Search

The current state of knowledge of lung defenses has been reviewed. First, mechanical factors such as aerodynamic filtration and mucociliary transport were considered. Then, in general terms, the contributions of alveolar macrophages, neutrophils, lymphocytes, and immunoglobulins, and the roles of complement, antiproteases, lysozyme, and fibronectin were examined. Interactions between these components may regulate their effect. Finally, the responses to five specific micro-organisms were reviewed to illustrate different aspects of the lung's defenses. Streptococcus pneumoniae was selected as a representative extracellular bacterial pathogen, Mycobacterium tuberculosis as an intracellular bacterial pathogen, Mycoplasma pneumoniae because it elicits significant humoral and cell-mediated immunity, respiratory syncytial virus as an example of a local viral pathogen, and measles as a viral pathogen that causes generalized disease. It was shown that these responses may not always be beneficial for the host. For each of the five infections, recommendations for improving the outcome were made.

Summary Comparative studies of pathogenicity and antigenicity were made of four strains of herpes simplex in order to investigate some of the differences which may exist between strains of a single viral species. Mice, rabbits, guinea pigs, white rats, hamsters, cotton rats and chick embryos were observed after inoculation of mouse brain emulsions by various routes. Although herpes simplex is a pantropic virus, differences between strains are accentuated by certain tests. Thus, death of the majority of animals following corneal infection of the rabbit or intranasal inoculation of the cotton rat can be used to indicate strains with prominent neurotropic tendencies, while marked local reactions after intradermal injection of the guinea pig are indicative of dermatotropism. These distinctions probably hold only for the particular species of animals and routes tested, as the strain which was most dermatotropic in our laboratory, “O”, was the cause of fatal encephalitis in a human being. It is not known whether these differences in potentiality of herpes strains are of epidemiologic significance. The development of neutralizing antibodies in rabbits after corneal and intra-abdominal inoculations was studied. Significant levels of antibody were present by three weeks and peak titers were attained by six weeks. The serologic relationships were investigated by testing the corneal reactivity of immunized rabbits to homologous and heterologous strains and by cross neutralization tests in mice and chick embryos. The chick embryo tests were found to be the most sensitive and satisfactory for this purpose.

Summary The virus of vaccinia may be cultivated for at least 3 weeks in roller-tube cultures of mononuclear cells obtained from the circulating blood of the rabbit. Following inoculation of the virus, the addition of homologous antiserum to this system does not bring about permanent inactivation of the virus. Mixtures of antiserum and virus giving no reaction in the rabbit's skin give rise to an infection of these mononuclear cells. The infection is maintained even if further amounts of antisera are subsequently added to the culture. The addition of 1 or 2 hemolytic units of complement in the form of fresh normal rabbit-serum does not enhance the effectiveness of the antiserum. In cultures of mononuclear cells, the virus does not increase as rapidly nor reach as high a titer as in cultures consisting principally of fibroblasts. In cultures of mononuclear blood-cells, complement and antiserum appeared to be more effective in temporarily suppressing the activity of the virus than in cultures consisting principally of fibroblasts. The possible application of these observatins in vitro to the dissemination of virus through the animal body and to the maintenance of latent infections is discussed.

Summary Complement-fixation tests with an egg-yolk-grown lymphopathia venereum antigen (“Lygranum CF”-Squibb) were performed on sera from patients with atypical pneumonia and from individuals with known exposure to venereal infection. The results were compared with those obtained with sera from patients with upper respiratory infections and influenza and from normal individuals. All tests included egg-yolk control antigens and Kolmer complement-fixation tests for syphilis. A modified micro Kolmer technic was used in testing with the “Lygranum CF” antigen which was comparable in sensitivity to the method recommended by the Squibb workers. There were 98 “controls,” 102 atypical pneumonia patients and 126 venereally exposed individuals who had satisfactory tests. Complete fixation with a serum dilution of at least 1 to 5 was found, respectively, in 28.6, 28.4 and 39 per cent of each of these groups. There was no correlation between the Kolmer serological test for syphilis and the “Lygranum” complement-fixation test. However, in the venereally exposed group there was a considerable number of patients whose serum reacted with the egg control antigen. Most of these showed positive Kolmer reactions. This phenomenon impairs the diagnostic value of the test among patients with venereal diseases. Twice as many atypical pneumonia as control sera reacted with the normal egg antigen. This observation is discussed. Quantitative titrations on a number of the positive sera from each group failed to reveal any clear-cut differentiation. However, quantitative study of more than one specimen of sera from each of 11 patients with respiratory infections revealed that 7 had a change in titer with progression of their disease. In 2, there was a rise in titer and in 5, a fall. In 4 of these 5, the first specimen to be examined was drawn after the second week of illness. Cutaneous and complement-fixation tests with “Lygranum” were performed on 77 venereally exposed patients. The serological test appeared more sensitive, though there were a few instances in which the cutaneous test was positive when complement fixation was negative.

