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Acute infections (AI's) in pediatric patients infected or exposed to the human immunodeficiency virus (HIV). 765

IS POSTSTREPTOCOCCAL REACTIVE ARTHRITIS ASSOCIATED WITH HLA-B27 OR OTHER HLA-DR ALLELES? • 1836

NECESSITY OF SURVEILLANCE RENAL BIOPSIES DURING INTRAVENOUS CYCLOPHOSPHAMIDE(IVCYC) THERAPY IN SYSTEMIC LUPUS ERYTHEMA TOSUS (SLE) NEPHRITIS. 2173

Introduction of Dr. A. Ashley Weech for the John Howland Award: From the American Pediatric Society, April 27,1977, San Francisco, California

The ontogeny of human antibody responses to pneumococcal polysaccharide antigens was studied by determining whether the age at immunization affects the level and/or immunoglobulin isotype of antibody produced. Twenty-nine healthy infants between 2 and 18 months of age and 13 normal adults were studied. Responses were found to vary markedly with the age at the time of immunization and with the pneumococcal serotype tested. Three general patterns of isotype-specific antibody response were observed in the infants: a high response in IgG antibody occurred as early as 2 months of age following immunization with type 3 pneumococcal polysaccharide; little or no response was noted in either IgG or IgM antibody with types 6,18, and 19; and intermediate responses with IgM antibody increases greater than IgG increases were found for type 23. These data suggest that different factors control the immunologic response of infants to various pneumococcal polysaccharide serotypes following immunization at various ages.

A nonlethal influenza infection [A/PC/1/73 (H3N2)] was given to infant mice to determine (1) the pathology of tracheal epithelium and lung, (2) the time course of viral shedding from the nose and lung, and (3) the subsequent development of protective immunity during adulthood. Both desquamation of the tracheal epithelium and lung pathology similar to that described in adults after influenza infection were observed in the infant. Animals infected at 3 days of age show virus shedding in 12 of 13 infant mice that persists for at least 2 days longer than in the adult. This longer duration of influenza infection did not result from either malnutrition or from intralitter transmission of virus. Recovery from virus shedding in both the upper and lower airway occurred in the absence of detectable serum antibody in six of seven mice. Infants that recover from infection, when rechallenged during adulthood, manifest complete protection in 11 of 13 mice after nonlethal challenge and no mortality after lethal challenge.

Orbital cellulitis is an infection involving the orbit and adjacent periorbital tissue without involvement of other facial tissues. The bacterial etiology, in contrast to that of facial cellulitis, has not been clearly defined. To gain insight into this problem, bacteriological and clinical data on 86 children with orbital cellulitis were reviewed. Peak age incidence was 2-4 yrs. and in 84/86 cases the involvement was unilateral. Differences in clinical presentation enabled identification of two distinct groups. Group I consisted of 42 children with an adjacent soft tissue focus of infection and included 30 children with recent trauma to the area. Group II included 44 patients with no apparent focus of infection. Blood cultures obtained on 21 patients in Group I were positive in only one; the isolate was S. aureus. In Group II, 10/31 blood cultures were positive; 8 isolates were H. influenzae and 2 were S. aureus. The difference in incidence of bacteremia was significant (p< 0.02). S. aureus and/or Group A streptococcus were recovered from wound or conjunctival cultures in 74% of 39 cases in Group I and 24% of cases in Group II (p

A family has been evaluated in which the observation of depigmented lesions of the skin constituted the major clue for establishing the diagnosis of incontinentia pigmenti (IP) in the otherwise unaffected mother of the proband. Such lesions are not commonly appreciated as manifestations of IP. They usually form streaked, hypomelanotic macules in the calves but may be found in other areas as well. Their presence in adult relatives of children with IP may provide the only clue of the inherited character of the disease, as in this family. Hence, a search for such lesions is important prior to genetic counseling of these families.

Although the familial occurrence of primary immunedeficiencies is not uncommon, the occurrence of immunedeficiencies among female family members is unusual. Most cases of familial immunedeficiencies occur in male siblings and usually obey an x-linked recessive mode of determination. Data are presented on two sisters with identical primary immunedeficiencies. One sister presented with recurrent otitis, pyoderma, and H. influenzae ventriculitis. The second sister presented with what appeared to be pauciarticular rheumatoid arthritis. Both sisters had identical findings of decreased concentrations of IgG and IgA, normal concentrations of IgM, deficient antibody production, and absent lymphoid follicles and germinal centers in their lymph nodes, in the presence of normal cell-mediated immunity. These data are consistent with the diagnosis of primary immunedeficiency with hyper-IgM (dysgammaglobulinemia, type I) appearing for the first time in sisters. Chromosomal analysis revealed both sisters to have normal female karyotypes and study of the family pedigree failed to reveal consanguinity. This immunedeficiency probably represents a previously undescribed autosomal recessive form of primary immunedeficiency with hyper-IgM.

