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Texas Cerebrospinal Meningitis Epidemic of 1911-12: Saving Lives with New York City Horse Immune Serum
A savage cerebrospinal meningitis epidemic swept the Southwestern United States, beginning in the latter part of October 1911, reaching its height during the months of January through March 1912, and finally dying out in May 1912. (1) Centered in Texas, the Texas health authorities, including Dr. Nash, the Dallas health officer, and Dr. Steiner, the state health officer, requested assistance from experienced medical researchers and clinicians then residing in New York City, which had itself been part of a devastating cerebrospinal meningitis world pandemic between 1904 and 1909. (1a-c) There were 800 new cases of cerebrospinal meningitis between October and February (1911-1912) in Dallas alone (population about 380,000 in 1910), and a total of over 2,000 cases for the entire state of Texas (population about 4,000,000 in 1910) (1d) by the termination of the epidemic in May 1912. (2-3)  
Sent to assist Texan health professionals on January 2, 1912, was Abraham Sophian, M.D. (1984-1957), a 30-year-old Kiev, Russia émigré and an early Cornell Medical School graduate (1906) affiliated with the Research Laboratory, New York City Health Department. He rushed to Dallas carrying with him 110 liters of horse immune serum (about 3,500 doses) containing precious antibodies to Neisseria meningitidis, the bacteria responsible for cerebrospinal meningitis. (2) He also taught the Texas health authorities how to safely perform lumbar puncture (spinal tap), administer the serum, and create a designated hospital for meningitis patients, among other strategies to improve public hygiene to bring the epidemic under control. Sophian personally directed the treatment of many patients and, when he departed from Texas in mid-February 1912, he was showered with gifts, including a loving cup, jewelry, and some $8,000 in cash by the city of Dallas and grateful citizens and physicians in other cities he visited as well as rural areas. (2, 2a) Sophian was successful in part because of the new knowledge about immune serum developed by his older colleague Simon Flexner, M.D., who, at the time of the New York City and Dallas, Texas, cerebrospinal meningitis outbreaks, was affiliated with the Rockefeller Institute for Medical Research, which he helped found. Epidemic and Pandemic Cerebrospinal Meningitis The cause of epidemic cerebrospinal meningitis was first identified in 1887 in Europe by Berliner physician Dr. Weichselbaum a mere 25 years before the Texas epidemic. (4) Scientifically named Diplococcus intracellularis meningitides and Neisseria intracellularis and known by those names in the older literature, the bacterium is commonly known as the meningococcus. This organism is the only known bacterium to cause epidemics of meningitis. Thus, the term “epidemic meningitis” or “epidemic cerebrospinal meningitis” always refers to the dreaded meningococcal meningitis caused by the Neisseria meningitidis bacterium. Epidemic cerebrospinal meningitis was endemic around the world, at least since 1805 when it was first described in Geneva, Switzerland. It became a pandemic—that is, an epidemic occurring worldwide, or over a very wide area, crossing international boundaries, and usually affecting a large number of people--in the early 1900s, according to assessments by Casadevall and Scharff and by Simon Flexner himself. (4,5) The meningococcus has a very strong appetite for human brain and spinal cord tissue where it causes severe inflammation of their coverings, called meninges. In the pre-antibiotic years before 1942, infection by the meningococcus promised gruesome death for 70-80% of afflicted people. People fortunate enough to survive the infection were often crippled with deafness, mental deficiency, and loss of fingers, toes, and whole limbs. Medical science researchers, including Georg Jochmann (1874-1915) in Germany (there were many epidemics there) and Simon Flexner and J.W. Jobling in America at the Rockefeller Institute for Medical Research in New York City, worked feverishly to develop an anti-serum for treatment. History of the Introduction of Anti-Meningococcal Serum In May 1905, Georg Jochmann, working at the Medical Clinic of Breslau, developed a serum (the clear, antibody-containing part of the blood that remains after all the blood cells and clotting factors have been removed) that protected smaller animals (guinea pigs, white mice) from death after injection with ground-up meningococcus culture. (6) Jochmann then induced Merck Company, the oldest pharmaceutical company in the world, to prepare the serum on a large scale by injecting meningococcal autolysate into horses, followed by harvesting their immune serum, which contained