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Manifesto of space medicine: The next dermatologic frontier
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Manifesto of space medicine: The next dermatologic frontier Arnold C. Toback, MD, and Steven R. Kohn, MD New York, New York As the fields of astronomy, cosmology,and space travel move rapidly forward, so must space medicine. The manned space program and medical knowledge and support have developed in tandem. Dermatology will play a fundamental role in survival during space flight. This paper reviewspast, present, and future accomplishmentsof the space program as they relate to medicine and characterizes some of dermatology's multiple roles in the future. It further explores the immunologicalterations noted during space flight and the attendant implications for health and well-beingboth in flight and on return to Earth, or to an Earthlike environment. (J AM ACADDERMATOL1989;20:489-95.)
The evolution of life on earth has occurred under the constant and profound force of gravity. When human beings venture into space, an environment of extremely low gravity, some of the basic ground rules of nature change. This change has provided the main impetus to the development of space medicine, which strives to understand the acute and long-term human health problems produced by the space environment. Physicians have been involved with the U.S. space program since its inception, and, to date, seven physician astronauts have flown in space. Medical knowledge pertinent to space flight has developed in tandem with the space program. Despite the opinion of noted physicians and scientists who believed that to send a human being into space was equivalent to a death sentence, l we entered the reaches of outer space when cosmonaut Yuri A. Gagarin flew one revolution around the earth on April 12, 1961. The United States entered the manned space program with the Mercury flights and the successful launch of Alan B. Shepard, Jr., into suborbital flight on May 5, 1961. This and the five Mercury flights that followed demonstrated that human beings were able to
From the Department of Dermatology, College of Physicians and Surgeons of Columbia University. Presented (A.C.T.) in part at the Inaugural Seminar "Skin in Space" of the Space Dermatology Foundation, Houston, Texas, November 5-6, 1987. Reprint requests: Arnold C. Toback, MD, Department of Dermatology, Collegeof Physicians and Surgeons of Columbia University,630 W. 168th St., New York, NY 10032.
work, think, and survive during a relatively brief sojourn into space; the longest flight in the Mercury series was 341A hours. The Gemini program was developed in preparation for the challenge of landing human beings on the moon, and it was notable for the first space walk by an American, Edward H. White II. It was shown that teams of two astronauts could survive more prolonged flights and perform exceptionally complex flight maneuvers. Although the astronauts were believed to be in "perfect health ''2 on return from their flights, the first subtle changes of space on the human body became apparent. The Apollo phase of the space program took human beings to the moon's surface and back again. Tragically, Apollo 1 wa~ also the setting for the first fatality in the space program, in which astronauts Grissom, White, and Chaffee died on the launch pad in a capsule fire. This disaster led to major modifications in materials and in the atmosphere in the capsule at launch for Apollo and future space craft? Other near disasters followed, most notably during the Apollo 13 mission, whose flight culminated in a race against decreasing air supply and lack of fuel to return the astronauts to Earth, during which one astronaut had a urinary tract infection caused by Pseudomonas aeruginosa. 4 It was clear, however, that three-person crews could survive not only a prolonged space flight but could visit the moon, function in its gravitational field (one sixth of the force of Earth's), and return without suffering any severe consequences. Americans made a total of six successful lunar landhags. 489
490 Tobaek and Kohn Sk-ylab was developed as the first U.S. laboratory in space. Before Skylab, medical data were obtained by preflight and postflight examinations. It was now possible to study the medical effects of extended space flight (up to 84 days). The present workhorse of the U.S. space program is the Space Transportation System (STS), the "shuttle." The shuttle carries astronauts into space for variable lengths of time, usually for 5 to 9 days. Studies can be performed in the on-board space laboratory (Spacelab), data interpreted on landing, and additional, more discerning questions addressed on subsequent flights. ADVERSE EFFECTS OF SPACE FLIGHT
