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Virion transcriptase activity of an influenza A virus strain isolated during a small local outbreak of influenza was found to be 16–20% of that of influenza virus strains producing an extensive epidem

Influenza and infection with Mycoplasma pneumoniae are common nonbacterial causes of pneumonia. Pneumonia also sometimes occurs as a complication of a viral infection such as varicella. This article describes the clinical picture seen with each type of infection and gives current recommendations for prophylaxis and therapy.

A 48-year-old healthy man developed diffuse pneumonia with refractory hypoxemia. Sputum cultures were negative for bacterial pathogens. Myxovirus particles were demonstrated by electronmicroscopy in the tracheal aspirate reflecting the high infectivity titer of the sputum. Positive end-expiratory pressure ventilation and ten days of extracorporeal membrane oxygenation were utilized to maintain the inspired oxygen concentration at 70 percent or less in an effort to prevent oxygen-induced lung damage. Despite these therapeutic and supportive measures, progressive pulmonary fibrosis ensued precluding the patient’s survival. This case demonstrated that the pulmonary parenchymal change produced by fulminant influenza pneumonia may not be reversible even during prolonged maintenance of adequate arterial oxygen tension with an extracorporeal oxygenator.

An analysis was made of the consumption of drugs by mothers of children with defects of the central nervous system (CNS), who had a history of influenza during the first trimester of pregnancy. “Maternal memory bias” was avoided by comparison with information similarly collected from a group of mothers of children with CNS defects but no history of influenza. A control group was collected for each abnormal group. Of the mothers with a history of influenza, 52 per cent reported consumption of drugs during the first trimester. The corresponding figure for those with defective children who did not have influenza was 28 per cent; and for the mothers of healthy infants, 11 to 17 per cent. We emphasize the frequently overlooked bias in epidemiologic investigations because of the complex study situation. Diseases and their causative agents and consequences cannot be distinguished from therapeutic agents as teratogens. Where drugs and viruses are concerned, this limitation should be borne in mind.

Surveys of prevalence of infection and usage of antimicrobial agents, conducted at Boston City Hospital at three-year intervals from 1964 to 1973, have shown little change in either prevalence of, or bacterial pathogens associated with, community-acquired infection. Prevalence of nosocomial infection at specific sites has varied from survey to survey, but no significant downward trends have been documented. Gram-negative bacilli and Staphylococcus aureus continue to be the bacteria isolated most frequently from patients with hospital-acquired infection. The surveys since 1964 have shown an increased proportion of patients receiving antimicrobial agents and decreasing use of therapy with more than one antimicrobial agent in the same patient. Despite the limitations of surveys of prevalence, they can be a useful aid in the control of infections within hospitals; their value is enhanced by the extent to which the staff of the hospital is kept informed of and utilizes the findings as a guide to improving the therapy and care of the patients.

SUMMARYInfluenza-like illness, cold and sore throat was the diagnosis given in over 80% of 5177 acute respiratory illnesses in patients swabbed over a 10-year-period. A pathogenic organism was isolated twice as frequently from patients with a sore throat or an influenza-like illness as from those diagnosed as suffering from croup or laryngitis and bronchitis. A laboratory diagnosis was commoner in school children than in older or younger persons.Most of the organisms isolated were found in association with all types of acute respiratory illness but, with increasing age of the patient, one particular agent or group of agents was more likely to be of aetiological significance.

Three cases of Haemophilus parainfluenzae endocarditis in previously healthy patients were diagnosed in one six-month period. The presenting clinical picture was not typical of endocarditis. The initial physical examination and laboratory studies were normal except for hectic fever. Blood cultures were negative until subculture to chocolate agar and incubation in CO2 was done. Antibiotic susceptibility testing in vitro revealed that the penicillins, cephalothin, and gentamicin were active against the organisms isolated. It is recommended that blood cultures be subcultured to chocolate agar and incubated in CO2 whenever endocarditis is expected and the initial cultures are negative. Two of the patients were treated with ampicillin; the third patient received ampicillin, streptomycin and tetracycline. All patients were treated for six weeks and were cured.