Antibody responses to Pneumococcal Polysaccharide type 3 (PnAb) are independent of T Cells in the murine model. To confirm the putative T cell independent nature of the response in humans, we studied PnAb secretion by in vitro lymphoctye cultures. Twelve day culture supernatants of blood mononuclear cells drawn before and 1 and 3 weeks post-immunization with Pneumococcal Vaccine were assayed for total IgG and PnAb by ELISA. Maximum PnAb secretion occurred at 1 week post-immunization in both unstimulated (177 ± 90 ng/ml) and pokeweed stimulated (300 ± 200 ng/ml) cultures. PnAb secretion was not due to polyclonal stimulation since no change in anti-tetanus toxoid secretion was found and a paradoxical decrease in total IgG secretion occurred (pre=2.4 mcg, 1 wk post = 1.3 mcg, p < .001). Addition of purified pneumococcal type 3 antigen (.001-10 ng/ml) had no effect on PnAb secretion. B cell enriched T cell depleted cultures had similar PnAb kinetics to unfractionated mononuclear cells: pre = 1.5 ± 1.6 ngAb/mcgIgG, 1 wk post = 180 ± 175 ngAB/mcgIgG, 3 wk post = 381 ± 380 ngAb/mcgIgG. Addition of T cells ± pokeweed mitogen, purified IL-2, or allogeneic T helper factor from mixed lymphocyte culture supernatant had no effect on PnAb secretion expressed per mcg total IgG. These studies suggest that Pneumococcal Polysaccharide type 3 is a T cell independent antigen in humans which may activate B cells in a manner distinct from conventional protein antigens.

Evidence was sought for the transfer of influenza specific non-humoral immunity from mother to infant mouse. We studied infant mice born to 3 groups of mothers: (1) influenza immune mothers in whom influenza-specific serum antibody was suppressed by passive antibody received prior to non-lethal influenza infection (I-Ab), (2) influenza immune mothers with antibody (I+Ab) and (3) non-immune controls. I-Ab and control mothers as well as their infants showed no evidence of influenza specific serum antibody 7 days after infection. In contrast, high levels of serum antibody were found in all I+Ab mothers and infants 7 days after infection (P

Previous studies from this laboratory demonstrated that patients with inactive rheumatic valvular disease generally maintain elevated levels of antibody to Group A streptococcal carbohydrate (A-antibody) following acute rheumatic fever, while A-antibody levels fall to normal in other post-streptococcal states. Immunization of rabbits with killed Group A streptococci was performed to define the conditions necessary to produce sustained A-antibody. A-antibody was assayed by the Farr technique utilizing 14C-A-carbohydrate. Rabbits immunized by Lancefield's schedule of thrice-weekly IV injections for 4 weeks produced very high A-antibody levels which promptly fell; boosting with a similar schedule induced the same response. Transient low A-antibody levels followed a single IV immunization, peaking at 6-8 days and falling by 14-20 days. Single IV boosts consistently recalled transient A-antibody responses. In contrast, a single subcutaneous (SC) dose of vaccine in complete Freund's adjuvant (CFA) led to sustained high A-antibody levels. Peak levels were reached by 35-45 days and remained elevated for at least 120-185 days. SC vaccine without CFA induced low level A-antibody which declined promptly and disappeared by 50 days. Because adjuvant effect appears to correlate with slow antigenic release from the depot, these data support the possibility that the sustained serum A-antibody levels in rheumatic heart disease represent chronic anti-genic stimulation by streptococcal A-carbohydrate or by cross-reactive tissue antigens.

Immunoregulatory cell function was tested prior to therapy in 3 children with systemic lupus (SLE) and 4 with mixed connective tissue disease (MCTD). Diagnoses were made by the American Rheumatism Association's clinical criteria and elevated anti-DNA with low C3, C4, and/or CH50 in SLE or elevated anti-ENA of RNP specificity in MCTD. Suppressor/helper function was evaluated by comparing pokeweed mitogen-induced IgG and IgM secretion in individual cultures of patients' lymphocytes (PBLs) with that produced in co-cultures of PBLs of patients and normals. SLE patients produced more IgG (mean ± S.E. = 10,100 ± 6100 ng per 2 × 106 cells) in individual cultures than did 105 normals (1,450 ± 2,100 ng); IgM production was similar in the two groups. Co-cultures of SLE PBLs with normals suggested normal immunoregulation in one patient, loss of suppressor function in one, and excess helper function in the other. Three of 4 MCTD patients produced normal amounts of IgG (3980 ± 1780 ng) and normal immunoregulation was found in co-culture. One MCTD patient had markedly low IgG (220ng) and IgM (70ng) production and this patient excess suppressor function in co-culture. Our results suggest that children with SLE may produce more IgG in response to pokeweed mitogen than normals and a variety of immunoregulatory abnormalities may be found in children with active, untreated autoimmune disease.

