpopulation of lymphocytes sensitive to gluten in persons with normal immune systems. In adults where abnormalities of cell-mediated immunity have sometimes been noted, the reason could be a loss of lymphocytes from the damaged mucosa of the gastrointestinal tract following prolonged antigenic stimulation. This indicates the need for strict adherence to a gluten-free-diet.Supported in part by a grant to A.A. by Stiftung Volkswagenwerk, FRG.     

Intensive short course chemotherapy for treatment of Greek children with tuberculosis.

This prospective study with an 18-month posttreatment follow-up evaluated the efficacy of intensive short course chemotherapy in Greek children with pulmonary or extrapulmonary tuberculosis. Between November, 1988, and March 1991 a 2-month regimen of rifampin, 10 to 12 mg/kg/day, isoniazid, 10 to 12 mg/kg/day, and pyrazinamide, 30 to 35 mg/kg/day, followed by rifampin and isoniazid for the remaining 4 months, was administered orally to 36 children with tuberculosis. Twenty-three boys and 13 girls ages 8 months to 12 years (mean, 5 1/2 years) were enrolled in the study. The diagnostic criteria for establishing tuberculosis were tuberculin skin test reactivity, radiographic findings compatible with tuberculosis, epidemiological data and clinical and laboratory findings. Four children had extrapulmonary and 32 had pulmonary tuberculosis; 9 of the latter were asymptomatic. Among the pulmonary cases there were 2 children with pleural effusion. Clinical response to therapy was apparent within 7 to 14 days; the pleural effusions resolved in 2 to 6 weeks and the pulmonary infiltrates cleared in 2 to 6 months. Hilar adenopathy regressed within 18 months or longer. No serious problems with drug tolerance or toxicity were noted during the treatment period. Temporary hyperuricemia and transient elevation in serum transaminases were observed in 11 patients but no drug modification was required. There were no posttreatment relapses. These findings suggest that intensive short course chemotherapy for the treatment of Greek children with pulmonary or extrapulmonary tuberculosis appears to be effective, safe, of good patient compliance and comparable to the longer treatment regimens.     

Cutaneous hypersensitivity reactions due to thiacetazone in the treatment of tuberculosis in Zambian children infected with HIV-I.

Tuberculosis is one of the most common infections in Zambian adults and children infected with HIV. In Africa, cutaneous hypersensitivity reactions attributed to thiacetazone during treatment of tuberculosis in adults infected with HIV-I have been well documented. This study monitored adverse drug reactions during treatment for tuberculosis over an 18 month period (1 April 1990 to 31 October 1991) in 237 children with a clinical diagnosis of tuberculosis (125 boys and 112 girls; 88/237 (37%) infected with HIV-I) and 242 control children (149 boys and 93 girls; 26/242 (11%) infected with HIV-I). Twenty two (9%) of the 237 children with tuberculosis developed hypersensitivity skin reactions during the course of treatment. Adverse skin reactions were seen more often in children infected with HIV than in those who were not (odds ratio 11.65, 95% confidence interval 3.07 to 34.88). These represented 19 (21%) of 88 children infected with HIV and three (2%) of 149 children not infected with HIV. These skin reactions occurred after a period of treatment ranging between two and four weeks among 14 children receiving the HST (isoniazid, streptomycin, thiacetazone) regimen and eight children receiving the HSTR (isoniazid, streptomycin, thiacetazone, rifampicin) regimen. Twelve (55%) of the 22 children who reacted adversely to treatment developed the Stevens-Johnson syndrome. All 12 of these children with the Stevens-Johnson syndrome were infected with HIV. The mortality among these children who developed the Stevens-Johnson syndrome was 91% (11 of 12 died within three days of the onset of the reaction). No further reactions were observed in the 11 children who recovered from the cutaneous hypersensitivity reactions after thiacetazone was discontinued over a period of six months of further treatment of tuberculosis. The results of this study were in part responsible for the recommendations put forward by the World Health Organization to avoid the use of thiacetazone in the treatment of tuberculosis in children infected with HIV.     

Transfer of tuberculin immunity from mother to infant

The purpose of our study was to investigate transfer of tuberculin immunity from mother to infant via breast milk by studying newborn lymphocyte blastogenesis induced by purified protein derivative antigen at 1-5 days of age, 4-6 wk of age, and 3 months of age. Our study consisted of four mother-infant groups: breast-feeding and bottle-feeding infants of tuberculin-positive and tuberculin-negative mothers. A difference in the groups was found only at 4-6 wk of age where 17% (4/23) of breast-feeding infants and 13% (2/15) of bottle-feeding infants of tuberculin positive mothers had lymphocyte blastogenesis to purified protein derivative. None of the infants of tuberculin negative mothers had purified protein derivative-induced blastogenesis. Analysis of covariance with tests for equality of slopes showed that the responses of tuberculin-positive mothers were significantly different from the responses of tuberculin-negative mothers (p less than 0.05). These studies suggest transplacental transfer of tuberculin immunity evident at 4-6 wk of age which wanes by 3 months of age. We could not find evidence of transfer via human milk.