Summary Serial specimens of sera obtained during the acute and early convalescent phases of illness from 8 individuals with clinical mumps were studied for the appearance of specific antibodies. The tests employed were complement fixation with soluble and viral antigens, agglutination-inhibition, and agglutination of human erythrocytes modified by treatment with mumps virus (Burnet test). The individual variations were marked. Nevertheless, in 6 of the 8 patients a complement fixing antibody was the first to be detected, and after 2 weeks all of the 8 patients reacted positively in 2 or more of the tests. There was no correlation in titer nor time of appearance of the complement fixing, agglutination-inhibiting nor modified cell agglutinating factors. It is therefore suggested that these represent distinct and independent responses to infection with the virus of mumps. Addendum. Since this manuscript was submitted for publication a paper on this same subject by Aikawa and Meiklejohn has appeared. (Aikawa, J. K. and Meikeljohn, G., 1949; The serological diagnosis of mumps. A comparative study of three methods. J. Immunol. 62, 261–270.) These authors also found the three tests studied by us to be valid indicators of the presence of antibody to the mumps virus.

Summary and Conclusions Analysis of 68 sera from infants under 6 months of age showed that although 31 of 34 newborns had detectable mumps complement fixing (CF) antibodies, the serum from only 1 infant over 44 days of age gave a positive CF reaction. The rate of disappearance of mumps complement fixing (CF) and agglutination-inhibiting (A-I) antibodies was followed in 4 infants, and although there was considerable variation, the average time of disappearance for both antibodies was surprisingly similar—53 and 45 days respectively. Since placenta-passing mumps antibodies as determined in this study disappear from the circulation rather early in life, one must look to other factors to account for the rarity of mumps in infancy.

Results with a VZV skin test as a marker of past infection were compared with histories of chicken pox and specific antibody detected by ELISA in 100 individuals—25 of whom were pediatric patients with malignant diseases. A negative or uncertain history was not reliable, neither were the skin test results among the oncology patients. However, among the normal individuals, the skin test when compared with the ELISA had a sensitivity of 85%, a specificity of 100%, and a positive predictive value of 100%.

Nonspecific enhancers of resistance may include (1) viral interference, (2) interferon, (3) interferon inducers, (4) bacterial interference, (5) bacterial products such as Coley's "toxins," endotoxins, or staphylococcal, BCG, and Corynebacterium parvum vaccines, (6) transfer factor, and (7) well-defined chemicals such as dinitrochlorbenzene, levamisole, and vitamin C. These are discussed only as they have been applied to man to learn whether or not they have enhanced his ability to resist infections and growth of tumors. Preliminary studies suggest that a variety of relatively safe and effective nonspecific enhancers may soon be available for clinical use.

SummaryQuantitative data are presented to show that both the mumps viral complement fixing and agglutination-inhibiting antibodies are transmitted from mother to child without any significant loss in titer. In contrast, titrations for streptococcus MG agglutinins show in most of the instances at least a 4-fold diminution of the maternal titer in the cord blood. There was no difference in results when specimens were from premature or full term infants.

Serial determinations of rubella hemagglutination inhibition (HI) antibody levels were performed on serum specimens obtained from 223 women who had rubella during pregnancy and their 223 children with congenital rubella. The decline in HI antibody following congenital infection was more rapid than following postnatal infection. By the end of five years, 27 of these children no longer had detectable HI antibody, although all mothers still had antibody. Among 270 children with congenital rubella who had reached their fifth birthday, 50 (18.5%) were seronegative. When 19 such seronegative children were given rubella vaccine [HPV]-77 (high-passage virus strain), only two (10%) of them seroconverted. In contrast, 134 of 135 (99%) normal children of the same age seroconverted.

VIRAL hepatitis and aplastic anemia are not rare. Their concurrence might therefore represent chance. However, within a four-year period, we have encountered 5 patients, all of whom died of aplastic anemia while convalescing from nonepidemic viral hepatitis. This experience suggests that more than chance may be involved and that the sequence of events may be causally related. This communication reports these 5 cases, including 4 autopsies, and compares them with 3 others found in the literature.1 All our patients were children or young adults who lived on Long Island or in New Jersey. Four were males. Pancytopenia followed the onset . . .