To determine if human antibodies to Pneumococcal Polysaccharide type 3 are restricted in IgG subclass diversity, we tested sera from normal volunteers drawn before and after immunization (n=9). Subclass-specific ELISA techniques using murine monoclonal antibodies to human IgG1, IgG3, IgG4 and the Ig fraction of sheep anti-IgG2 were developed. Enzyme-conjugated antibodies were shown to be specific by testing against homologous and non-homologous IgG subclasses in direct ELISA using WHO myeloma reference standards. The relative sensitivity of each subclass antibody conjugate differed as shown by reaction in competitive binding ELISA where 50% inhibition of binding for IgG1=0.1 mcg, IgG2=1.75 mcg, IgG3=0.25 mcg and IgG4=0.175 mcg. End-point serum titer was defined as that dilution giving an optical density twice nonspecific background and was normalized to reflect the relative sensitivity of each subclass-specific assay. Preimmunization geometric mean titers of serum antibody were IgG1= 13.5, IgG2=258.7, IgG3=7.0, and IgG4=3.5. Post-immunization titers were significantly higher for IgG2=955.0 (p

The role of cell-mediated immunity In the pathogenesis of acute rheumatic carditis was investigated by measuring in vitro cytotoxicity of peripheral lymphocytes to myocardial fibroblasts. The microcytotoxicity assay was adapted using as target cells, 51Cr-labelled fibroblasts derived from explants of left atrial appendage. Lymphocytes and plasma were separated from peripheral blood of patients and incubated with target cells in Eagle's minimal essential medium containing 10% fetal calf serum. An effector:target cell ratio of 200:1 was utilized. Cytotoxicity was quantitated as % release of 51Cr activity. Studies to-date on lymphocytes from four non-rheumatic individuals showed a mean cytotoxicity of 9% (0-20%). Lymphocytes from two patients with acute rheumatic fewer without carditis, showed only 12% and 18% cytotoxicity. In contrast, lymphocytes from two patients with acute rheumatic carditis released 81% and 90% of the radioactivity. Three patients with chronic rheumatic carditis showed cytotoxicity of 10%, 11% and 34% respectively. No significant cytotoxicity was obtained with fresh plasma alone and no enhancement of cytotoxicity occurred following addition of homologous plasma to lymphocytes. Lymphocytes from the above patients produced similar low levels of cytotoxicity (less than 20%) when skin fibroblasts were used as target cells. These data suggest that lymphocyte-mediated cytotoxicity to myocardial tissue is present and may play a role in the pathogenesis of rheumatic carditis.

Thirty-seven infants delivered between 10/78-12/78 were followed throughout the 1/79-3/79 influenza A Brazil (HINI) epidemic. At delivery cord and maternal blood was collected. Motherinfant pairs were monitored for respiratory illness. Nasal wash samples obtained from 3 mothers, I neonate and I sibling at the time of acute illness were positive for A Brazil (HINI). Acute and convalescent sera were drawn from each pair, and again at the termination of the study. The sera were analyzed by ELISA for H1 hemagglutinin specific IgG antibody. Twenty-one mothers were seronegative and 16 were seropositive for influenza antibody at the time of delivery. During follow-up, 15 infants of the seronegative mothers and 8 infants of the seropositive mothers had symptoms of influenza illness. Seven infants of the seronegative mothers and only one infant of the seropositive mothers had a rise in influenza titer (P

DiGeorge Syndrome (DGS) consists of the association of CHD, immunodeficiency, and hypoparathyroidism. Since recent data suggest that DGS is more common than usually appreciated, we prospectively tested immune function during the first 3 months of life in 22 infants referred for evaluation of CHD and 7 age-matched controls. CHD patients as a group had T-cell rosettes (TCR) lower (mean ± SE = 48% ± 5) than age-matched controls (64% ± 4) or older normals (71% ± 2). Eight of the 22 CHD infants had TCR below 2 standard deviations from the mean for age-matched controls (