Summary Ninety-six strains of influenza A and 113 influenza B were found in the two MRC/PHLS surveys. In the general practitioner survey the majority of strains were isolated from cases diagnosed as influenza but in hospital most came from cases diagnosed as having other respiratory infections. In the latter survey isolation rates were higher in upper respiratory tract infection than in lower ones but in the general practice survey this trend was reversed. Influenza-like symptoms tended to increase with age, while coryza and vomiting was commoner in the younger age groups. The frequency of influenza virus infections found in the survey is compared with those found in Glasgow over the last decade and their effect on the incidence of lower respiratory tract infection discussed.

From January to March, 1974, twenty-four cases of Reye's syndrome encephalopathy and fatty liver) were diagnosed in Cincinnati, Ohio. The epidemic coincided with an epidemic of influenza B, intermediate type. In eighteen of twenty-three cases (78%) in which viral studies were done, an acute viral infection was found in either the patient or a close contact with similar prodromal symptoms. Influenza-B infection was confirmed in twelve patients and twelve contacts, although influenza A, parainfluenza 1, adenovirus, and varicella-zoster virus infections also occurred. In four cases there was evidence of two different viruses infecting the patients or their contacts. Cellular immunity was studied in six cases and responses to phytohaemagglutinin and specific viral antigen were normal. This is the first epidemic of Reye's syndrome in which the association with viral infection has been confirmed in most patients by virological techniques. Impaired cellular immunity could not be implicated as the cause of the unusual reponse to infection.

During an epidemic of influenza A2 var. Hongkong and a subsequent period of high incidence of influenza B in Stockholm from January through April 1969, 130 influenza cases were selected for a study on the effects of bacterial superinfection. Bacterial involvement was demonstrated through frequent cultures from nose, throat, nasopharynx and sputum samples, together with serologic reactions in acute phase and convalescence sera against potentially pathogenic airway bacteria. It was found that bacterial involvement could not be shown statistically to influence the maximum temperature recorded, but did increase the duration of fever, the incidence of pneumonia, leukocytosis, and erythrocyte sedimentation rates over 50 mm/l h. When indicated by both bacterial findings and significant antibody titer increase, it also resulted in a higher frequency of granulocytosis. The bacteria most often involved were pneumococci, dominating in acute respiratory illness also in influenza-free periods, but the severity...

SUMMARYStatistical methods are described in detail for the calculating and comparing of cross-infection rates. In addition the use of these rates has been extended to study the influence of age and of different virus types on susceptibility to cross-infection in children's wards.

Virologic, serologic and clinical records at two Montreal hospitals revealed 19 adults and 27 children with influenza A2 (Hong Kong variant) infections during the winter months of 1971/72. Serious disease and two deaths were encountered in 14 (51 percent) children with underlying disease and 15 (55 percent) below three years of age. Six (22 percent) children had pneumonia, nine (33 percent) gastrointestinal symptoms, two conjunctivitis, and two meningitis. Of seven (37 percent) adult patients with complications, six (32 percent) had pneumonia, two pancreatitis, and five (26 percent) underlying disease. Two adult patients with no previous history of illness had a fulminant course and died within 48 hours of admission. Influenza continues to be associated with severe illness in a few patients especially, but not exclusively, in high risk individuals.

Official statistics relating to infant mortality in Belfast and Dublin for the period 1900–69 are analysed.

Changes in the inhibitory properties of human nasal mucus were found to be positively correlated with objective signs of influenza virus infection during the 1950 epidemic. In approximately 80% of the cases the inhibitor index was significantly increased during the acute stage of the disease, and reverted to normal during convalescence.Various respiratory diseases other than epidemic influenza did not cause similar changes.Examination of the inhibitory pattern of nasal mucus is proposed as a presumptive test for influenza virus infection, and its merits are discussed under the headings of reproducibility, specificity and sensitivity.

