Charles Edward Smith: Coccidioidomycologist and public health leader

Introduction

In 1927–1931, when Charles Edward Smith (1904–1967) attended Stanford University Medical School (then in San Francisco), little was known about Coccidioides immitis, for which he would soon become an indefatigable investigator and the preeminent authority. In 1891, another medical student, Alejandro Posadas, had discovered the organism at the University of Buenos Aires when he saw a 35-year-old Argentine soldier with numerous grotesque skin lesions, including destructive nasal ulcerations, a large purple mass involving most of his right cheek, and another on his left arm resembling a cauliflower. Biopsies revealed organisms similar to the protozoan Coccidia, and Posadas successfully transmitted the disease to several mammals by inoculating them with material from the patient, who eventually died of progressive infection. ¹ In 1896, doctors in California described a similar fatal case in a 40-year-old laborer from the San Joaquin Valley. An autopsy revealed granulomas with protozoa-like organisms, which the authors named for their microscopic appearance and apparent clinical virulence: Coccidioides (“resembling Coccidia”) immitis (“not mild,” “merciless”). ¹

In 1900, investigators cultured material from another lethal California case and isolated a mold, which, when injected into a rabbit, transformed into spherical structures. These findings proved that C. immitis is a fungus with two forms (dimorphic): (1) mycelia, which grow in cultures or soil and produce highly infectious barrel-shaped spores and (2) spherules, which propagate in tissue. ¹

In 1929, Harold Chope, one of Charles Smith’s medical fraternity brothers, inadvertently provided a major revelation when recruited to study C. immitis in the laboratory of Ernest Dickson, a Stanford pathologist and Professor of Public Health. ² On his very first day, Chope opened an old culture, breathed on the plate, and inhaled some of the miasma of spores that arose. Nine days later he developed pleuritic chest pain, followed by cough, purulent sputum, headache, myalgia, weight loss, and a right upper lobe pneumonia. Later, erythema nodosum appeared, and sputum specimens, which disclosed spherules on microscopy, grew C. immitis. Given the lethality of previously reported cases, Chope’s prognosis seemed dire, and news media characterized the young investigator as an imminent martyr to science. Sent by the school to a luxurious site in Arizona from which to shuffle off this mortal coil, he, surprisingly, recovered.

Smith’s early research

When Chope left Stanford in 1932, Dickson invited Charles Smith to assume his vacant laboratory position. ² Smith had received his MD in 1931 and spent one year as a house officer at Alameda County Highland Hospital in Oakland. Dickson, a Canadian, felt that Smith needed more training and hustled him off to the University of Toronto for a Diploma in Public Health, stipulating that he return to work on C. immitis. Smith’s initial investigations with the fungus were unpropitious: he spent 1934–1936 injecting it into guinea pigs’ testicles to induce orchitis and evaluate the therapeutic effects of hyperpyrexia, then a treatment for neurosyphilis. Regrettably, his interventions were unavailing: whether made febrile by pyrogen injections or by directly heating their gonads, the animals died faster than untreated controls. During this period, Smith had an episode of pleuritic chest pain, suspicious for tuberculosis, but with negative sputum samples. He later realized that he had failed to diagnose his own laboratory-acquired infection with C. immitis. ²

In 1936, the significance of Chope’s attempts at research seven years earlier became clear when Dickson solicited the help of California’s Kern County health authorities in studying C. immitis infections. ³ One of them, Myrnie Gifford, was investigating an acute disease known variously as “San Joaquin Fever,” “Desert Fever,” “Desert Rheumatism,” or “Valley Fever,” and characterized by erythema nodosum, cough, chest pain, fever, pneumonia, and arthritis. Preparing for Dickson’s visit, she examined case histories of C. immitis infections and noted that 3 of 15 patients had developed erythema nodosum. ³ When informed of this observation, Dickson recalled Chope’s illness, and they hypothesized that Valley Fever might represent C. immitis infection. Dickson labeled the disease “coccidioidomycosis,” ¹ a neologism that Smith regretted: he wrote the word incorrectly for years before realizing that it has four is. ²

