New Aids for the Wounded

I

THE presence of typhus in the German armies has brought home to every one of us a question of national importance: how far has science been able to defend the soldier against infection? Answers to that question have been coming in from Dunkirk and Pearl harbor, from Libya, China, and Russia, from crowded Canadian ports and from our own training camps. We know of the death toll from infection in the last war; are there more hopeful signs in this conflict?

When war intensifies the danger of infection, researches conducted under desperate pressure occasionally yield valuable help; such as the Carrel-Dakin treatment and the improvement in the production of tetanus antitoxin during the last war. But the best research in treatment of wounds goes on during the years of peace in laboratories untroubled by air raids. There is no time to argue therapies when meningitis breaks out in an air-raid shelter. When typhus strikes Madrid or Nashville, insecticides are more important than the precision instruments of research. It is because of experiments conducted within the last years of peace that we can hope in the immediate future to protect the world from tetanus and typhoid, from influenza and typhus.

Since the First World War the wounded have benefited from four powerful aids: the sulfonamides, tetanus toxoid, the Orr-Trueta plaster-cast immobilization, and the availability of transfusions with which to combat shock. Wound excision or débridement, that is, the removal of all dead and devitalized tissues, remains the basic procedure in the conquest of infection. But this is a surgical operation. In the period between injury and surgical help it is the sulfonamides and immunity against tetanus that hold back the bacterial invaders: these are the critical hours when, in times past, fatal infection all too often set in. Colonel Leonard Colebrook once estimated that the streptococci were responsible for 70 per cent of all deaths due to infected wounds in the last war. In an English hospital, he and Major A. E. Francis recently studied the effect of the local application of sulfanilamide to sixty-two face and jaw injuries. Under this treatment the streptococci almost always disappeared in from three to four days.

Within certain limitations the sulfonamides are of incalculable value both in preventing the infection of wounds and in curing infection. At first these drugs were given by the mouth. Once infection is established, the body’s defenses swiftly mobilize; and the sulfonamides were believed to act by paralyzing the bacteria until the intricate antibacterial forces of the body could annihilate them. But it was found that even a heavy diet of sulfonamides taken by mouth could not produce a sufficiently powerful concentration in wounds. Repeated tests showed that amounts of sulfonamides obtained in this way could kill or inhibit only a small number of certain bacteria and that even this action required several hours. The result was not comparable to the knockout blows of the old-line disinfectants.

Since Dunkirk it has been discovered that, when solid crystals of the sulfonamides are packed into wounds, from seventy-five to a hundred times the concentration of these drugs can be maintained in the tissues of the wound than is possible by oral administration. The increased antibacterial action so obtained is not accompanied by marked injury to the human cells that are so essential for healing. This new therapy does not mean that the surgical toilet of the wound can be omitted. But it does mean that during the time between injury and the operating table the bacteria can be held in check.

It is probable that for our armed forces such sulfonamide prophylaxis will include both the oral administration of one of these drugs and also packing it into the wound as soon as possible after injury. It is obvious that such treatment will become the duty of the casualty clearing station. Both in Great Britain and in this country, sulfanilamide is the preferred drug for this stage of treatment. This drug is more soluble than its descendants; it is especially active against the streptococci of wound infection and it is relatively cheap, a factor that must be considered in view of the large amounts that are needed.

II

Burns are very prevalent in this war, in aerial combat and in naval engagements in which men must often escape through oil-covered waters. At Pearl Harbor more than 60 per cent of the injuries were burns. In this disaster it was found that sulfanilamide powder caked, and this form of application was abandoned. Sulfanilamide in mineral oil provided a combination that was both soothing and antibacterial.

Another preparation for the treatment of burns was introduced by Dr. K. L. Pickrell last August. This is a three per cent solution of sulfadiazine, the baby of the family, in a special solvent, triethanolamine. When this solution is sprayed upon extensive burns, which are then left without dressings, the healing that occurs is incredible to the nonsurgical mind, which cannot understand how a human being could be so horribly burned and survive. It is quite possible that in the right solvents the sulfonamides will provide valuable alternatives for the older burn remedies, such as tannic acid or gentian violet jelly, or even replace them. Incidentally, the value of transfusions to counteract the shock that follows severe burns should encourage anyone who has given blood to the Red Cross. Let the citizen donor remember what his plasma means to the burned and wounded on a battleship in action.

