SPECIAL
REVIEWS
JOSEPH SroERs, JR., M.D., Editor
CHEMOTHERAPY
OF
RESPIRATORY
VIRAL
DISEASES
By FRANK L. HORSFALL, JR., M.D.
New York City
T
HERE has arisen recently a tendencytoward thinking that infectious dis-eases no longer present problems of social importance in the economically more
ad-vanced countries. This tend is more notable
among a few biologists who are concerned with ideas about diseases than among physi-cians who are confronted daily with infec-tious diseases as established facts. The on-gin of the idea is easily traceable to the
striking effects that modern antimicrobial
drugs have had on the mortality of many severe infectious processes. Not only has the
over-all mortality from microbial infections been diminished, but also, and more dna-matically, the mortality in childhood has been greatly reduced. Judged from the view-point of the mortality statistician, the mil-lennium is at hand and microbial infection need not be an important cause of untimely death. However, as every physician knows, infections are as common as in the old days and morbidity statistics have not been much improved by chemotherapeutic successes.
If viral diseases of the respiratory tract were the killers that untreated microbial infections of this tract are, no one could suppose that infectious diseases may be considered as only of minor importance. Although relatively few patients die of respiratory viral infections, the burden of
disease they cause is enormous, greater than
From the Hospital of The Rockefeller Institute for Medical Research, New York City.
Presented as part of the symposium on respira-tory viral diseases at the twenty-second Annual Meeting of the American Academy of Pediatrics, Miami, Oct. 9, 1953.
(Received for publication Nov. 5, 1953.)
that of all other maladies in combination. It appears that mankind suffers throughout at least one-tenth of its life span from viral
diseases of the respiratory tract. One may take the view that a cold on some other acute respiratory illness is an unpleasant inevitability which may go away in a week on so. However, the patient with one has a different view of the misery experienced and the time lost and knows, too, that an-other won’t be too long in coming. His question is : What can be done to stop these things and let me get on with what I was
doing?
At least seven separate viral diseases of the respiratory tract have been recognized and identified through careful study. These cause about two thirds of all episodes of illness and are definitely more frequent among children than in adults. In approxi-mate order of incidence, they may be
an-ranged as follows : Common cold, one type
of acute respiratory disease or ARD, three
types of influenza, designated A, B and C, primary atypical pneumonia, and psitta-cosis or ornithosis. Altogether these seven diseases are thought to account for about
90% or more of all respiratory infections. Among them, only psittacosis, which is the least common, has an appreciable rate of mortality. But the others cause an enormous lot of illness, from 5 to 7 attacks pen person per year, with the attack rate highest in children. For psittacosis, there is now effec-tive and specific chemotherapy which markedly alters the course of the disease. For the other six diseases, many claims re-garding therapy have been made and it
claims have stood up under critical trials. Let us discuss the most solidly established instance first: the effects of antimicrobial drugs in psittacosis.1 This disease results from infection with one of the largest viruses and is almost always contracted from contact with members of the bird family. The virus is as large as some small bacteria and its reproduction can be stopped by certain chemotherapeutic agents effective against bacteria. Sulfonamide drugs are not of much value in this disease nor is streptomycin. Penicillin, however, in large doses, may, in some cases, be curative. Certain of the so-called broad spectrum drugs are even more active than penicillin. Auneomycin or terramycin have been demonstrated to have usefulness in the treatment of psittacosis and either appears to be more effective than chloramphenicol. The recommended dosage is similar to that employed in acute bacterial infections of the intestinal and urinary tracts and therapy should be continued for at least one week.
Now we must approach areas of
dis-ease in which the therapeutic evidence is much less decisive and it will be wise to proceed with caution.