A spirillum was repeatedly recovered by blood culture from two children. This organism resembled the Spirillum minus which has long been associated with one form of rat bite fever, Sodoku. In Sodoku the spirillum is usually recovered by animal inoculation and no previous record has been found in which a diagnosis has been made by blood culture. The organisms recovered from the two patients were morphologically indistinguishable from the classical Spirillum minus, but were unique in that they could be maintained for many months on standard liquid and solid bacteriologic media. Their in vivo resistance to penicillin and arsenicals was marked and therefore also unusual. Both patients were seen because of recurrent fever, eruption and symptoms referable to the central nervous system, respiratory and intestinal tracts. The first child was admitted to The Mount Sinai Hospital debilitated and febrile. A spirillum was recovered repeatedly on routine blood culture, although there was no definite history of rat bite. Treatment with arsenicals and penicillin and streptomycin failed and the patient died. The second child was admitted with a history of repeated respiratory infections and indolent skin ulcers and hemiplegia. He had apparently been bitten by a rat while in Florida 3½ years before the spirillum was first recovered from his blood. Treatment with penicillin and sulfarsphenamine was ineffectual. The organism was sensitive in vitro to streptomycin but as much as 2 gm. a day for several months failed to do more than induce several negative blood cultures. Treatment with aureomycin finally succeeded in sterilizing the blood stream and healing the ulcers. Coincident with this there was a striking improvement in the child's general condition. The clinical course of these two patients and the unusual bacteriologic findings set them apart from classical rat bite fever and suggest use of the term "Spirillum Fever."

IT HAS been shown that colonization by one strain of Staphylococcus aureus of the nasal mucosa of adults 1-4 and the nasal mucosa and umbilicus of infants 5-11 interferes with subsequent colonization at those sites by other strains of coagulase positive staphylococcus. This phenomenon, called bacterial interference, has been successfully utilized to curtail epidemics of S aureus in newborn nurseries. A similar protective effect has been demonstrated in adults. In two separate controlled studies, carriers of S aureus who were deliberately colonized following local nasal and systemic antibiotic therapy were protected from recolonization when directly challenged by a second strain of S aureus . 1,2 Cessation of recurrent bouts of furunculosis following recolonization was reported recently in one individual 3 and in one family. 4 The present study demonstrates that artificial colonization with the 502A strain not only protects families against recolonization by the original resident strain of S aureus but

E. RICHARD STIEHM (UCLA Center for the Health Sciences, Los Angeles, Calif.): Many patients with rubella syndrome have a systemic immunologic deficiency. Were your sero-negative rubella patients tested for their response to other antigens to exclude a nonspecific diminution of antibody response, rather than specific tolerance to rubella virus? Dr. FLORMAN: Several of our children by history had had regular measles vaccination. It was possible for us to test their sera and find that they had responded with perfectly fine titers of antibody against rubeola. JANET HARDY (Johns Hopkins Hospital, Baltimore, Md.): Dr. FLORMAN and his associates have attempted to answer some interesting and important questions. Individual variation in response to immunologic stimuli may perhaps lead to the emergence of a number of different answers. In this regard I would like to comment on a patient followed by Dr. JOHN BORDLEY and me, with the help of Dr. JOHN SEVER. This was a child born early in 1964 whose mother presumably had inapparent rubella approximately one-third the way through her pregnancy. She has a history of exposure. When her child was just over 1 year of age her serum rubella HAI titer was 1:512. At this age the child was found to have a severe hearing loss (50 dB in the right ear, 80–90 dB in the left ear), small body size, and mild peripheral pulmonic stenosis. His rubella HAI titer was 1:128; further serologic determinations at 30 and 36 months of age showed no detectable HAI antibody in a dilution of 1:4, nor did he have neutralizing antibody at 30 months. At 5 years of age he was exposed to, and developed, clinical rubella, with lymphadenopathy and rash. Attempted viral isolation 5 days after the appearance of the rash was not successful but some 3–4 weeks later his rubella HAI titer was 1:512. Subsequently, he experienced a further depression of auditory sensitivity and he now has a severe hearing loss in both ears. He is a highly intelligent child—IQ 137 (Leiter nonverbal test) and there is no question about the validity of the test results. One further comment pertains to our experience in an epidemiologic study carried out in 1967 by Dr. JOHN GRANT, Maryland State Department of Health. This study was a survey of all the children born in 1964 in several areas in Frederick County, Maryland to determine the number of children with congenital rubella. Of some 600 children screened, 8–10 had defects compatible with congenital rubella, but more than 50% had no rubella HAI antibody. This points out the problem of the limited usefulness of serologic study in the retrospective diagnosis of congenital infection in both the clinical and epidemiologic setting. Dr. FLORMAN: I think you have touched on the really crucial point, and that is: are these children who are seronegative susceptible to reinfection by wild virus? Your case is very pertinent. JOSEPH W.ST.GEME, Jr. (UCLA Medical School, Harbor General Hospital, Torrance, Calif.): Is it possible that these children have very low levels of neutralizing antibody? Dr. FLORMAN: We have not yet tested these children who no longer have detectable HI antibody for the presence of neutralizing antibody. Dr. HARDY: May I comment on that? Because we have, and there is no neutralizing antibody. PEARAY L. OGRA (State University of New York, Buffalo, Buffalo, N.Y.): I would like to raise one question in regard to the disappearance of rubella virus antibody in these children. It has been reported in the past that there are children with congenital rubella syndrome who do not have any detectable neutralizing or hemagglutinizing antibody in the newborn period. Is it possible that some of these children who had no detectable HI antibody after 6 months—that the preexisting serum antibody was all transplacently acquired maternal antibody—failed to have an immunological response to start with? Secondly, did you try by any means to identify immunologically the immunoglobulin class with which this antibody activity was associated? Presence of γM antibody would suggest active fetal production rather than maternal transport. Dr. FLORMAN: As you noticed in our charts, we excluded all determinations on patients' sera except those that were obtained after 6 months of age, because we too were concerned that the determinations done earlier might represent transplacentally acquired antibody. Consequently, all these children had responded with detectable levels of antibody earlier in life, even those who by the age of 2–5 years had lost it. DOUGLAS E. Cox (Wayne State University Medical School and Children's Hospital of Michigan, Detroit, Mich.): Is your twin, which was discordant for congenital rubella and became seronegative before 5 years of age, dizygous by placentation and membranes or by difference in some genetic marker? (Subsequent communication with the authors (viz., Dr. Louis Z. COOPER) has confirmed clear documentation of dizygosity by both criteria.)