the precious antibodies to meningococcus. Jochmann lost no time in infusing this specially-prepared horse serum into humans with cerebrospinal meningitis, the results of which he reported to the Kongress fur Innere Medizin in April 1906. He injected about 10-15 cc (1 tablespoon) of horse serum both subcutaneously and intraspinally into 38 people sick with epidemic meningitis in Germany. He received a prompt beneficial clinical response and, during the course of the year, was able to cut the mortality rate of patients in half, from 53% in untreated cases to 27% in treated cases. (7) In America, Simon Flexner, M.D., initiated similar work developing immune horse serum, although he did not himself treat patients, as described below. Simon Flexner’s Background
Simon Flexner (1863-1946) was a prolific medical scientist and older brother of Abraham Flexner (1866-1959) (the latter authored the 1910 Carnegie Foundation-funded “Flexner Report” on the state of the nation’s medical schools). Born in Louisville as the middle son of a very large German immigrant family, Simon never attended high school or college but was a proficient auto-didact whose innate curiosity and intelligence—and access to a microscope used for urinalyses and some books located in his older brother Jacob’s drug store—enabled him to learn the basics of what is now called pathology. Youngest brother Abraham attended high school in Louisville and matriculated at 10-year-old Johns Hopkins University in Baltimore, which earlier had been founded with a bequest of seven million dollars by the man of the same name, to be equally divided between a university and a hospital. (8) When Abraham returned to Louisville from Johns Hopkins after completing his two years of education (he majored in Greek language), he told Simon, who was working at Jacob’s drug store, that the Hopkins hospital was still under construction but a new professor, Dr. William Henry Welch, had newly returned from studying in Germany and had been hired as professor of pathology. Simon Flexner (henceforth, Flexner) was very interested in obtaining further training under Welch but needed the M.D. (medical doctor) credential to apply to the program. He obtained that degree in 1889 from the Medical Institute of the University of Louisville, which had an “academic department” staffed by the leading practitioners of the region who gave lectures during the four winter months and apprenticed students the rest of the year. Flexner had already gotten to know some of these physicians well, especially the microscope buffs, at Jacob Flexner’s drug store where they often congregated. Flexner’s long hours at the drug store, which operated open 24 hours/day, prevented him from attending many medical school lectures, but he read extensively. He barely earned the M.D. diploma, promising the skeptical dean that he would never practice medicine on live patients but would restrict his work to laboratory pathology, which was his true love. He eventually matriculated at Johns Hopkins with financial help from Abraham, and there became very close to Welch, even penning his biography in 1941. (9) Later Simon moved his professional affiliation from Johns Hopkins to the University of Pennsylvania (instead of the brand-new Cornell Medical School, founded in 1898, which earnestly recruited him) and finally to the Rockefeller Institute of Medical Research where he ended his glorious career. Simon Flexner’s Work on Anti-Meningococcal Serum In September 1903, Simon sailed for Europe to spend a semester in Berlin at the laboratory of Professor Salkooski, where the first studies of autolytic enzymes had been made. (10) “The knowledge he acquired of chemical methods for measuring enzyme activity was to be particularly valuable in helping him make possible what was probably his greatest single scientific contribution: the ‘Flexner’ serum effectively terminating the recurrent epidemics of cerebrospinal meningitis”, noted his biographer. (10) Simon’s work on the anti-meningococcal serum began a little after Jochmann’s in 1905 (see above). (11) On August 25, 1906, he reported in the “Journal of the American Medical Association” that he had successfully produced a specific immune serum, which protected small animals against fatal doses of injected meningococcal autolysate (soluble products of the meningococcus). He obtained the same results with monkeys who were first injected with the immune serum and then injected with meningococcal autolysate (into the space around the monkey’s spinal cord). However, a virulent form of meningitis ensued in the monkeys that did not receive antiserum (control monkeys). Indeed, the cerebrospinal meningitis induced by Flexner in the large monkeys used resembled in all important clinical and pathological findings the disease in the human being (each