On the basis of extensive studies carried out in volunteers during World War II, it can be concluded that primary atypical pneumonia is induced by one or more viruses of medium size.2 Information about the agent is incomplete for it has not been possible to handle it readily in experimental animals. Although atypical pneumonia only
in rare instances is fatal, it may cause pro-tnacted illness and vigorous efforts have been made to find effective chemotherapeu-tic measures. Sulfonamide drugs, even in large doses, do not exert a favorable effect. Similarly, penicillin has not been found to be beneficial even when massive doses are
given. In the period since 1949, numerous
reports on the effects of auneomycin on atypical pneumonia have appeared. Some workers have reported that the drug was beneficial and definitely shortened the clinical course of the disease. Others,
how-ever, have found no evidence of a signifi-cant chemotherapeutic effect. It is pertinent to comment that in the most carefully con-trolled and most extensive studies the least effects were demonstrated. In reports on more than 150 patients treated with
aureo-mycin the average duration of the disease
was about nine days. Whereas, in over 100
patients not given chemotherapy, the
aver-age duration of the illness was about 10
days. A review of all the available
pub-lished data makes it doubtful that there are
sufficient grounds for regarding auneomycin or terramycin as an effective chemothera-peutic agent in atypical pneumonia. Such alterations as these drugs may cause in the temperature curve are probably attnibuta-ble to mild antipyretic effects. It appears clear that they do not decrease the period
during which pneumonia is present. In the
Hospital of the Rockefeller Institute, we have long since given up using either drug in atypical pneumonia for we have been unable to see any definite indication that
they shortened the course of the illness or
were otherwise beneficial.
Influenza A and B, as well as the condi-tion recently identified as influenza C, are caused by viruses of medium size which are particularly well suited to laboratory
study.3 A large amount of precise
informa-tion has been accumulated about these agents and the respiratory diseases they in-duced. Influenza is commonly a self-limited infection and in previously healthy persons does not often incapacitate for longer than a week or 10 days. In children, it tends to be milder than in adults though the first few days may be highly unpleasant. In the
SPECIAL REVIEWS 595
known. What relation, if any, that agent
may have had to influenza viruses as we
now know them is a question that probably cannot be answered.
In considering the use of chemotherapy
in influenza, it will be well to discuss the common uncomplicated diseases and the rare complicated infections separately. In-fluenza, when not associated with secondary bacterial infection, is not favorably influ-enced by any of the chemotherapeutic agents so far available. Neither the sulfona-mide drugs nor penicillin, whatever the dosage used, has been found to alter the course of the illness in the slightest degree. Although there have been claims that aureomycin was helpful in the disease, critical studies have failed to show any significant effect. As evidence of this, in 69 patients with proved influenza A, no benefit
,from the use of the drug was obtained.4 In addition, there is no reason to suppose that terramycin, chioramphenicol or other more recent antimicrobial agents would be beneficial for it has been thoroughly es-tablished that none is effective against in-fections with these viruses in experimental animals. It should be emphasized that there is usually no important distinction between viral infections in animals and in man. Chemotherapeutic agents which are not effective in viral infections in experimental animals have not been shown to be effective against infections induced with the same virus in human beings.
Secondary bacterial infections, when they occur during an attack of influenza, re-spond to antimicrobial substances in a man-ncr closely similar to such infections in pa-tients who do not have the viral disease. The most severe of the complicating infec-tions is bacterial pneumonia and those caused by staphylococci or Friedll#{228}nder bacilli are the worst of the lot. Prompt
in-stitution of chemotherapy is vital when bacterial pneumonia develops during in-fluenza. Although penicillin is highly effec-tive in pneumococcal or streptococcal pneu-monia, it is not effective against
Hemo-philus influenzae or Fniedl#{228}nder bacillus pneumonia. Both the latter diseases can be treated satisfactorily with sulfonamides or stneptomycin.’#{176} With Fniedl#{228}nder pneu-monia, treatment should be begun at the earliest possible time and pursued vigor-ously in order to prevent a fatal issue. Staphylococcal pneumonia, though rare, is often associated with infection by an in-fluenza virus. We have seen a number of such cases in the past two years and have
treated the disease successfully by using massive doses of penicillin along with the maximum tolerated doses of streptomycin and continuing treatment for 3 to 4 weeks or more.
The question arises as to the usefulness of antimicrobial chemotherapy during in-fluenza as a prophylactic against possible secondary bacterial infection. In previously healthy persons, the incidence of complicat-ing infections is very low and it is our view that there is no adequate justification for giving these potent drugs when the risk of bacterial infections is so small. However, in previously ill, malnourished or debilitated patients, it may be useful to reduce even the slight risk of bacterial complications by the use of penicillin as a prophylactic. The so-called broad spectrum drugs seem less desirable for this purpose, not only be-cause of the frequency with which they cause toxic reactions, but also because of the marked imbalance they induce in the normal bacterial flora of the upper respira-tory tract.