Researchers in the 1920s had shown that intradermal injection of filtrates from cultured C. immitis, called coccidioidin, provoked cutaneous reactions in infected patients. After Dickson’s visit, county health officials began skin testing all Valley Fever victims. Most recounted dust exposure; all had cutaneous reactivity, compared to 25% in randomly selected county residents; and among the 104 subjects, 94% were white, while 60% of cases of disseminated disease occurred in non-whites. ³ These observations indicated that coccidioidomycosis was common; ethnic differences, at least partly, governed the host’s response to the fungus; and infection presumably developed from inhaling airborne spores originating in contaminated soil. Indeed, investigators in 1932 had established the habitat of C. immitis in Kern County itself by isolating the fungus from dirt around the barracks of a ranch where four cases of infection had occurred. ¹

In 1937, Smith began an 18-month study of the disease, funded by foundation money from a prosperous fruit company, in which he traveled to Kern and Tulare counties in southern San Joaquin Valley every week.^2,4 On Sunday evenings, he caught a train from San Francisco to Bakersfield, where he stored a 1937 Ford, called “The Flying Chlamydospore,” the term for the infectious form of the organism. He drove the vehicle for the next three days to see patients and then returned on the Wednesday-night train. By contacting health departments, labor camp foremen, and medical personnel, he elicited the names and locations of 432 subjects with Valley Fever, defined in his study as erythema nodosum or erythema multiforme caused by C. immitis, as evidenced by reactive skin tests or positive sputum cultures. About half of the victims were farm workers or their family members who in the 1930s had emigrated from the “Dust Bowl” of the Midwest, especially Oklahoma, Arkansas, and Texas. There, poor agricultural practices and protracted drought had desiccated the topsoil, which winds dispersed, along with the farm crops, creating dust storms that darkened the skies. The migrants, unfortunately, encountered another dust problem in California. Color 8 mm films that Smith took during his travels in the San Joaquin Valley illustrate the aridity of much of the land and the substantial volume of dust—some undoubtedly contaminated with C. immitis spores—generated by wind, motor vehicles, and farm equipment. ⁵

Smith’s observations led to several important conclusions. Considering the interval between exposure and illness in Chope’s case and others, he deduced that the incubation period of coccidioidomycosis was 1–3 weeks. He demonstrated that cutaneous reactivity developed 2–17 days after symptoms began, and it seemed prolonged. To strengthen this hypothesis, Smith persuaded Chope, whose infection had occurred nine years earlier, to undergo his first coccidioidin test. His response was a 6 × 8 cm area of blistering and necrosis, leaving a permanent scarred forearm. Chope declined further skin testing. ² Smith recognized that cutaneous reactivity indicated a strong immunologic response to C. immitis, which apparently exempted people from future infections: rarely, if ever, did Valley Fever recur. Moreover, no infections developed among laboratory personnel with positive skin tests. ⁴ Smith also confirmed that inhaling spores was the usual mechanism of acquiring C. immitis. In fact, 18 of his research personnel in San Francisco had incurred coccidioidomycosis, which, like Chope’s illness, could only have arisen from inhaling spores in the laboratory. ⁴

Smith found that the infection was almost surely not contagious. Most victims had shared their beds with at least one other person, and such partners rarely developed disease during the expected incubation period. Fortunately, Valley Fever was usually self-limited, with no clinical sequelae, but he noted that few victims were from dark-skinned ethnic groups. C. immitis infection did occur amongst them, but usually as a widespread disorder. Indeed, Gifford had earlier shown that death from dissemination was 23 times greater for African-Americans than Caucasians and 170 times higher for Filipinos. ³

In Smith’s study, most patients with Valley Fever were new arrivals in the area. He speculated, however, that they constituted only a small fraction of all coccidioidal infections. Skin testing performed by Gifford on 2718 schoolchildren had demonstrated that reactivity increased with duration of residence in the region and many infections were asymptomatic: approximately 80% of children were positive after 10 years or more, but only about 5% had a history of Valley Fever. Accordingly, Smith calculated that his 432 symptomatic patients translated into about 8000 new infections in the area. ⁴