The adverse effects of space flight were noted as early as Gemini. The first hint of cardiovascular deconditioning was seen, as well as the loss of exercise capacity, bone density, and red cell mass. The space adaptation syndrome, or space motion sickness, occurs in 40% to 50% of all astronauts), 6 Within the first few minutes to hours of flight, affected persons develop sudden, brief episodes of vomiting, usually unaccompanied by nausea and associated with an almost universal loss of appetite. 6 Malaise, irritability, lack of initiative, somnolence, and a mild, nonspecific headache are common. Symptoms plateau over hours and typically resolve suddenly and dramatically between 30 and 48 hours. No correlation has been found with earth-bound motion sickness; some of the astronauts who were most resistant to provocative tests of motion sickness before flight suffered most in flight. Seemingly just a nuisance, this syndrome may lead to an important lapse of productivity, which may be especially significant during a short flight. At present there is no definitive therapy, although the use of scopolamine/dexedrine combinations appear to lessen symptoms. The cause may involve discordant neurovestibular input, with misinterpretation of signals sent from graviceptors in the inner ear to the central nervous system.7 Cardiovascular changes begin to occur simultaneously with weightlessness. A fluid shift of 1.5 to 2 L from the lower to the upper portion of the body occurs during the first hours of flight? This causes facial edema, distended head and neck veins, and "bird legs" from decreased calf girth. Diuresis occurs but diminishes during the first 6 days as the intake of fluid lessens from decreased thirst? In fact, diuresis starts before flight while the astronaut
Journal of the American Academy of Dermatology
is in the prelaunch reclining position, sometimes for many hours. Usually, heart rate, systolic blood pressure, and pulse pressure are elevated in flight, whereas diastolic blood pressure is decreased compared with preflight pressure. I~ Stroke volume and cardiac output are increased during the first month of flight, then remain constant. Echocardiograms before, during, and after flight have revealed decreased right ventricular volume throughout the flight, whereas left ventricular volume initially increases the first day, then decreases beginning the second day and continuing thereafter? On return to Earth, cardiac output and stroke volume are both decreased, most likely reflecting reduced blood volume. 1~ Although orthostatic hypotension is common, recently it has been lessened by prelanding fluid intake, as well as by the use of the positive pressure flight garment (the G-suit)J 2,13 Generally, the longer the flight, the longer it takes for complete readaptation to the Earth's environment. On return from the 237-day Soviet flight, the cosmonauts barely could move. TM In fact, there was speculation that if the flight duration had been significantly longer, the cosmonauts might not have been able to withstand the stress of reentry. In-flight exercise of up to 3 hours/day does not appear to stop all cardiac deconditioning effects but does seem to shorten the period of readaptation. 1~ Weightlessness greatly reduces the muscular force required to maintain an upright posture. When the stress of gravity on the vertebral disks is removed, astronauts become taller. Muscle atrophy occurs in space, with attendant negative nitrogen balance. 5 Soviet cosmonauts wear "penguin suits" of elastic material on long flights to provide constant compressing force on the spine, which necessitates continued muscular work by the weight-bearing muscles. In general, as with the heart, exercise programs reduce but do not prevent muscular atrophy. Bone loss and negative calcium balance,* with loss of 3.2% to 8% of bone calcium and continual excretion of calcium both in urine and stool, have been noted on flights longer than 2 weeks. This loss appears proportionate to mission length. On the astronaut's return to Earth, bone loss reverses, but *An overviewof bonedcmineralizationin space flight. In: Final report phase III: research opportunitiesin bone dcmineralization[NASA contractor report 3795]. NASA Office of Space Science and Applications, 1984:5-24,