monkey was autopsied). The cerebrospinal meningitis infection Flexner induced in his monkeys ran a very short, fatal course, noted Sophian. (11) In spite of his early successes in the laboratory with his serum, Flexner expressed some reservations—at least early on—about the safety and efficacy of his serum as a treatment for cerebrospinal meningitis in humans. He noted, for example, in March 1907 that injection of NORMAL (non-immune-prepared) serum in his monkeys “exercises a certain degree of protection” from the effects of meningococcal autolysate! (12) Nevertheless, Flexner continued his studies and later immunized horses for large-scale production of the antiserum for use in humans. First Use of Anti-Meningococcal Serum in the United States The first opportunity to use the immune serum in the United States occurred in May 1907 during a cerebrospinal meningitis epidemic in Akron, Ohio. (13) “Here the serum produced striking results,” exclaimed Sophian. As against a previous mortality rate of 90% (8/9 people with meningitis not treated with antiserum had died), the recovery rate for those treated with the serum was about 75% (8/11 patients treated with antiserum at the City Hospital of Akron survived). All 11 cases were confirmed by bacteriological examination of spinal fluid and blood. The serum was administered by Dr. Ladd, a private practitioner in Cleveland. “Very soon [Flexner’s] serum was extensively used in this country at the beginning of a fresh epidemic in New York, Philadelphia, [and] Castalia [Ohio]. In Edinburgh [Scotland], it was used by Dr. Claude Ker, and in Belfast, by Dr. Gardner,” effused Sophian. (13) Flexner followed up with a detailed analysis of the 11 serum-treated cases reported to him by the physicians in Akron, Ohio, and published the results and a discussion of each case in November 1907 (14). Flexner’s “Case I” concerns a 12-year-old school girl with a very stormy 96-day course of cerebrospinal meningitis who received a total of 82.5 cc (about 5 ½ tablespoons) of serum injected into the space around her spinal cord during multiple sequential lumbar punctures over the course of her violent illness. Each time she received the serum infusion, her condition promptly improved. In his discussion of the case, Flexner remained very interested in the possibility that lumbar puncture alone (with drainage of cerebrospinal fluid) may improve the patient’s condition, as well as infusion of the serum. The school girl apparently was discharged without sequelae on the 96th day of her hospitalization. (14) The case histories published by Sophian and Flexner about people ill with cerebrospinal meningitis are worth reading to gain a deep appreciation of the struggles involved in caring for extremely sick epidemic meningitis patients in the early 1900s (e.g., using chloroform to terminate seizures and perform lumbar puncture). Later in 1913, Flexner published results he had carefully collected of the use of his serum in 1,300 people with cerebrospinal meningitis from epidemics around the world. He noted the difficulties inherent in aggregating reliable data from around the world but took at face value the mortality rates reported to him. For example, the rates reported WITHOUT use of his serum were: Greater New York City, 73%; Boston 69%; Hartford, 76%, several cities in Ohio, 70-90%, Porterville, California, 90%, Texas, 75%, Leith, 75%, Edinburgh, 80%, Glasgow, 75%, Belfast, 70%, Breslau, 63%, Flatten, 67%, France, 75%, Belgium, 78%, Milan, 56%, Palestine, above 80%, and Athens, 59%, among others. (15) Thus, he was supremely pleased to learn that of the 1,294 cases of cerebrospinal meningitis in the world that WERE treated with his serum, 894 recovered and 400 died—a mortality rate of 31%. (16) Flexner’s final conclusion about the efficacy of his serum, which he committed to writing, as was his habit, follows: “In view of the various considerations presented, the conclusion may be drawn that the anti-meningitis serum, when used by the subdural method of injection, in suitable doses and at proper intervals, is capable of reducing the period of illness; of preventing, in large measure, the chronic lesions and types of the infection; of bringing about complete restoration of health, in all but a very small number of the recovered, thus lessening the serious, deforming, and permanent consequences of meningitis; and of greatly diminishing the fatalities dude to the disease.” (17) Sophian and the Texas Cerebrospinal Meningitis Epidemic Though Flexner and other observers designated 1904 to 1909 as the time frame of the world pandemic of cerebrospinal meningitis, the disease continued to surface after 1909. For example, Texas and Louisiana were severely stricken with an epidemic of cerebrospinal meningitis during the winter of 1911-1912, as mentioned earlier.  