As to therapy in the acute respiratory disease, termed ARD,7 which was mentioned earlier, there is unhappily but little to say. The agent responsible for such infections has been recognized only by tests in human volunteers and has not yet been dignified with a name. It appears to be a virus and
very little is known of this agent. As yet, no adequate evidence has been accumu-lated regarding the effects of available chemotherapeutic agents in this disease in man.
Few infectious diseases have been ac-corded as much therapeutic attention as the common cold.8 The drugs and nostrums that have been claimed to affect favorably this malady are too numerous to count. During recent years many carefully con-trolled studies on the efficacy of certain of these substances have been carried out. That the so-called antihistaminic drugs were no more effective against the common cold than are various placebos became ap-parent to the lay public shortly after it had been conclusively demonstrated in critical tests on natural infections in man. So, too, with the various antimicrobial drugs. None has proved of clear usefulness and there is no good evidence to support the view that any of these substances affects the course of the common cold. Recent exten-sive studies in the laboratory and in human volunteers have served merely to under-line the ineffectiveness of available chemo-therapeutic agents in this ubiquitous malady.
I am all too aware that, with the exception of psittacosis, this commentary on the ef-fects of currenfly available antimicrobial substances on viral diseases of the respira-tory tract has been a recitation on discour-aging failures. This presently unsatisfactory situation need not be considered as ground for therapeutic nihilism and may not con-tinue indefinitely. The chemotherapeutic substances which so far have been tested extensively against viral diseases of the respiratory tract are those which were de-veloped to combat bacterial infections, not those which might be expected to affect illnesses induced by viral agents. Corn-pounds of the latter sort have only re-cently been come upon and it is still too early to know whether they will be of prac-tical usefulness in viral diseases in man. But more than an encouraging beginning
has been made in the laboratory and there is reason to think that further advances in this direction can lead to the finding of substances which will have value as chemo-therapeutic agents against a number of common viral infections in patients.
Despite the fact that many thousands of substances so far tested have failed to exert a significant effect on viral infections, there are certain substances which have shown striking inhibitory activity. Compounds are now known which do markedly modify the course of several viral diseases in experi-mental animals, and it is probable that some would affect similarly the same
dis-eases in man.
Infections induced by small or medium-sized viruses, like those of influenza or the common cold, represent the greatest chal-lenge for they are far removed from bac-teria and reproduce in a manner which is not entirely understood. Within the past two years, it was demonstrated in our labo-ratony that certain chemical derivatives of benzimidazole which bear a structural re-lationship to part of the vitamin B12 mole-cule are highly active against influenza virus infections.9 Amounts as small as a few hundredths of a milligram of certain of these compounds stop reproduction of influenza viruses even when given after infection has been established with the agents.’#{176}’11 There is reason to suspect that
the more potent of such compounds may act by selectively interfering with some phase of nucleic acid metabolism necessary for virus reproduction. They appear not to damage the tissues of the host animal and have not caused toxic effects in the dosages used to inhibit the viral infection.
sub-SPECIAL REVIEWS
stances are poisonous in larger doses and can cause death of experimental animals. As might be expected, it is thought that amino acid analogs act by interfering with some aspect of protein metabolism required
by viruses.
It may come as a surprise to learn that none of the substances which have recently been discovered to interrupt the reproduc-tion of viruses do so by acting on the virus itself. Unlike antimicrobial compounds, such as penicillin or streptomycin which act directly on bacteria and prevent their con-tinued growth, the so-called antiviral corn-pounds have no demonstrable direct effect on viruses themselves. Viruses are not mac-tivated by such compounds and in their presence readily penetrate susceptible cells. As is now well known, viruses have no sepa-rate life of their own and can multiply only when inside susceptible host cells. When a potent antiviral compound, of the sort men-tioned above, is present, the virus does not reproduce fully even though it is inside normally susceptible cells and such cells re-main undamaged. It is thought that the
more potent antiviral compounds, such as derivatives of benzimidazole, affect meta-bolic processes of the host cell which are
es-sential for the support of virus multiplica-tion. Thus, the effects of these compounds are indirect and, instead of operating on the
infectious agent itself, as is the case with
bacteria, they are mediated through the
tissues of the infected host. This is a new
biologic principle not previously utilized as a basis for the development of chemothena-peutic compounds and may prove to be a powerful lever in approaches to the finding of antiviral substances useful in man.