In 1939, Smith further challenged the impression that Coccidioides was usually immitis when he reported that routine autopsies revealed four cases of arrested lung infection, including nodules, scars, and lymph nodes containing caseous, sometimes calcified, material with organisms. Injecting spherules into the veins of experimental animals reproduced the findings of pulmonary granulomas that later calcified. ¹

In 1939, Smith inadvertently discovered an alternative to skin tests for diagnosing C. immitis infection.^2,6 After demonstrating that serum from infected guinea pigs did not inactivate coccidioidin in vitro, he was dilatory in cleaning the glassware. When examining the test tubes a week later, he detected a discrete “button” of precipitate on the bottom, which was absent in samples from uninfected animals. This discovery led to the serum precipitin test. His coccidioidin preparation also turned out to be an effective antigen for complement fixation tests, and in 1940 he started using both serologies to diagnose coccidioidomycosis. ⁶ He discovered that the precipitin test was most useful in detecting acute infections, while complement fixation was best for disseminated disease.

Smith also reported the first recognized coccidioidal epidemic. ⁷ In 1940, 14 Stanford students and faculty members took a biology field trip to an area near the San Joaquin Valley, and 10–16 days later, seven students became ill with headache, backache, chest pain, fever, and night sweats. All had abnormal chest radiographs and positive serology, and C. immitis grew from four sputum specimens. Smith’s detective work disclosed that infection occurred when the victims saw a rattlesnake crawling into a hole. One student captured it, but only after his vigorous digging dispersed considerable dust. Four months later, Smith recovered C. immitis from the soil around the hole.

Smith not only described an epidemic of coccidioidomycosis, but he created one. In the late 1940s, working in his laboratory on the first floor of a Stanford building, he transferred some C. immitis isolates from one medium to another on George Washington’s birthday, a holiday when the other occupants were gone. About two weeks after they returned; however, several of them, in offices throughout the building, became ill with the disease, re-emphasizing the hardiness and high infectivity of the airborne fungal spores.

Smith had learned that lesson before. After washing the clothes from his trip to the rattlesnake hole, Smith’s wife developed erythema multiforme, but he did not suspect that she had acquired acute coccidioidomycosis by inhaling spores from his soiled garments until erythema nodosum appeared a little later. ² Indeed, Smith ruefully acknowledged his ineptitude in diagnosing infection in his family. He had not recognized his own case as a young researcher, and when his elder son developed a mild pneumonia, Smith did not implicate C. immitis, either. Later, he remembered that he had brought home some cotton bolls from the San Joaquin Valley for his son, retrieved the material, and isolated C. immitis. Only when his younger son became ill after playing in Smith’s laboratory did he make a prompt diagnosis of acute coccidioidomycosis in a family member. His “not very creditable diagnostic batting average of .250” made him sympathize with clinicians who failed to recognize the disease. ²

Coccididoidomycosis during the Second World War

In 1940–1941, another group of newcomers entered the San Joaquin Valley. With war looming, the Army Air Forces decided to train pilots year-round there because of the favorable weather and abundant space for emergency landings.^2,8 Smith warned military leaders about the risk of C. immitis infections, but they decided that the area’s attractive topography and climate outweighed the medical concerns. Smith began skin testing all recruits when they arrived at two bases in the southern San Joaquin Valley, and then semiannually for those with negative responses. This study confirmed that people with reactivity to coccidioidin did not incur infections, which were most frequent in the summer, especially in dry months following heavy rainfall in the preceding winter and spring. ⁹ Presumably, the increased moisture augmented proliferation of C. immitis, whose spores were then disseminated by wind when high temperatures converted the soil to dust. Smith also demonstrated that 60% of infections were asymptomatic. ⁹