Dr. Nash and others in Texas who had heard about Flexner’s serum requested purchase of the serum. As previously noted, Dr. Sophian accompanied 110 liters of the serum, produced in the Research Laboratory of the New York City Health Department under the direction of William H. Park, M.D., to Dallas Texas. Sophian taught the health authorities and practitioners how to administer the serum, which involved lumbar puncture and a serum administration protocol. The lumbar puncture procedure was so carefully detailed in Sophian’s book “Epidemic Cerebrospinal Meningitis” (1913) that it could be used as a guide to teach medical students today. (18-19) The protocol for administering the serum follows: “The injection protocol involved lumbar puncture, removal of a volume of cerebrospinal fluid, and slow introduction of 30 cc of serum by gravity flow. Dosing was repeated every 24 hours until the patient improved….The injection of serum into the lumbar subarachnoid space produced a therapeutic benefit for the brain but required considerable expertise,” noted Casadevall and Scharff. (4)
Flexner, in one of his papers, acknowledged Sophian’s work in Texas. To wit: “The serum was employed in many of the cases, and the reports from Texas and Louisiana are available for 1911-1912 [references Sophian’s book]. They are specially valuable since they indicate what can be accomplished by the employment of the serum not only inside hospitals but outside and, as often happens, under the disadvantages of poor surroundings and, doubtless, by physicians without previous experience in the performance of lumbar puncture. “Of the total cases reported from the cities (exclusive of Dallas) and counties in Texas numbered 1,956. Of them 562 received no serum and the mortality was 77 percent. 1,394 were given one or more injections of the serum and the mortality was 37 percent…the figures for three cities that suffered heavily in the epidemic follow.
“Among the group of cases observed by Dr. Sophian, 19 were in a dying condition when first given the serum and survived the injection less than twenty-four hours. Excluding these almost hopeless examples lowers the mortality among the 161 remaining cases [treated personally by Dr. Sophian] to 15.5%,” concluded Flexner. (20) Prophylactic Measures Against Epidemic Meningitis in Texas Epidemic Sophian wrote that “most writers agree that it is necessary to treat contacts in epidemics of meningitis.” (21) There were no antibiotics in the first quarter of the 20th century, so treatment of contacts entailed measures that could be employed by everybody in an infected community. The treatment endorsed by Sophian was classified into: 1. Quarantine. 2. Medical treatment—local and internal. 3. Specific treatment. (1) Serum prophylaxis. (2) Active vaccination. 1. Quarantine Sophian strongly advocated “quarantine [his terminology] of the sick and of as many known carriers as possible” as the single most important step in the control of an epidemic. Carriers are healthy people who harbor the Neisseria meningitidis organism in their throats and nose (nasopharynx) as demonstrated by throat culture, and who capably transmit their meningococci to others through coughing and sneezing. Others who acquire the meningococcus in THEIR nasopharynx may be susceptible to the bacteria and progress rapidly to cerebrospinal meningitis. 2. Medicinal Treatment By local medicinal treatment, Sophian meant disinfectants, such as hydrogen peroxide (1/2-1% strength) and salt solution, applied and inhaled to the throat and nasal area. This approach appeared to work well in 60 carriers in one institution (their throat cultures turned negative for meningococci), which enabled their release from quarantine. 3. Specific Treatment By specific treatment, Sophian meant production of specific immunity, which could be produced either by injecting serum, causing a passive immunity (i.e., lumbar puncture and infusion of Flexner’s serum), or by injecting a vaccine, causing an active immunity. (22) Sophian was very interested in the efficacy of vaccination against the meningococcus but understood the need for further experimental work on laboratory animals. Indeed, today meningococcal vaccination is mandatory in many settings where human beings reside in crowded spaces. (22a) Sophian was far ahead of his time in his ideas about developing a meningococcal vaccination, which he published in the Journal of the American Medical Association. (23) Undesirable Effects of Autoimmune Serum in Humans Horse antibodies to the meningococcus are foreign proteins that, when injected into a human for the treatment of cerebrospinal meningitis, could and did cause reactions. As early as 1903, researchers in Germany had identified reactions subsequent to a first injection of certain foreign proteins. von Pirquet and Schick gave the name “serum sickness” or “serum disease” to the phenomena. (24) Sophian acknowledged that this phenomenon was a “very frequent complication in serum treated cases of meningitis, probably due to the fact that the serum is unrefined and very large doses are used.” (25) Indeed, the symptoms occurred in about 60% of cases under his treatment.