DEPRESSED LEVELS OF ANTIBODY TO GROUP A STREPTOCOCCAL CARBOHYDRATE IN JUVENILE RHEUMATOID ARTHRITIS

Respiratory infection with Mycoplasma pneumoniae in children is uniformly considered to be mild and benign. patients with sickle cell disease may have frequent episodes of pulmonary infection and/or infarction and are known to be unusually susceptible to pneumococcal disease including overwhelming sepsis. We recently observed 4 children (ages 4–12 years) with sickle cell disease who had pulmonary infection attended by a severe course of illness. Clinical features included diffuse pneumonia (4 patients), pleural effusion (2), prolonged febrile states (3), respiratory distress (3), moderate to marked leukocytosis (4) and pleuritic pain (3). None of these patients responded to penicillin and/or ampicillin. All 4 patients had significantly elevated cold hemaglutinin titers. M. pneumoniae was isolated from both patients cultured for this organism. In 3 patients serologic evidence of M. pneumoniae infection, as manifested by a rise in the mycoplasma complement fixation (CF) or growth inhibition (GI) titer, was obtained. One patient showed no rise in CF titer but an elevation of the GI titer. The course of this disease was of a severity rarely observed in M. pneumoniae infection. The reason for the unusual severity of this ordinarily benign disease in this group of patients is not clear at present but may be related to concomitant pulmonary infarction or to an underlying immune defect. In addition to pulmonary infarction and pneumococcal infection, the differential diagnosis of pulmonary disease in patients with sickle cell disease and leukocytosis must include mycoplasmal infection, especially when penicillin unresponsiveness is noted.

Androgenic hormones have been reported to increase erythropoiesis by direct stimulation of erythroid marrow. Because androgens also possess a renotrophie effect, the contribution of reneal mass to erythropoietin production was investigated. Rats were injected for 6 weeks with depotestosterone (in cotton seed oil), prior to and after nephreetomy. controls received cotton seed oil or were sham-operated. Endogenous erythropoietin production was suppressed during the experiment by transfusion with packed red blood cells. Erythropoietin production was stimulated by subjecting the animals to hypoxia for 18 h. Kidneys were then removed and blood obtained for erythropoietin bioassy. Hypoxia resulted in variable increase in erythropoietin levels in all animals. This vairation in erythropoietin production was found to correlate closely with the relative renal mass (renal weight : boy weight ratio), with erythropoietin levels increasing proportionately to renal mass in animals receiving either testosterone or in controls. Animals not subjected to hypoxia did not show any increase in erythropoietin levels, despite administration of androgens and resultant increase in renal mass. These studies show that the enhanced production of erythropoietin by androgens during hypoxia is due not only to its direct action on bone marrow, but is also related to the renotrophic effect of the steroid.

The use of “transfer factor” to correct a partial defect in cellular immunity to Candida albicans was studied in an 8-year-old girl with chronic granulomatous mucocutaneous candidiasis. The patient first presented at age 5 years with extensive deforming encrusted lesions on her face, head, trunk and extremities. No evidence of endocrinopathy or antibodies to endocrine tissue was found. Her general humoral immunity was intact. She had a normal complement of granulocytes and lymphocytes. Candida aggregation activity was present in her serum. Her skin test response to C. albicans extract was consistently negative. Her lymphocytes underwent blastogenesis to PHA, diphtheria toxoid and C. albicans extract. However, in the presence of exogenous transfer factor, blastogenesis to candida increased. Transfer factor extracted from her cells did not transfer immunity to non-sensitized cells. Amphotericin B therapy cleared her skin lesions temporarily, but neither fresh frozen plasma injections nor 5-fluorocytosine was effective. Following 2 injections of transfer factor, she developed a positive skin test response to C. albicans extract, and her lymphocytes produced leukocyte inhibition factor (LIF) to candida. After a third injection there was appreciable clearing of the skin lesions. These findings indicate that exogenous transfer factor can restore cellular immunity to candida in a patient with chronic mucocutaneous candidiasis and may be an effective treatment for this disease.

A population of 160 children (mean age = 6.6 years) was followed at 2-month intervals over a 2-year period with serial determinations for 3 streptococcal antibodies: antistreptolysin O (ASO), antideoxyribonuclease B (anti-DNAse B) and anti-nicotinamide-adenine-dinucleotidase (anti-NADase). Antibody dynamics of the more than 1,000 sera collected (mean no. bleedings/child = 7.3) were examined by comparing geometric mean titers (GMT) and significant rises at different times of the year. GMTs for all 3 antibodies increased during the summer and fall when streptococcal skin infections were common but leveled off or fell during the winter and spring despite a high prevalence of respiratory illness and positive throat cultures for group A streptocci (up to 70%). The smallest number of rises for all 3 antibodies occurred during the respiratory season. During the summer anti-DNAse B titers tended to rise more sharply and reached maximum levels sooner than the other two antibodies. Although GMTs were lowest in the 1–3-year age group, these children also showed marked rises during the summer and fall. Rises in ASO were less frequent than responses in the other two antibodies, especially after 3 years of age. Plateauing of GMTls occurred at a later age for anti-DNAse B than for the other two antibodies. This extraordinary, inverse seasonal pattern of antibody levels and responses emphasizes the predominant influence of skin infections in this population and raises the possibility of a curious immunological unresponsiveness to streptococcal respiratory infections during the winter month, behavior which may contribute to the low frequency of acute rheumatic fever relative to acute nephritis in this population.