Lockjaw, that classic survival from the days of Hippocrates, has been defeated, not by man-made drugs but by clever biological methods. Tetanus is not really an infection, but an intoxication with one of the world’s most powerful poisons. The bacilli lurk safely in their hideouts and send forth their toxins like longrange bombers. For many years we have had antitoxin with which to neutralize the tetanus toxin. Because we dare not gamble on our own production of antitoxin after injury, we used horses to produce antitoxin for us. It was such antitoxin that cut the incidence of tetanus in the First World War and that has constantly protected civilians since then.

Antitoxin is not enough: its protection is only transitory. But now, thanks to the newly developed tetanus toxoid, the soldiers and civilians exposed to tetanus hazards can be made actively immune to the disease far ahead of the time of injury. Toxoid is the tetanus toxin itself, made nonpoisonous by chemical treatment. It closely parallels diphtheria toxoid now in such general use. Like a beneficent rattlesnake deprived of its fangs, tetanus toxoid still retains its power of inciting in us the production of our own antitoxin. Troops are given immunizing injections of toxoid on enlistment, and the immunity so produced is further increased by another injection a month before they go on active duty.

Excellent results with tetanus toxoid were obtained in France, first with cavalry horses, then with men. The Russian Army adopted it in 1937. Italy began to use it in 1938 and there were exactly five cases of tetanus among 500,000 Italian troops engaged in the inglorious conquest of Ethiopia. Ninety per cent of the British forces in the Battle of France had been immunized. There were twelve cases of tetanus among the unprotected, none among the immune, although many of them did not reach England until five or six days after injury. Our own forces are now protected with tetanus toxoid. The soldier’s identification tag now bears the letter T followed by the year of its wearer’s injections — for example, T40-41.

The situation is more complicated in regard to gas gangrene, the air-hating, evil partner of tetanus. The difficulty is that this disease can be caused by a number of different microbes; consequently the problem of the chemist or of the immunologist is far from simple. In the accidents of peacetime this type of wound infection remains a major danger. In the last war it was one of the chief causes of amputation. Débridement, even if done within a few hours, is not always sufficient to prevent the often hideously rapid spread of this infection. But help has come, again in the sulfonamides. Authorities now recommend the local application of either sulfathiazole or sulfadiazine, not of sulfanilamide. The trouble is that not all the organisms involved in this infection are equally susceptible to any drug, and we cannot expect the clean-cut results here that can be obtained under other conditions with these chemicals. A better drug may even now be a formula in a chemist’s brain or in process of synthesis. Perhaps the logical approach is to prevent the intoxication by means of toxoids. In March 1941, W. J. Penfold, J. C. Tolhurst, and D. Wilson reported such a substance which stimulated the production of antitoxin in twelve human volunteers. If such a toxoid can be perfected, it may well be one of the great advances of this war.

III

Surgeon General Parran states that the British made two miscalculations in their medical preparation for the war. They planned for as many as 30,000 casualties a day — a figure which has not been reached thus far. And they did not foresee a persistence of night bombing that would force thousands of civilians into unsanitary, damp, and overcrowded all-night shelters. It is under these conditions that droplet contagions flourish. This was promptly indicated by a jump in the incidence of epidemic meningitis in England from 1500 cases in 1939 to 12,500 in 1940.

Although epidemic meningitis is caused by a microbe, no method of vaccination against it has been developed. It must be attacked by preventive methods such as the proper spacing of cots, by the detection of carriers during an epidemic, and by treatment after the disease has made its brutal appearance. Until 1937, treatment was entirely with immune serum, the value of which could not be questioned. Dr. A. B. Wadsworth found that in 9760 cases treated with serum the mortality was 36.8 per cent. In a series of 1313 cases that did not receive serum, the mortality was 74.3 per cent.