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bone mineral content probably does not return to baseline. Whether bone loss will be irreversible on extended flights is not known. In-flight exercise has been shown to slow, but not halt, calcium loss. The cause, whether hormonal or otherwise, has not been fully elucidated. Evidence suggests that blood parathyroid hormone and 1,25-dihydroxyvitamin D levels are normal during space flight. 1~ Red blood cell loss was discovered on Gemini, during which it averaged 9% for a period of 30 to 60 days (range, 2%-21%). 17For unknown reasons, red blood cell loss stabilizes on long flights. Hemolysis caused by the high oxygen content in the capsule was suspected initially but has been subsequently refuted. Serum erythropoietin levels are not decreased in flight, although average absolute values were always lower than preflight levels.18 Further, erythmpoietin levels showed no increase in response to the red cell loss. Red blood cells may undergo splenic sequestration or suppression of bone marrow red blood cell production may occur. All hematologic values normalize on the astronauts' return to Earth, but the process may take days to weeks? Excess radiation exposure has not yet been a problem. 19 Above Earth's atmospheric protection, cosmic rays and charged particles either from deep space or from our sun are encountered. The potential for future problems exists when space flight is extended into and through the radiationrich Van Allen belts encircling the earth. The greatest exposure has been 8.0 rem (Skylab 4), ~9 well below the accepted safe limit of 25 rem/ mission? Because charged particles may be extremely penetrating, complete protection is now technologically impossible. HEALTH MAINTENANCE FACILITY The permanent presence of human beings in space is no longer a fantasy. The Soviets have had space station Mir in orbit since 1986. In 1984 President Reagan mandated the development of the U.S. space station, which will be called Freedom (Fig. 1). Hardware for the space station is slated to be launched by 1994, with a completion date set for early 1996.* The space station will consist of crews of 6 to 8 *Space station development plan. Submitted to the Committee on Science, Space, and Technology, US House of Representatives. NASA, 1987:46.
Dermatology and space medicine 491 persons; eventually up to 20 crew members are anticipated. The mission duration will average 3 to 6 months. It is unlikely that a practicing physician will be a member of each crew. The approach to medical care aboard the space station uses the truly futuristic construct of the health maintenance facility. The general goals of such a facility include maintaining crew health, preempting the need for in-flight rescues, and stabilizing an ill patient until rescue is effected, t5 This self-contained facility, with the constrictions imposed by a weight limit of 1200 pounds and a size limit of 53 cubic feet, is being developed to assist in diagnosis and treatment of a variety of medical problems. If a medical problem cannot be resolved on board and a rescue is necessary, it will take anywhere from 14 to 28 days for the rescue completion, at an estimated cost of $125 to $175 million, t5 Three classes of illness have been defined to facilitate the development of computerized protocols. Class 1 concerns minor medical illnesses such as respiratory infection and headaches. Class 2, for which the heakh maintenance facility is geared, consists of potentially life-threatening illnesses such as renal stones, blunt head trauma, decompression sickness, diverticulitis, and appendicitis (medical management). Class 3 illnesses, which are acutely life-threatening and probably not survivable on a space station, include massive burns, severe head trauma, and massive myocardial infarction. In these situations, proper storage of space suit-clad human remains is the end point. Instruments for minor surgery are being developed, as well as surgical tables and intravenous drug delivery systems that do not depend on gravity flow. The skills required of a space surgeon will differ from those needed by an Earth surgeon.2~Even the clearing of air from a syringe will not be a simple maneuver, inasmuch as tapping or shaking the syringe leads to the dispersion rather than the separation of air into solution, CUTANEOUS CONDITIONS "Rash" and contact dermatitis have been noted in flight in at least three instances, but diagnosis or implicated agents have not been verified.21 Additionally, at least one astronaut has had a "boil," and skin irritation from fiberglass exposure occurred in three others? ~ Subclinical tinea pedis caused by Trichophyton mentagrophytes and tinea cruris caused by 71. rubrum, respectively, were noted before flight in two Apollo astronauts. 4