In 1943, members of the Women’s Army Corps arrived, providing an opportunity to discern gender distinctions. Erythema nodosum occurred in 25% of white women compared to 5% of white men, confirming the female predominance for this cutaneous manifestation: in his earlier study of 432 Valley Fever patients, the female:male ratio was almost 3:1. ⁴ Ethnic differences, however, were even more pronounced: erythema nodosum rarely appeared in African-Americans, who also had a rate of dissemination more than 10 times greater than Caucasians, even though all recruits had similar food, housing, and medical care. Smith also found that disseminated infection almost always developed in the weeks or months following the initial illness, unlike miliary tuberculosis, which often is the reactivation of a primary infection that has been quiescent for years. ¹⁰

Military training in the Southwest also helped delineate the geographic extent of C. immitis: skin testing and cases of active disease revealed that the fungus resided not only in California but also in southern Nevada and Utah, western Texas, and, especially, Arizona, whose southern and central areas had the highest rate of infection in the United States. ⁹ Because acute coccidioidomycosis in recruits disrupted training (causing an estimated 35 lost days per case), military authorities asked Smith to propose methods to decrease its frequency. Planting and diligently watering lawns, paving roads, and surfacing airfields cut the infection rate in half by diminishing dust exposure. Further reduction occurred through constructing swimming pools, encouraging aquatics instead of field sports, and spraying highly refined oil onto areas where recruits exercised.

At this time, no effective therapy existed. Because one treatment for tuberculosis was protracted bed rest, Smith prescribed it for a soldier with a coccidioidal lung cavity, which slowly closed. Smith was quite proud of his apparently successful therapeutic regimen until he saw in the camp’s newspaper that his patient was the star end on the football team, having spent much of his time on the playing field rather than in bed! ²

In 1942 another group of newcomers arrived in areas endemic for C. immitis. In May, the United States government required all people of Japanese descent living on the Pacific Coast to go to “Relocation Centers.” Over 110,000 people, about two-thirds of them American citizens, went to 12 such internment camps, one on the Gila River Indian Reservation about 50 miles southeast of Phoenix, Arizona. Smith noted that outbreaks of C. immitis infections occurred among its approximately 13,000 residents. ⁸

Other involuntary residents lived nearby—prisoners of war (POWs). Over 425,000 captives, mostly German, were incarcerated in more than 500 locations throughout the United States. About 13,000 POWs were on a former military reservation in Florence, Arizona, including all those with active tuberculosis, assigned there for its putative therapeutic climate of heat and dry air. Unfortunately, the conditions were also salutary for C. immitis. Complaining that the region was unhealthy and prisoners were becoming ill, the German government accused the United States of violating the 1929 Geneva Conventions concerning treatment of enemy prisoners. Smith visited Florence early in 1944 and discovered that acute coccidioidomycosis was indeed common. He estimated that two-thirds to three-quarters of new arrivals became infected annually. ⁸ Two POWs had died, and of the 89 patients with tuberculosis, 10 had become ill with C. immitis. One U-boat officer who had a tuberculous pleural effusion on one side developed a coccidioidal effusion on the other. Although this infection apparently did not unduly harm the tubercular patients, military authorities re-located them to facilities outside endemic areas to avert further C. immitis exposure and obviate criticism about their treatment of prisoners.

The 1929 Geneva Conventions required that captives, other than officers, work, so long as they were paid and their jobs did not involve war operations or jeopardize their health. In 1945, German POWs incarcerated elsewhere in California were sent to the San Joaquin Valley as farm laborers. During two months that summer, about 10% of them were hospitalized for coccidioidomycosis, compared to 0.6% of personnel at a nearby airfield. The difference occurred because dust was well controlled at the military installation, but not in the nearby farms. After Smith investigated this outbreak and informed authorities about the cause of the infections, they relocated the prisoners to a more salubrious area. ⁸

In the late 1940s, Smith tested an erroneous theory that the reservoir of C. immitis was rodents and that wind disseminated spores from their dead bodies. He buried mice that had died of infection in three locations beside a highway and drove there monthly to examine the carcasses. His activities aroused the attention of a deputy sheriff, who detained him for suspicious behavior. After tracing the vehicle’s license plates to Stanford, he released Smith, attributing the affair to erratic professorial conduct. ²

Administrative career

After the 1940s, Smith’s research career focused primarily on the immunological aspects of C. immitis infection and an ultimately unsuccessful search for an effective vaccine. Besides his scientific ventures, however, Smith was busy with other responsibilities. ¹¹ He was consultant to the Secretary of War in 1941 and was a member of several military commissions during the war. From 1944–1966, he was President of the California Board of Health. He was active in the American Public Health Association as an executive councilor, Chairman of the Lasker awards committee, member of the executive board, and part of the Committee on Professional Education.