“They [signs of allergic reaction] usually appear on the eighth to tenth day after the first dose of serum. Not infrequently one sees the accelerated reaction on the fourth to sixth day after the first injection in cases where the dose of serum has been repeated. I have met with a number of cases who have had the immediate reaction within ten minutes to one-half hour after the injection of serum. These cases had probably been sensitized by a previous injection of horse serum for some other disease,” he wrote. “Ordinarily the symptoms are annoying but not alarming. They are, chiefly marked general, giant [welts], at times a general errythema [sic] [redness]” and fever, chills, swelling, nausea, vomiting, headache, and arthritis, among others. Sometimes lamented that sometimes the reaction to the horse serum could be distinguished only with difficulty from the symptoms of the meningococcal infection for which the serum was administered. Treatment was supportive, according to Sophian. Advent of Antibiotics to Treat Meningococcal Meningitis When penicillin became available for clinical use in the early 1940s, serum therapy quickly vanished, not only for epidemic cerebrospinal meningitis, but for many other infectious diseases, including diphtheria, tetanus, scarlet fever, pneumococcal pneumonia, and non-epidemic meningitis caused by Haemophilus influenza. (26) As a result, over the past fifty years, there has been relatively little interest in passive antibody therapy for bacterial infections. However, the rising resistance of some bacteria to antibiotics, the limitations of antibiotics in people with compromised immune systems, and the availability of technology to generate human (rather than horse) antibodies to specific microorganisms, has sparked renewed interest in this approach. (26) Summary Much of what is known today about the behavior of the meningococcus in humans was learned under very difficult circumstances in the early 1900s during a widespread pandemic of cerebrospinal meningitis that swept the world, leaving practitioners helpless in the face of the high-mortality disease. The development of auto-immune serum in animals by Simon Flexner, M.D., and development of the lumbar puncture procedure to inject the serum into the space around the spinal cord in humans by physicians such as Abraham Sophian, M.D., cut mortality rates in half. Serum sickness developed in more than half of the patients. Vaccines against the meningococcus, which is the only bacteria that causes epidemics, were considered in the early 1900s. Today, antibiotics treat cerebrospinal meningitis more safely and effectively than did horse immune serum, and vaccines against the disease are mandatory in many settings. Emerging bacterial resistance to antibiotics and technology available to generate human antibodies has sparked renewed interest in passive antibody therapy for bacterial diseases. Sources: 1. Abraham Sophian: “Epidemic Cerebrospinal Meningitis.” CV Mosby, St. Louis, 1913, p. 15. 1a. “Cerebro-Spinal Meningitis” in The New York Times, March 5, 1905, p. 8. 1b. “Cerebro-Spinal Meningitis” in The New York Times, March 26, 2005, p. 28. 1c. “Cerebro-Spinal Meningitis: Widespread Epidemic Character: What the New York Board of Health is Doing” in The New York Times, April 5, 1905, p. 9. 1d. Population estimate of Texas in 1910 at: http://www.window.state.tx.us/ecodata/popdata/msa1.xls; accessed August 21, 2006. 