Striking elevations in concentrations of total serum lipids were observed in patients with infection caused by gram-negative bacilli. The elevated levels of total lipid in these patients were due mainly to marked increases in serum concentrations of triglycerides or free fatty acids or both. In contrast, patients with severe infection caused by gram-positive cocci had normal concentrations of total serum lipids. Those with fever but no infection and those with influenza had normal concentrations of total serum lipids and normal levels of the major lipid classes. Patients with infectious or serum hepatitis demonstrated a moderate hyperlipidemia, which resulted from increased concentrations of serum triglycerides and free cholesterol. Lipoprotein electrophoresis demonstrated that the hyperlipidemia in patients with severe infection caused by gram-negative bacilli was related to increased levels of pre-beta-lipoproteins. In patients with hepatitis there were increased levels of pre-beta-lipoproteins...

SummaryThe route of administration, either intradermal, subcutaneous, or intramuscular, did not significantly affect the antibody response following Asian influenza vaccination. Antibody titers produced were proportional to the total amount of vaccine inoculated whether given as a single dose or divided into 2 injections separated by an interval of 3 weeks. Hemagglutination-inhibition antibody titers in post-vaccinal sera were greater when determined with the TC and EFME lines of Asian virus than with early or later passages of the straight E line. Neutralization titers with the TC line in monkey cultures were considerably greater than those determined with the E lines in the allantoic sac. The geometric mean hemagglutination-inhibition antibody titer of a large group of postinfluenzal sera was used as the baseline for evaluation of antibody response to vaccine by using the same virus line and method of in-activation of non-specific inhibitor in sera in both cases.

Dick, Elliot C. (Tulane University School of Medicine, New Orleans, La.) and William J. Mogabgab . Characteristics of para-influenza 1 (HA-2) virus. III. Antigenic relationships, growth, interaction with erythrocytes, and physical properties. J. Bacteriol. 83: 561–571. 1962—Hemagglutination-inhibition tests with rabbit and rooster immune sera showed HA-2-like strains of para-influenza 1 to be nearly as closely related antigenically to para-influenza 3 (HA-1) virus as to the Sendai strain of para-influenza 1; however, convalescent sera from humans infected with para influenza 1 virus exhibited four-fold or greater increases in antibody to HA-2 and Sendai viruses, but seldom to HA-1. Para-influenza 1 (HA-2) infectivity was destroyed within 2 hr at temperatures approaching 50 C; at 36 C, infective virus disappeared by 80 hr. At a temperature of 44 C or below, the hemagglutinin (HA) titer remained unchanged for 100 hr; but at temperatures above this, hemagglutinin was destroyed rapidly. Virus infectivity was found to be most stable at very slightly acid or neutral pH and to be increasingly labile at pH values more extreme than 5.7 and 8.7. Hemagglutinin was generally more resistant than infectivity to extremes of reaction; this was most notable in the alkaline range. In primary monkey-kidney tissue culture, virus was adsorbed in 5 hr, new infective virus was noted in 11 to 15 hr, and maximal amounts were detected at 60 hr and maintained through 132 hr. Production of hemagglutinin paralleled that of infectivity. The tcid 50 /HA ratio was approximately 4.5. With human type “O” erythrocytes, the HA titer of Copenhagen 222 virus suspensions was raised two- to fourfold by increasing the temperature of reaction and sedimentation from 4 C to room temperature. It could not be demonstrated that this thermal effect was due either to an increased total adsorption at an elevated temperature or to a greater rate of adsorption; the rate of hemagglutination was, however, increased by fourfold at the higher temperature.

Three study groups, composed mainly of adults, were tested for signs of infections with viruses, Mycoplasma pneumoniae (MP) and bacteria. The 3 groups consisted of 44 patients hospitalized for acute respiratory illness, 78 patients treated at home for the same condition, and 77 control subjects without respiratory symptoms. All of them were screened by serological methods for certain respiratory viruses, MP, and bacteria. Nasopharyngeal and throat swabs were cultured for bacteria and respiratory viruses (with the exception of rhinoviruses).Serological tests indicated fresh infections with viruses, MP, and bacteria or combination of these agents in 50% of the hospitalized patients, in 42% of the home patients, and in 8% of the controls.Multiple infections were noted in 14% of the hospitalized patients, as against 6% of the home patients and 1% of the control subjects. The distribution of aetiological agents did not differ appreciably between hospitalized patients and home patients.