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Journal of the American Academyof Dermatology
Fig. 1. Artist's rendering of the planned U.S. space station. (Courtesy NASA.) Fig. 2. Primary irritant contact dermatitis caused by electrode patch of electrocardiographic monitoI on the chest wall of Mission SpeciaIist D. Lind during U.S. shuttle flight 51-B. (Courtesy NASA.) Fig. 3. Astrophotograph of the Andromeda galaxy (M31; NGC 224). Extensive fissuring of the fingertips of astronauts occurred aboard Skylab, as well as one case of primary irritant contact dermatitis caused by the chest wall electrode patch of an electrocardiographic monitor (W. Thornton, MD, personal communication, November 6, 1987) (Fig. 2). Nasal and oral carriage of Staphylococcus aureus was found repeatedly in Apollo 13, 14, and 15 astronauts. It was further shown by phage-typing techniques that intercrew transfer of S. aureus is a common occurrence during spacecraft. 4 Just as we have discovered and defined uniquely tropical diseases, so will there be cutaneous conditions unique to the environment of space. Known dermatologic diseases that may affect an astronaut's skin in space may occur in unusual or uncharacteristic ways, particularly those that depend on gravity (e.g., the acz.entuation of the appearance of distal lesions in lower extremity
palpable purpura in systemic vasculitis). Some conditions will be exacerbated by the space environment. As aforementioned, postflight increases in S. aureus, as well as r-hemolytic streptococcus carriage, have been noted consistently.4 Sequential microbiologic analysis of the Skylab facility showed an accumulation of bacteria and yeast specific for each of the preceding groups of astronauts, all cohabiting within the same environment. 4 Since bathing is difficult, we may see more pyoderma, which may be particularly troublesome because of the recent demonstration of antibiotic resistance of certain bacteria during spaceflight.22 In contrast, some dermatologic conditions may be improved by the space environment (e.g., stasis dermatitis). Researchers in dermatologic space medicine may use known research techniques to ask and answer questions pertinent to space habitation and Earth-based physiology. For example, the tools of
Volume 20 Number 3 March 1989
Dermatology and space medicine 493
Table I. Comparison of T cell reactivity before and after fright Flight Mission
Soyuz 6,7,8 Apollo 7-13 Skylab II,III,IV ASTP Salyut 4 Salyut 6 Salyut 6 STS 1 STS 2 STS 3 STS 4 STS 5 STS 6 STS 8 STS 41B STS 41C STS 41D
duration (days)
T cell reaetlvity
5 6-12 28,59,84
Decreased No change Decreased
9 30,63 96 140 2 2 8 7 5 5 6 8 7 6
Decreased Decreased No change Decreased Decreased Decreased Decreased Decreased Decreased Decreased Decreased Decreased Decreased Decreased
Modified from Taylor GR, Neale LS, Dardano JR. Aviat Space Environ Med 1986;57:213; Cogoli A, Tschopp A. Experiment A08/ 32/CH: "Effect of spaceflight on lymphocyte activation." Proceedings of a workshop held at DFVLR-Instititute of Aerospace Medicine, Cologne, Germany, March 9-t 1, 1983:57-61. ASTP, Apollo-Soyuz Test Projot; STS, Space Transportation System
(Shut,e).
photobiology may prove to be valuable in answering the therapeutic dilemma of calcium loss in space as well as on Earth. T CELL FUNCTION Studies during the Apollo flights revealed an unexpected alteration of T cell function, whereas B cell function appeared intact. 23 Numerous confirmatory studies have been performed on subsequent flights. Table I presents a brief summary of spaceflight and T lymphocyte function. These studies are based on the lymphocytes extracted from blood that was drawn before and immediately after flight. Most studies measured the response of T cells in vitro to mitogen stimulation (PHA or ConA, which are selective T lymphocyte stimulators), with subsequent determination of DNA or R N A synthesis.*, 24,25 *Cogoli A, Tschopp A. Experiment AO8/32/CH: "Effect of spaceflight on lymphocyte activation," Proceedings of a workshop held at DFVLR-Institute of Aerospace Medicine. Cologne, Germany, March 9-11, 1983:57-61.