At Stanford, Smith was in the Department of Public Health. He had joined the discipline because he was more interested in preventing diseases than treating them and felt that this emerging field of medicine needed young physicians. Throughout his academic career, he was passionate about the importance of public health and health care delivery and how it differed from clinical medicine. In 1949, he became Professor at the University of California School of Public Health in Berkeley and in 1951 was appointed its third Dean, a position he held until his death in 1967 and in which he oversaw numerous important developments. In 1955, the school moved into Earl Warren Hall, named for the former California governor and then current Chief Justice of the US Supreme Court, who had helped procure public financing for its construction. In 1960, it granted its initial PhD and the following year offered a residency program in preventive medicine for MDs, the first school of public health to receive such accreditation. In 1965, he testified before the US Senate on an act to help fund the construction of health facilities.

He traveled widely to participate in various public health activities (he held 100,000-mile cards from two different airlines), attended countless meetings, and accepted administrative responsibilities for campus-wide issues, such as heading a committee to establish a dental school at the University. He received many appreciative letters for such activities from the University’s President, Clark Kerr (whose tiny handwriting, like that of the poet William Butler Yeats, resembles a mouse’s electrocardiogram ¹² ).

Kerr, who had earlier served as Chancellor and said “the three major administrative problems on campus are sex for the students, athletics for the alumni and parking for the faculty,” ¹³ encountered other student passions when unrest on the Berkeley campus erupted with the Free Speech Movement in 1964–1965 and, later, with protests against the Vietnam War. The Board of Regents felt that Kerr was too lenient, and one of the major themes in Ronald Reagan’s 1966 campaign for Governor of California was to “clean up the mess at Berkeley.” In January 1967, Reagan sacked Kerr, who said that he left the University the same way he entered it: “fired with enthusiasm.” Kerr sent several notes thanking Smith for support during those turbulent times. ¹¹

The Free Speech Movement arose because University rules severely restricted on-campus political activities. ¹⁰ Protests against these regulations led to speeches, marches, sit-ins, class boycotts, and the occupation of Sproul Hall, site of administrative offices at the opposite end of the campus from the School of Public Health. One day during this turmoil, a march led by one of the protest’s charismatic leaders, Mario Savio, passed by Warren Hall. Smith left his office, greeted the protestors and welcomed them to that part of the University. He then entered a lecture hall where public health students had earlier gathered to discuss whether they should join the class boycotts and told them that never before in his tenure had there been any student action in that end of the campus and how delighted he was to finally be included. His response calmed a brewing storm among some of the most fervent public health students, who concluded that support for free speech thrived in that corner of the University, at least. ¹⁴

Smith did not completely escape the administrative challenges of political unrest, however. During the 1966–1967 school year, opposition to the Vietnam War intensified, and three public health students organized a forum for speakers to discuss the topic of war and health in one of the classrooms. They posted announcements of the upcoming program, but found that the signs were gone the next day, and one of them was asked to meet with the Dean. According to the student, Smith angrily stated that such discussions were impermissible and that outspoken opposition to the war might seriously damage the school’s budget, which depended heavily on military contracts. ¹⁴ In a memorandum describing his actions, however, he asserted that the group had not obtained the proper University authorization to qualify as an approved student organization and that their posters seemed to imply that the School of Public Health endorsed a specific political viewpoint. ¹¹ When the student asked a professor to intercede in the dispute, Smith relented, and the forum held its meetings in the school. He had encountered a difficult quandary, for his budget indeed faced potential reductions not only from the military but also from the state, whose newly elected governor, Ronald Reagan, was hostile to the university and eager to diminish its funding. ¹⁵ Smith’s specific political views about the Vietnam War are unclear, but as a high school student in 1922, he wrote an impassioned anti-war essay, “The Red Scourge,” alluding to the blood shed during the First World War. ¹¹