Under the conditions of our experiments, the local potentiation of immunity to influenza reported by FazekasdeSt Groth and Donnelley could not be demonstrated.We should like to thank Dr C. H. Andrewes and Dr A. Isaacs for their advice and criticism, and Messrs E. Owen and D. Eade for their technical assistance.

(1970). Thomas Francis, Jr., MD. Epidemiologist to the Military. Archives of Environmental Health: An International Journal: Vol. 21, No. 3, pp. 252-255.

The discovery that thalidomide can cause human malformations has been followed in recent years by a large number of reports of malformations in the offspring of women who have taken other drugs in pregnancy. But it has remained uncertain whether any of these drugs are teratogenic, since those reporting on them have not been in a position to relate their findings to the distribution of malformations in the general population. There are two reasons why population data are needed for the interpretation of associations between drugs and malformations. Firstly, the relative frequencies of the different types of defects in the general population need to be compared with those in affected children born after exposure to the drug in question; if teratogenic, it is likely to cause only a few specific types of defects, which will therefore be present in an abnormally high proportion of the exposed group. Secondly, comparisons between the population incidence of malformations at different times are needed to detect or exclude the changes that are likely to occur if any drug which is being used increasingly has teratogenic properties. These changes may be either prolonged trends or shortterm fluctuations. If a drug is used to treat endemic conditions such as anxiety or morning sickness, its output is likely to rise gradually as it becomes more widely known, and consequently any related increase in the malformation rate is also likely to be prolonged. Short-term fluctuations in incidence may occur if a teratogen is being used in the treatment of epidemic diseases (of which the commonest in pregnancy is influenza). In three previous reports (Leek and Millar, 1962, 1963; Leek, 1963) we examined the incidence of certain malformations in Birmingham for shortterm fluctuations between 1957 and 1961, and found

DURING the past sixteen years influenza has been, I imagine, the virus that has received most study and attention in the laboratory, though poliomyelitis must run it very close. It has been studied by workers trained in very different disciplines and approaching it from many angles. Perhaps most novel and exciting is the work based on Hirst's1 discovery of the power of the virus to agglutinate red cells of fowls. Directly deriving from this finding is the demonstration that influenza virus, or a part of it, has an enzyme-like action upon a carbohydrate-containing protein; this protein is present in serum . . .

SUMMARYThe haemagglutinin of influenza virus A 2/Hong Kong/1/68 was shown to be markedly different from that of previously isolated A 2 virus strains. No haemagglutination-inhibiting (HI) antibody to A 2/Hong Kong/1/68 virus was detected in serum specimens collected in 1966 from persons aged 60 years or less. In contrast, HI antibody tests with 270 sera collected in 1968 indicated that 9·6% had demonstrable HI antibody at low titres, and 35·2% of 454 postepidemic (1969) sera had demonstrable HI antibody at relatively high titres. Most sera from persons aged 80 years and more collected in 1968 and 1969 had demonstrable HI anti-body to influenza virus A 2/Hong Kong/1/68. No HI antibody to the Hong Kong virus was detected in pre-epidemic sera from children aged 6 months to 3 years, whereas 32 % of postepidemic sera had HI antibody. The acquisition of HI antibody to A 2/Hong Kong/1/68 was not accompanied by an increase hi the incidence or titres of HI antibody to heterotypic A 2 influenza viruses. For sera from children aged 4–11 years, an increase of HI titre to heterotypic A 2 influenza was found.

A hypothesis predicting that increase in the rate of synthesis of host messenger RNA would be associated with antiviral activity was examined. Biochemically, Isoprinosine or NPT-10381 (methisoprinol) increased the rate of rapid labeling of polyribosomal RNA and protein in uninfected monkey kidney cells in tissue culture. In tissue-culture systems, Isoprinosine exerted antiviral effects against influenza virus, PR-8 and A2 strains; herpes virus, LU strain; polio virus 3; and adenovirus 10. In in vivo mortality studies, Isoprinosine was observed to exert therapeutic antiviral effects against the A2 strain of influenza and, as well, against a herpes infection of newborn mice. Experiments were carried out which demonstrated a correlation between the in vivo anti-influenza (PR-8) effects of Isoprinosine and reduction in the virus titer in lungs of infected mice.