Current ideas in the virus field would lead one to suspect that the most effective
way to interrupt the reproduction of viruses is to alter the metabolism of either nucleic acids on proteins. But these are delicate and critical biosynthetic processes and they may do unexpected things when tampered with and lead to unpleasant results in the host. Because of this, it is essential to proceed
slowly and with caution and to explore the potentialities of the new compound widely in experimental animals before attempting to treat patients with them.
As an example of what the future may hold in this field, a brief account of the development of effective chemotherapy against a fatal virus pneumonia may be pertinent.13’ 14 There is a natural disease in
mice which closely simulates atypical pneu-monia in man. The chief difference is that mice almost invariably die of their infec-tion. The disease is caused by a virus much smaller than that which induces influenza in man. About six years ago we found very unexpectedly that extracts of certain bac-teria modify the course of this infection.
It proved to be the carbohydrate at the sun-face of the bacterial cell-the so-called cap-sular polysaccharide-which is the active inhibitory substance. In pure form the poly-sacchanide is highly potent and nontoxic. As little as 2 &g. given once is sufficient to protect the animals against this disease. The substance stops reproduction of the virus and as a result also restricts the develop-ment of pneumonia. After inoculation of more than 100 fatal doses of the virus, pneumonia is present by the third day and control animals die of their disease on the
sixth or seventh day. Even if the poly-sacchanide is not given until the third day of the disease, the infection can be cured and the animals recover. Thus, it is now possible with a compound of known nature to treat successfully a severe disease in-duced with a small virus in a mammalian host.
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bacteria, there are already indications of specificity in the effects of chemothena-peutic agents. Compounds which are highly potent against some virus diseases are ineffective against others. Because of this, it will, in all probability, be necessary to find and have at hand a number of active com-pounds if the various viral infections of man, including those of the respiratory tract, are to be treated successfully.
REFERENCES
1. Meyer, K. F., in Viral and Rickettsial In-fections of Man, ed. 2, edited by T. M. Rivers, Philadelphia,
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B. Lippincott Company, 1952, p. 440.2. Horsfall, F. L., Jr., in Viral and Rickettsial Infections of Man, ed. 2, Philadelphia,
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B. Lippincott Company, 1952, p. 383. 3. Ibid., p. 392.4. Thalmann, W. G., Kempe, C. H., Worrall,
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A., and Meiklejohn, G., Aureomycin in treatment of influenza : Controlled study,J.A.M.A. 144:1156, 1950.
5. Alexander, Hattie E., in Bacterial and Mycotic Infections of Man, ed. 2, edited by R.
J.
Dubos, Philadelphia,J.
B. Lip-pincott Company, 1952, p. 515.6. Morgan, H. R., and Cheever, F. S., in Bacterial and Mycotic Infections of Man, ed. 2, Philadelphia,
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B. Lippincott Company, 1952, p. 408.7. Commission on Acute Respiratory Diseases, Experimental transmission of minor respiratory illness to human volunteers by filter-passing agents. I. Demonstra-tion of two types of illness characterized by long and short incubation periods
and different clinical features,
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Clin. Investigation 26:957, 1947.8. Honsfall, F. L., Jr.,2 p. 378.
9. Tamm, I., Folkers, K., and Horsfall, F. L., Jr., Inhibition of influenza virus multipli-cation by 2, 5-dimethylbenzimidazole, Yale
J.
Biol. & Med. 24:559, 1952. 10. Tamm, I., Folkers, K., and Horsfall, F. L.,Jr., Inhibition of influenza virus
multipli-cation by alkyl derivatives of
benzimida-zole. I. Kinetic aspects of inhibition by
2,5-dimethylbenzimidazole as measured by infectivity titrations,
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Exper. Med. 98:219, 1953.11. Tamm, I., and others, Inhibition of in-fiuenza virus multiplication by alkyl
derivatives of benzimidazole. III.
Rela-tionship between inhibitory activity and chemical structure,
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Exper. Med. 98:245, 1953.
12. Ackermann, W. W., Role of 1-methionine in virus propagation,
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Exper. Med. 93: 337, 1951.13. Horsfall, F. L., Jr., and McCarty, M.,
Modifying effects of certain substances
of bacterial origin on course of infection with pneumonia virus of mice (PVM),
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Exper. Med. 85:623, 1947.14. Ginsberg, H. S., and Horsfall, F. L., Jr., Therapy of infection with pneumonia virus of mice (PVM): Effect of polysac-charide on multiplication cycles of virus
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