Gerald W. Fernald

Microtubular discontinuities as acquired ciliary defects in airway epithelium of patients with chronic respiratory diseases

A critical relationship exists between ordered ciliary ultrastructure and optimal mucociliary clearance in the respiratory airways. Structurally defective cilia derived from heritable syndromes or from epithelial cell injury may promote or exacerbate chronic disease processes. A lesion of airway epithelial cilia characterized by microtubular discontinuities and previously associated with primary ciliary dyskinesia (PCD) has been documented in other forms of chronic airways diseases, including cystic fibrosis (CF). Nasal cilia obtained by curettage of the inferior nasal turbinate from 89 patients without CF but exhibiting symptoms favoring PCD were evaluated by transmission electron microscopy. Of the 89 patients in the study group, 19 (21.4%) were diagnosed with PCD. Among the PCD patients, 16 (84.2%) exhibited microtubular discontinuities. Nine patients from this group without ultrastructural evidence of PCD also exhibited these defects, however. Furthermore, seven of eight nasal biopsy specimens from patients with CF in a separate disease control group exhibited microtubular discontinuities. Microtubular discontinuities were quantitatively negligible among control groups of healthy human subjects and individuals experimentally and naturally subjected to acute airway injury. These data provide evidence that ciliary microtubular discontinuities represent acquired ciliary defects reflective of chronic airway disease injury and are not components of a primary structural abnormality in PCD.

Factors Influencing Growth Inhibition of Mycoplasma pneumoniae By Immune Sera.

Summary Studies on growth inhibition of M. pneumoniae revealed three interdependent major variables: number of organisms used in titrations, amount of antiserum, and time of test incubation. A linear relationship between the logarithms of the number of organisms inhibited and the antiserum dilution was observed in which the regression ratio was 2.0. Heat-labile factors in normal sera, required for inhibition of M. pneumoniae, were readily provided by incorporating fresh frozen horse serum into the growth medium. Other animal sera could not be used because of the presence of heat-labile inhibitors; commercial guinea pig “complement” additionally contained 2 heat-stable inhibitors, specific antibody and sodium azide. Control of the factors indicated provided means of producing immune inhibition measurements of varying sensitivity which were reproducible within a 4-fold range at the 95% confidence level.

Epidemic pneumonia in university students

Longitudinal surveillance of pneumonia in a university student health service was conducted from 1965-1971 and 1984-1987. Of 104 pneumonia cases documented by chest x-ray, only six were presumed to have bacterial etiology; the remaining 98 were characteristic of atypical pneumonia syndrome. Mycoplasma pneumoniae was the etiology in 51% of the pneumonias in the 1960s and 13% in 1984-1987. Pneumonia incidence was highest in the fall semester in seven of 11 years studied. Annual incidence followed a three- to four-year periodicity. Both of these observations mirror the epidemiology of M. pneumoniae in the world population. Symptoms of cough, headache, malaise, and absence of the physical finding of wheezing were seen more consistently in M. pneumoniae pneumonia than in other atypical pneumonias; other clinical features varied among epidemics. Rapid cold agglutinin tests were positive in 27% of our clinically diagnosed pneumonias and in 36% of those with documented mycoplasmal infections. This study appears to provide a basis for predicting future epidemics of atypical pneumonia in student populations.

Cystic fibrosis: Overview

Cystic Fibrosis (CF) is one of the most common familial recessive diseases. Prevalence varies with ethnicity and is especially high in Caucasians, affecting about 1 in 2000 to 1 in 4000 live births (for review, see 1-3). In Hispanic Americans, African Americans, and Asian Americans, the disorder is less prevalent (1 in 9200, 1 in 15,000, and 1 in 31,000, respectively) (1-3). CF is a multisystem disease, affecting the respiratory, digestive, and male reproductive systems (13). Pulmonary disease is the major cause of morbidity and mortality, with chronic lower airway infection and inflammation leading to bronchiectasis and, eventually, to extensive airway damage and fibrosis of lung parenchyma (1,2). Disease severity can range from infertility (in males) without any pulmonary manifestations to recurrent sinusitis and bronchitis with onset in young adulthood to severe lung, pancreatic, and liver disease with onset in infancy. The great majority of CF patients suffer from pancreatic insufficiency, and more than 95% of males with CF are infertile, due to azoospermia secondary to agenesis of Wolffian duct structures (1,2). Some affected individuals demonstrate pancreatic sufficiency, which is correlated with a milder clinical course and increased survival (nonclassic CF) (1,2). Early diagnosis of CF is important, since it can help to prevent malnutrition and failure to thrive in infants and children through pancreatic enzyme replacement and chronic bacterial airway infection through antibiotic prophylaxis.