Plasma enzyme activities were measured in mice up to 10 days after infection with the following viruses: Riley's enzyme-elevating (RV), Friend leukaemia (FLV), Moloney leukaemia (MLV), polyoma (PV), vaccinia (VV), influenza A (IV), lymphocytic choriomeningitis (LCM), and encephalomyocarditis (EMC). RV caused significant increases in plasma lactate dehydrogenase (LDH), phosphoglucose isomerase (PGI), and aspartate transaminase (AST) activities within 4 days following infection. The preparation of FLV first obtained caused similar effects, but after it had been freed from RV by passage throfgh rats it caused no early increases in plasma enzyme levels, althofgh its Friend disease-inducing potency was undiminished. MLV and PV were withoft effect on plasma enzyme levels before the appearance of gross neoplastic disease. Mice having a Moloney lymphoma showed increased levels of plasma LDH, PGI, AST, alanine transaminase (AL), aldolase (ALD), and alkaline phosphatase (AlkP). In such mice RV caused a synergic increase in LDH and PGI activities, an additive increase in AST activity, and no change in ALT, ALD, or AlkP activities. VV, IV, and LCM caused no changes in any of the plasma enzyme activities studied, althofgh IV and LCM proved fatal within the period of study. EMC was invariably fatal within 3 days, and infected mice had greatly increased plasma LDH, PGI, AST, ALT, and ALD activities. Detailed study of these changes suggests that plasma enzyme changes in EMC and in RV infections are due to different pathological processes.

Data are presented which enhance the idea that the influenza virus is an unstable agent. They indicate that the O-D type of variation is not a discontinuous mutation but rather is a reversible phenomenon. The O and the D forms of virus both appear to be inherent in the virus particle; the dominance of one or the other form seems to be subject to chance occurrences, but is influenced by the conditions under which the virus is propagated. The capacity of the O form of virus to agglutinate guinea pig but not chicken crythrocytes is a relative, not an absolute phenomenon; allantoic fluids which exhibit clear-cut O form hemagglutination may be made to exhibit D form merely by addition of suitable buffer to the test system. That point is of importance from the viewpoint of the mechanism of influenza virus hemagglutination.

An experimental model has been developed for the reproducible transmission of influenza virus infection from experimentally infected mice to uninfected cage mates. Infector mice transmit influenza virus infection most readily during the period 24 to 48 hours after initiation of their infection. This restricted period of transmission is not due to declining titers of infective virus in the nose, trachea, or lungs of infector mice after 48 hours of infection, since peak titers in these tissues are maintained for another 48 hours. A mouse-adapted strain of A2 virus was found to be more readily transmitted than the mouse-adapted CAM strain of influenza A1 virus, although the CAM strain induced higher pulmonary virus titers and more extensive lung lesions.

Antigenic variants of influenza A virus strains emerge on serial passage in ovo in the presence of immune serum against different but related strains. An old laboratory strain (PR8) which had been through hundreds of animal passages was as readily modified by this procedure as recently recovered strains. Such variants apparently can be obtained at will and show antigenic patterns which are reproducible and appear to be predictable in terms of the immune serum used for their selection. Variant strains retain their new antigenic patterns on serial passage in ovo in the absence of immune serum. Limited serial passage in ovo of strains in the absence of immune serum did not result in the emergence of antigenic variants. Similarly, serial passages of strains in ovo in the presence of immune serum against widely different strains, which failed to show significant cross-neutralization, did not lead to the appearance of antigenic variants.