Overall, Smith was considered a very gifted leader. He was shrewd in understanding and interacting with the University’s bureaucracy. His faculty and students flourished in an atmosphere of academic excellence and collegiality. They remember him with great fondness, especially emphasizing his amiability, accessibility, and physical vigor. ¹⁴ Carrying a bulging briefcase, he traveled through the corridors of Warren Hall as though on roller skates, but would happily pause to chat with students or colleagues. He always seemed to be smiling, and his irrepressible ebullience radiated energy and excitement. He possessed a magnetic charm that seemed to bring out the best in others and made them feel better about themselves. He even wrote to some of the students’ mothers, praising their offspring and stating what a pleasure it was to have them in the school. One mother proudly framed the letter. He took great interest in the students’ progress, encouraged them to pursue their individual interests, and provided consistently positive assessments when evaluating their work, including numerous enthusiastic letters of recommendation. In one case, he personally called the Minister of Health in India, persuading him to extend a foreign student’s study period at Berkeley for an extra year. ¹⁴ He was far ahead of his time in promoting gender equality and the well-being of international and minority students and scholars. For example, he wrote letters each semester on behalf of Indian students sponsored by the Ford Foundation, delineating their progress and praising the organization for its wisdom in offering them fellowships.

Smith conducted research while a dean, but mostly early in the morning, separating it clearly from his administrative responsibilities. He supervised the world’s premier reference laboratory for coccidioidal serology, where he had standard forms for reporting the test results and their interpretation. Nevertheless, he checked each to determine if he knew the person submitting the specimen. If so, he added a personal note. The laboratory employees adored him, and he reciprocated. For example, when a student was covering the laboratory one Christmas, Smith left a message: “Keep the home fires burning, but not too hot, for remember, Santa must come down the chimney.”

That note was typical of his warm, kindly touch. When the American Public Health Association honored him with the Bronfman Award for Public Health Achievement in 1962, praising his “boundless energy” and numerous accomplishments, he received scores of congratulatory letters from colleagues, friends, former students, and such luminaries as Chief Justice Earl Warren and California Governor Pat Brown. He answered each with gracious, individual comments, acknowledging how much his success depended on others, who deserved a chunk of the award. After he died on 18 April 1967 of a myocardial infarction, numerous tributes mentioned his kindness, wisdom, statesman-like qualities, and dedication to human well-being. He was acclaimed for a merry spirit and for his quick, generous response to requests for advice, which included lengthy handwritten notes and telephone calls.

He went by several names. To some, including his wife, he was Ed or Edward; to others Chuck or Charlie; to those in Canada, Smitty; and, especially for some of his students, Uncle Snuffy (named after a character in a newspaper comic strip called “Barney Google and Snuffy Smith”). He was active in his church and discerned no inherent conflict between science and faith. In an address in 1955 at Pomona College, which one of his sons attended, he spoke of three types of responses to the relationship between religion and science. He disdained two: (1) the unreflective acceptance of religious dogma and (2) the belief that science justified agnosticism or atheism. Instead, he thought that science magnifies the marvels of God and cited Louis Pasteur as a paragon of a scientist with enlightened faith. His admiration was steadfast: the Commencement speech that he had given on graduating from Sacramento Junior College 30 years earlier was “The intellectual and moral significance of Pasteur.”

Like his model, Smith had intense curiosity and astonishing energy. Although he did not discover coccidioidomycosis, through his enthusiastic, tenacious investigations he defined the disease: its epidemiology, clinical features, and immunology. Unlike Pasteur, however, who was rigid, authoritarian, solitary, and brusque, ¹⁶ Smith was gregarious, collaborative, generous, and kindly. Such qualities allowed this gifted scientist to become, in addition, a beloved colleague and an exemplary dean.