2. “Back from Winning War on Meningitis: Dr. Sophian Reports Epidemic in Dallas and Other Texas Cities Practically Stamped Out.” The New York Times. February 15, 1912, p. 5. 2a. “Texas Gifts to Dr. Sophian: Grateful to Rockefeller Institute Specialist for Fighting Meningitis.” Special to The New York Times. Feb. 4, 1912, p. 14. 3. Sophian, p. 258. 4. Arturo Casadevall, Matthew Scharff: “Serum Therapy Revisited: Animal Models of Infection and Development of Passive Antibody Therapy. In “Antimicrobial Agents and Chemotherapy”, August 1994, p. 1697. 5. Sophian, pp. 1-10. See also: Simon Flexner: “The results of the serum treatment in thirteen hundred cases of epidemic meningitis” in Journal of Experimental Medicine” May 1913, 17:555; available online at: http://www.jem.org/cgi/reprint/17/5/553?maxtoshow=&HITS=10&hits=10&RESULTFORMAT=1&author1= 6. “George Jochmann” at: http://www.whonamedit.com/doctor.cfm/2819.html; accessed August 20, 2006. 7. Sophian, p. 175. 8. James Thomas Flexner: “An American Saga: The Story of Helen Thomas and Simon Flexner.” Fordham University Press, 1984, p. 124. 9. Simon Flexner and James Thomas Flexner: “William Henry Welch and the Heroic Age of American Medicine”. The Johns Hopkins University Press, 1941. 10. James Thomas Flexner, p. 420. 11. Sophian, p. 176. 12. Simon Flexner: “Concerning a serum-therapy for experimental infection with Diplococcus intracellularis” in “The Journal of Experimental Medicine”, March 1907, p. 185. Available online at: http://www.jem.org/cgi/search?sendit= 13. Sophian, p. 177. 14. Simon Flexner and J.W. Jobling: “Serum treatment of Epidemic cerebro-spinal meningitis” in “Journal of Experimental Medicine” January 1908 10:141-203, available online at: http://www.jem.org/cgi/reprint/10/1/141?maxtoshow=&HITS=10&hits=10&RESULTFORMAT=1&author1= 15. Simon Flexner: “The results of the serum treatment in thirteen hundred cases of epidemic meningitis” in Journal of Experimental Medicine” May 1913, 17:556; available online at: http://www.jem.org/cgi/reprint/17/5/553?maxtoshow=&HITS=10&hits=10&RESULTFORMAT=1&author1= 16., Ibid, p. 564. 17. Ibid, p. 574. 18. Sophian, pp. 170-175, 19. Ibid, p. 179. 20. Simon Flexner: “The results of the serum treatment in thirteen hundred cases of epidemic meningitis” in Journal of Experimental Medicine” May 1913, 17:572-73. Available online at: http://www.jem.org/cgi/reprint/17/5/553?maxtoshow=&HITS=10&hits=10&RESULTFORMAT=1&author1 21. Sophian, p. 185. 22. Ibid, pp. 187-191. 22a. CDC MMWR: “Prevention and Control of Meningococcal Disease: Recommendations of the Advisory Committee on Immunization Practices, May 27, 2005, Vol. 54, No. RR-7. Available online at: http://www.cdc.gov/mmwr/preview/mmwrhtml/rr5407a1.htm; accessed August 20, 2006. 23. Abraham Sophian and J. Black, “Prophylactic Vaccination against Epidemic Meningitis,” in The Journal of the American Medical Association 59 (1912): 527-32. 24. CE Pirquet and B Schick: “Wien klin Woch.” 1903, 16, 1244, as noted in Moyer S. Fleisher and Lloyd Jones, in “Serum Sickness in Rabbits: I. Manifestations of Serum Sickness. In “Journal of Experimental Medicine” 54 (4), 1931, available at: http://www.jem.org/cgi/reprint/54/4/597?maxtoshow=&HITS=10&hits=10&RESULTFORMAT=1&title=serum+ 25. Sophian, p. 236. 26. Arturo Casadevall, Matthew Scharff: “Serum Therapy Revisited: Animal Models of Infection and Development of Passive Antibody Therapy. In “Antimicrobial Agents and Chemotherapy”, August 1994, p. 1695. |
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