Cortisone acetate, hydrocortisone, and hydrocortisone acetate depress the resistance of mice to pneumococcal and influenza viral infections, although hydrocortisone acetate is somewhat less effective than the free alcohol, when given subcutaneously. Pituitary adrenocorticotropin, even in highly purified form and in oil and beeswax, does not significantly alter the resistance of mice to these experimental infections, even when given in doses which may cause profound eosinopenia, lymphopenia, and weight loss, and which are at the limit of tolerance of the animals. Corticosterone depresses resistance to pneumococcal infections significantly, but fails to alter resistance to influenza viral infections. The findings suggest that murine adrenals may produce one of the known adrenal steroids such as corticosterone along with another steroid, or may produce a steroid other than cortisone, hydrocortisone, or corticosterone. When resistance is decreased by adrenal steroids, survival time is invariably shortened, and the effect of the steroid hormones is frequently demonstrable within the 1st day after infection with pneumococci, making it unlikely that the depression of resistance that is seen is primarily due to depression of antibody formation. A single dose of 5 mg. of cortisone may cause depression of resistance and may decrease the survival time for 3 to 6 days afterward. Growth hormone (somatotropic hormone) in highly purified form, and in the doses used, did not overcome the weight loss induced by cortisone, but the animals treated with growth hormone and cortisone regained their lost weight more rapidly than those receiving cortisone alone. Growth hormone alone caused a slight increase in the rate of gain in weight over controls. Growth hormone alone did not increase resistance to infection, and did not increase the survival time, in mice infected with either pneumococci or influenza virus. Growth hormone in various dosages failed to overcome the effect of cortisone in depressing resistance to these infections. Cortisone, hydrocortisone, corticosterone, and corticotropin did not alter significantly the titers of influenza virus attained in the murine lungs during the first 2 days after infection, but cortisone and hydrocortisone markedly delayed the rate at which virus titers declined during the subsequent 6 days. Corticosterone and corticotropin delayed the rate at which the titers declined but slightly, and growth hormone had no apparent effect, as compared with controls. Growth hormone did not overcome the effect of cortisone and hydrocortisone on viral titers. No detectable antibody was found as late as 6 days after infection, in controls or in hormone-treated animals.

An epidemic of A2 influenza in a hospital for mentally retarded children provided an opportunity to evaluate the prophylactic effectiveness of Amantadine-HCl (1-adamantanamine). The clearest evidence of suppression of influenzal disease was noted in those children who had high levels of antibody prior to the epidemic. In contrast, a significantly greater number of children in the control group (placebo) who had high levels of antibody developed febrile disease.

THE ACTION OF HALOGENS ON INFLUENZA VIRUS WITH SPECIAL REFERENCE TO THE ACTION OF IODINE VAPOUR ON VIRUS MISTS

The immunofluorescence (IF) method as a means of speeding up the laboratory diagnosis of influenza B is discussed on the basis of a study of 29 outpatients with influenza-like illness during an outbreak of influenza B. The results of the IF staining are compared to findings by viral isolation and serology. The importance of an adequate sampling technique is stressed as well as the often experienced difficulty of interpreting staining results in cell preparations taken directly from the patient. The specific diagnosis is easily reached after 1–2 days incubation of infectious material in cell cultures from which cells then are scraped for IF testing.

SummaryAsian influenza A viruses isolated during the Baltimore epidemic in Oct. 1957 were in the R phase of the P-Q-R variation although indistinguishable antigenically from the Q phase prototype v...

Haemagglutination-inhibiting antibodies against A, A′ and A2 strains of influenza virus and against one strain of influenza B were estimated in sera from blood donors in Sydney in February 1958 and in April and October 1961.The A2 antibody increased substantially while both A and A′ antibodies declined slightly. There was a great decline in influenza B antibody during the same period.Thanks are due to Dr Phyllis M. Rountree who suggested this study. Miss Patricia Taylor gave excellent technical assistance in the early part of this work.

1. By means of a quantitative immunoelectrophoretic technique, serum protein changes have been followed in seven patients before and during the week following inguinal herniorrhaphy, and in a single case of influenza. 2. The twenty proteins studied are grouped according to whether they rise (orosomucoid, α1-antitrypsin, Gc-globulin, caeruloplasmin, haptoglobin, β1A–C-globulin and proteins numbered 45, 99, 101 and X); fall (pre-albumin, α2HS-glycoprotein and protein No. 9); or show no significant change (α2-macroglobulin, haemopexin). α1-Lipoprotein fell in the case of influenza but did not change in the hernia patients; α1-easily-precipitable-glycoprotein increased in the hernia cases only. 3. The nature of the ‘acute phase reaction’ and the factors which elicit it are discussed.