Translated into human lives, a mortality rate of 36.8 per cent was still too high. It was sulfanilamide that changed the picture, and again, as in wound therapy, this discovery came just in time. From British troops in France in 1940, from our own camps, come reports of lives saved by the use of the sulfonamides. Enormously hopeful are the results of the use of sulfadiazine in a series of thirteen cases of meningitis during the recent epidemic in Halifax. Doctors J. H. Dingle, Lewis Thomas, and A. R. Morton reported in June that, although one case died ten hours after admission, the other twelve recovered promptly and completely. From Cape Town, Doctors F. C. Gray and J. Gear have suggested that, when meningitis hits a camp, men found to be carriers be given sulfapyridine. We may now be assured that when this disease strikes our own youth, as undoubtedly it will, the odds will be overwhelmingly in favor of prompt recovery, thanks to the sulfonamides.

In sharp contrast to meningitis, influenza is a disease not directly influenced by these drugs. Our knowledge of this plague has advanced since the First World War: we now recognize its virus nature and have taken strides towards its prevention by vaccination. Although last year was a lucky one, premonitory rumors have recently come from prison camps in Europe and there has been a fresh epidemic in Puerto Rico. We must hope that science will win in this race between the vaccine and the virus. The American Medical Association reported that in the First World War there were more than 20,000,000 cases and about 450,000 deaths in the United States in less than six months. We must be on guard, for conditions are once again propitious for this world traveler.

The influenza problem is still clouded. Not all strains of the virus are alike. The original one, collected from many parts of the world, causes influenza A. But recently an influenza-like disease swept through a children’s hospital at Irvington on the Hudson. No relationship could be established between this virus and the A strain. The second virus has also been found in other parts of the United States and in the West Indies. We must now recognize influenza A and the new type, influenza B. Influenza C, D, . . . Z may be brewing in some African jungle, Russian steppe, or Icelandian fishing village. One of the most important tasks in the world today is to perfect as rapidly as possible vaccines that will be effective against different strains of this virus. The use of fertile eggs in the preparation of the vaccine may mark an improvement over earlier methods. The electron microscope may also be able to point the way of attack. This we know: the right vaccine will be needed by our armed forces and civilians. Already there is evidence that in vaccinated groups the incidence of influenza may be as much as 50 per cent lower than in the unvaccinated group.

IV

Although medically speaking we have conquered venereal disease, statistics show a wide gap between possibility and achievement. Science knows how to control it but the community is careless. In the First World War 338,746 officers and men of the United States Army were treated for venereal disease. This was the equivalent of twenty-three army divisions, or, according to Surgeon General Parran, to the loss of seven million days of active duty. It is estimated today that, of 16,500,000 men subject to the draft, some 300,000 will be found to have active syphilis. And yet Earle Moore has said that ‘syphilis is almost, if not quite, a completely preventable disease.’ Syphilitic prophylaxis fails in only about 0.5 per cent of the cases.

Since the First World War there has been great improvement in the diagnosis of syphilis. Increasing recognition of late forms of the disease, the new continuous intravenous injection of arsenic, the malarial treatment of paresis and other types of late neurosyphilis — all are methods that have furthered our control of this infection. In the British Army the venereal disease rate is keeping low, 8.4 per 1000 men in the first five months of 1941. It can be kept low in our own services, but only through the combined efforts of the men themselves, the medical corps of the services, the Public Health Service, and all state and municipal agencies concerned with the care of enlisted men. Carelessness on the part of any one of these groups will cause a rise in the venereal disease rate. For civilians a follow-up of draftees unacceptable because of active venereal infection is a problem of vital importance to every community.

While the sulfonamides have been of no value in syphilis, their truly astonishing effect upon gonorrhea has revolutionized the treatment of this disease. As each new drug has appeared, it has been tested and found to have some efficacy. The latest of the series, sulfadiazine, may well be the best, although sulfathiazole has shown itself of specific usefulness. But one must view with profound skepticism any claims of 99 or 100 per cent cures of this infection with either drug. Some strains of the gonococcus are resistant to all of the sulfonamides. Such germs persist in acute infections or they retire to the deeper tissues and turn their victim into that most dangerous of persons, a carrier. We know that from such carriers the bacteria can be recovered by new methods which as soon as possible must be part of every public health laboratory. One shudders to think how many carriers must have been turned loose upon an unsuspecting world in the last war for lack of the methods now available. It is now highly probable that sulfonamide-resistant strains of gonococci will necessitate the development of some effective alternatives for these drugs.