Previous experience with immune serum globulin (ISG) indicated 1) that it did not prevent viremia in children with rubella infection, and 2) that it did not prevent congenital rubella. This report describes the protective effect of an experimental lot of high titer antirubella human immunoglobulin (RIG) in 33 children exposed to the Brown strain of rubella virus (RV). RIG was given to 22 of the susceptible children 24 or 96 hours after intranasal exposure to RV. Six other children received ISG. The dose of RV was either 104TCInD50 or 101TCInD50, and the dose of immunoglobulin was 0.3 ml/kg of body weight. In the group that received RIG: 1) passively acquired rubella antibody was detected transiently after inoculation in 15 children; 2) no detectable viremia was observed; 3) pharyngeal shedding of RV was decreased and 4) the rubella specific IgM response was depressed. RIG was more effective when given at 24 hours against low dose virus challenge, preventing or delaying seroconversion; it was less effective in modifying infection when given at 96 hours after high dose challenge. These data suggest that RIG may be useful for the prevention of congenital rubella.

CONJUNCTIVITIS and photophobia are among the classical signs and symptoms of measles. The photophobia usually disappears when the rash fades, and it is thought to be due to keratitis. Every case of measles studied early in its course by Thygeson was found to have keratitis. What is not generally known is that signs of keratoconjunctivitis may appear in the prodromal stages of measles and persist for as long as 3 months. Because these signs may be found even in modified measles, their presence may serve as a useful and prompt clinical aid to diagnosis in doubtful situations. It is the purpose of this communication to describe and differentiate the keratoconjunctivitis of measles as seen by slit-lamp biomicroscopy and to report our experience with 34 children. Origin and Plan of Study Our attention was directed to this condition in the spring of 1961 by 2 children who had complained for several

Herpes simplex virus (type 1) was recovered from the cerebrospinal fluid and urine of a 2-month-old infant who had been born with diffuse brain damage and stigmata of intrauterine infection. At 1 month of age, he had microcephaly, intracranial calcifications, and "owl eye" inclusion bodies in his urine. At 3 months, herpes simplex virus was again recovered from his urine and he had IgM antibody specific for herpes simplex virus that persisted until he was 1 year old. When our findings are added to those of the five similar instances known to us, it seems reasonable to include this virus among intrauterine infective agents that may cause such congenital malformation as diffuse brain damage, mental retardation, microcephaly, intracranial calcifications, microophthalmia, retinal dysplasia, and chorioretinitis.

Severe recurrent pneumonitis occurred in a 6-year-old city boy who lived near a market in which live chickens were sold. His pulmonary disease improved when he was removed from the area. He was shown to have precipitins to an antigen prepared from hen litter. These antibodies decreased as he improved.