Immunology of Mycoplasma Infection

“Mycoplasma(s)” is the trivial name for organisms in class Mollicutes, which contains two families and five genera (Freundt, 1974a; Edward, 1974). These organisms are distinguished from bacteria by the absence of cell wall and small size, with a genome mass of 4-8 x 108 dations (Bak et al., 1969). Although they resemble large viruses in size and filterability, unlike viruses they are able to grow on cell-free media. The lack of a cell wall also accounts for the resistance to penicillins which characterizes all mycoplasmas. This class of microorganisms is thus unique in that it includes the smallest free-living forms to be found in nature.

Chronic pulmonary disease associated with an unusual genetic type of α1 -antitrypsin deficiency in childhood

Chronic pulmonary disease (CPD) occurs in most individuals with the common α1-antitrypsin (α1AT) deficiency phenotype, PiZZ, and less frequently in heterozygotes (PiMZ; normal = PiMM). A few other variants are associated with lesser degress of deficiency, but their roles in pathogenesis of disease are unclear. For example, the incidence of CPD in PiSS and PiSZ individuals is not known, although Fagerhol has reported that these phenotypes may predispose to CPD. His two patients had asthma and chronic bronchitis rather than emphysema per se.An 8-yr-old boy with severe asthmatic attacks and chronic in flammatory lung disease was found to have a serum α1AT level of 85 mg/100 ml (31% of nl. mean) and trypsin inhibitory capacity of 0.55 mg/ml. Genetic typing by immunofixation and by antigen-antibody crossed electrophoresis indicated that he was PiSZ. Sweat chlorides and serum IgG are normal; IgA and IgM are borderline. The patients father is PiMZ; his mother and sister are PiMS. Both parents have mild obstructive changes in their pulmonary dynamics, but are clinically well. The sister is apparently normal.The clinical progression and prognosis with α1AT variants other than PiMM, MZ, and ZZ are unknown. The relative frequencies of these phenotypes make genetic typing and long-term followup important in order to clarify these question and to ascertain the need for genetic and medical counselling.

Immune Response of the Hamster to Experimental Mycoplasma Pneumoniae Disease

The Syrian hamster (Mesocricetus auratus) first was used for experimental Mycoplasma pneumoniae infections soon after the introduction of this species as a laboratory animal in the United States. Isolation of an infectious agent from patients with atypical pneumonia by intranasal inoculation of cotton rats (Sigmodon hispidus) with sputum samples was reported in 1942. Although unsuccessful for primary isolation of the agent, the hamster could be used for propagation of organisms recovered primarily in the cotton rat. Both animals developed pneumonitis in consequence of infection. Immune responses of patients and experimental hosts were demonstrated by the neutralization of sputum infectivity for animals following incubation of the inoculum with convalescent sera (2).

NEW INSIGHT ON MYCOPLASMA PNEUMONIAE INFECTIONS IN EARLY CHILDHOOD

Respiratory illness due to M. pnewnoniae is common in school age children (peak age 9 yrs.) but rare in infants, a consistent epideraiologic finding which never has been explained adequately. Monitoring of respiratory tract microflora in 50 infants and young children attending the Frank Porter Graham Day Care Center (DCC) yielded 15 isolations of M. pnewroniae from 1968-1973. These infections occurred in the fall and early winter of each year and coincided with identification of this agent in children with lower respiratory disease seen in a local pediatric practice. Frequent medical evaluation revealed only mild rhinitis and cough in half the DCC subjects. Infected children ranged in age from 2 months to 8 years. Diagnostic serologic rises (complement fixing and growth inhibiting antibody), occurred in all but one culture-positive child, as well as in several with negative cultures. Titers tended to wane rapidly and 3 children became reinfected after 3 yrs. In vitro stimulation of peripheral lymphocytes with M. pneumoniae was performed on all infected children during the last year of the study. Antigen reactive cells were detected frequently only in children over 6 yrs. of age. These findings suggest that recurrent unsuspected infection with M. pneumoniae occurs during infancy and early childhood and that pneumonic disease, common in school-aged children, is an expression of increasing host immune response to the organism.