The destruction of water mains, as in the bombing of Coventry, instantly creates a public emergency in regard to drinking water. A soldier or a refugee will drink any water he can get, even water from a puddle in a ditch. In our Spanish-American War the typhoid rate was 141 cases per 1000 men a year. If that rate had continued to the First World War, there would have been 560,000 cases and 56,000 deaths instead of 1529 cases and 277 deaths among 4,000,000 men. Vaccine for our armed forces is made in the Army Medical School in Washington, which prepares some 8500 gallons of this typhoid soup a year. Much work has been done recently to strengthen the vaccine. The source of the bacilli used for this purpose is a tenderly sheltered typhoid carrier in Panama. The vaccine is given our troops combined with the paratyphoid vaccines. With vaccination, sanitation, and control of carriers typhoid fever should remain in exile, an inexcusable filth disease.

Dr. Philip Manson-Bahr, writing of Libya, states that bacillary dysentery is the disease most to be feared in desert warfare. No successful vaccine has been made for this infection. But there is one very promising lead for its conquest. This is in the use of a certain group of the sulfonamides, those effective in the gastro-intestinal tract. The progenitor of what promises to be a long line of drugs was sulfaguanidine, a chemical that first appeared in December 1940, after careful investigation by Dr. E. K. Marshall and his associates. Other and related compounds are now being studied. Such drugs promised to be helpful in two ways: first, in the treatment of intestinal infections; second, in the prevention of peritonitis after operations upon the intestines.

After Rats, Lice and History no humbler pen would venture upon the subject of typhus except that the strange germs of this disease, conveyed by lice, have helped to stop Hitler’s armies in Russia and may interfere with an advance through Spain to the Mediterranean. The fact that the louse has no national prejudices and passes easily across borders makes this outbreak of typhus in Europe a peril to be faced with all of the knowledge at our command. If experimentally infected typhus rats can be tenderly transported to New York by Clipper, it is not improbable that a few less carefully chaperoned rats or lice might slip in with less publicity. The author too well remembers the day in 1919 when typhus struck a remote Armenian village sheltering thousands of refugee children. The delouser had balked at the mountain passes, and the armamentarium consisted largely of souvenirs of a happier day in the form of Mothersill’s seasick remedy and a cleanser for straw hats! It is impossible to say how many of this year’s victims in Russia, in the ghettos of Poland or in Spain, will be saved, but medically we are in a much stronger defense position than we were in the last war.

Typhus is not caused by bacteria, but by a curious organism intermediate between them and the filterable viruses. The group of microbes that are responsible for typhus, our own Rocky Mountain spotted fever, and the Japanese disease with the alluring name of tsutsugamushi are called Rickettsiæ, in honor of Howard Taylor Ricketts, the distinguished American scientist who established the nature of these infections and who died of typhus in Mexico City in 1910, a victim of his courageous investigations. One common feature of this group of infections is that they are transmitted by arthropods, a choice selection of which includes lice, wood ticks, and rat fleas.

Epidemic typhus has been one of the great plagues of history. Foci of this infection lurk in the paths of armies in Russia, Poland, Rumania, and Northern Africa. According to Dr. John E. Gordon, there were 135,000 deaths from typhus in a population of 2,500,000 during the Serbian retreat in 1915. There were 10,000,000 cases of typhus in Russia between 1919 and 1922. The mortality varies, but in Europe maybe from 10 to 50 per cent. A recent report from Germany indicates a mortality of from 60 to 70 per cent in persons over fifty years of age. Zinsser concluded that the mild Brill’s disease of our northern cities is true European typhus, probably representing relapses from earlier attacks in immigrants from typhus centres of Europe.

There is no need for us to indulge in any feeling of detachment in regard to typhus. We have our own endemic form, the organisms of which can be distinguished from those of European typhus by certain animal tests. Our typhus centres are in Alabama, Georgia, and Texas. In 1939 Nashville had an outbreak of seventy-five cases. This form of the disease is called murine typhus because its agent is the rat, and it is generally carried by rat fleas. It is associated with our peanut-growing areas. Where the rat goes, along the railroad or the highway, or cross-country, infecting wild rodents in his progress, the fleas go too. It is certainly to be hoped that the exigencies of defense will not result in carelessness in either the disposal of garbage or the extermination of rats.

Over the centuries millions of human beings have died in the stupor of typhus; slowly there has been developed a vaccine which at last brings promise of help. Step by step we have progressed from the distasteful grinding up of the intestines of infected lice, to the growing of the organisms in rats exposed to X-rays, on to the delicate tissue culture methods, and thence to what may be the final stage, the use of chick embryos, a method perfected by Dr. H. R. Cox of the National Institute of Health. In Bolivia three American scientists are now studying the efficiency of our typhus vaccine. If our troops must enter typhus-infested regions, in all probability it will be possible to protect them by vaccination. The roll of men who have died fighting typhus is too long, but these results would satisfy the best of them.

As the Indo-Japanese situation becomes acute, that comfortably remote disease, cholera, comes nearer. It has already been reported in Greece and it has often before crept into the Near East. As late as 1921 an epidemic in the Ukraine flared to 176,885 cases. The conditions there today must be even more favorable for an outbreak. Cholera might easily do more damage than bombs in Japan. Fortunately we have long had a vaccine for cholera and this has recently been improved. But the protection it affords is so short-lived that the vaccine is given only when the disease appears. There is also reason to believe that some of the sulfonamides will be helpful.

Oriental plague, or Black Death, killed one fourth of the world’s population in the years from 1314 to 1351. There were 250,000 cases of this disease in the world in 1925. Plague is now endemic in the Near Eastern areas occupied by British troops. There must be grave danger of it in China. We must also remember that plague is harbored by many animals in the western part of our own country. It lurks in ground squirrels and in chipmunks in California and in prairie dogs in New Mexico. If the plagueand typhus-carrying rats should ever stage a first-class demonstration, the results would not make pretty reading. There is a vaccine for plague, but its value seems to be controversial. More encouraging are some reports from Asia that the sulfonamides have been of value in this disease. It is to be hoped that between the rat catchers and the chemists we can keep an extremely firm grip on this merciless pest.

We boast of mosquito control in Panama, but our troops go to Bermuda and to other tropical isles whose picturesque mangrove swamps are full of yellowfever mosquitoes. We must not forget that the jungle form of this disease is endemic in South America and in Africa. This is a virus disease, not susceptible to the sulfonamides. But since 1936 a vaccine has been made available by the Rockefeller International Board of Health. It is an attenuated virus of the disease grown, like the typhus organisms, in living chick embryos. Since 1938 it has been given to almost 2,000,000 persons in Brazil. A supply is now on hand for our army. It is improbable that the disease will ever again kill the thousands it did in pre-Goethals days. Again sanitation and biology conquer, this time the mosquito and the virus.

Like yellow fever, the ultimate conquest of malaria will be through sanitation. Meantime quinine keeps the Burma Road open. One may lecture learnedly about keeping minnows in the brooks and screens in the windows, but there are many places in the world today where minnows and screens, not to mention windows, are as hard to procure as French wines and avocados. No vaccine has yet been developed for malaria. Quinine remains the great protection of the shivering millions. But this venerable remedy is now supported by atebrin and plasmoquine. Tomorrow the chemical laboratories may give us something better, but perhaps the ditchdiggers will conquer first.

Here, then, is a story of great progress, from the treatment of wounds to the prevention of remote plagues, now brought home to us by the war. These facts are not pleasant, but they are of importance to every person in the world. While we bemoan the hideous events of our era, we may take some consolation in the fact that our enemies are now most of them large and subject to mechanized conquest. The hidden enemies, the microbial foes, are generally in retreat. It takes time to complete their defeat only because of the necessary gap between the knowledge of the laboratories and its application. The space between a Washington laboratory and the remote fastnesses of South America, Arabia, or India must be spanned. When the advances of biology and chemistry can be placed at the disposal of the inhabitants of the dirtiest tent in the outermost haunts of man, the job will be nearing completion. Remember it is less than a hundred years since Pasteur showed the way.