Table II. Areas of potential dermatologic research of the immune system during spaceflight T lymphocyte Primary sensitization: DNCB, SADBE, urushiol Anamnestic response Antigens known to produce positive reactions to patch tests; skin test (Candida. mumps) Lymphokine release: MAF/MIF Surface receptor expression: T cell antigen, I1-2 Production of I1-2 Response to exogenous 11-2 Tumor rejection Graft rejection T cell subsets in biopsy specimens of patch-tested skin Macrophage/Langerhans cells Quantifications during and after flight Functional evaluation Antigen uptake II-1 release In-flight response to exogenous MAF/MIF B lymphocyte Primary sensitization with vaccine Antibody response during and after flight Anamnestic response to booster vaccination Antibody response during and after fright Keratinocyte ETAF production TdT expression by immature thymocytes in the presence of keratinocytes Interferon Production after tumor/viral challenge Clinical response to exogenous interferon Wound healing Time course Response to bio-occlusive dressings (e.g., Duoderm, Vigilon, Tegaderm) Tensile strength of healing wounds DNCB, Dinitrochlorobenzene; SADBE, squaric acid dibutyl ester; 1l, interleukin; MAF, macrophage activating factor; MIF, migration inhibiting factor; ETAF, epidermal cell--derived thymocyte-activating factor; TdT, terminal deoxynucleotidyl transferase.
Two studies have been performed on the shuttle with the use of in-fright analysis? ~,~7 The first involved lymphocytes that were drawn before the flight and exposed to mitogen in fright. Compared with ground controls, lymphocyte activation was only 3% of normal. All cells were viable, and cell-to-cell aggregation was seen in flight) 6 To further elucidate this T cell phenomenon, lymphocytes obtained from the astronauts before, during, and after flight were mitogenically stimulatedY In-flight lymphocyte activity was depressed
Journal of the AmericanAcademyof Dermatology
494 Toback and Kohn by 90% and returned to normal by 13 days after flight. As part of this same study, lymphocytes obtained immediately before launch were mitogenically stimulated in flight. Half these cells were centrifuged in flight at 1 G. The unspun lymphocyte response to mitogen was markedly depressed but improved with centrifugation. Interestingly, the centrifuged group still showed decreased activity compared with that of the control group indicating an unknown component to the weightless state or shuttle environment. T cells are an essential component of the immune system. They are the critical ceUs in that portion of the immune response known as cellmediated immunity, and they are involved in the regulation of B cell function and antibody-directed cell-mediated eytotoxicity?8 It is clear that the skin is intimately involved with the immune system, specifically with T cells. 29 The skin is accessible, abundant, relatively easy to follow clinically, and eminently harvestable. These characteristics enable dermatologists to devise experiments addressing two important questions about the immune system and, more broadly, about the survival and well-being of human beings in space: 1. What is the extent of immune dysfunction? 2. What will be the clinical implications of the dysfunction? To approach these questions we propose studies summarized in Table II, which may help to elucidate the reported T cell abnormalities of space flight. Simple patch testing with known contact sensitivity-producing allergens requires a number of systems to function correctly and synchronously to produce a positive response. We are presently preparing with the National Aeronautics and Space Administration (NASA) a.patch test study to be performed in flight as a gross clinical screen of cell-mediated immunity. This table also enumerates studies to assess the function of macrophage/ Langerhans cells, B cells, and keratinocytes, all of which interact with or are influenced by T lymphocytes. Macrophages and their circulating form, monocytes, may be involved in the observed T cell abnormalities inasmuch as decreased circulating monocytes have been found in shuttle crew members who also exhibited poor T cell blast transformation?4 Studies of interferon in space have shown mark-
edly increased in vitro lymphocyte production of aria-interferon, whereas gamma-interferon production by spleen cells of rats is decreased?~3~Interferons have a variety of functions, including inhibition of viral replication and enhanced killing of tumor ceils?2 The possible clinical relevance of these changes might be explored by measuring the production of interferons with viral or tumor challenge in laboratory animals in space. If production is inhibited or clinical consequence is clearly shown, the response to exogenous interferon could be therapeutically important. To date no astronaut in the American spaceflight program has sustained significant in-flight injury that has required extensive wound healing (W. Thornton, MD, personal communication, November 6, 1987). However, because we know that macrophages and lymphocytes are important in the healing process, 33 assessment of wound healing in space should be pursued. If abnormalities in the immune system are uncovered on the basis of these study prototypes, the following questions would need to be answered. 1. Will space travelers be immunosuppressed? Is so, will all space travelers be immunosuppressed or are certain subgroups at risk? 2. If immunosuppression is found, what will be the potential clinical consequences? For example, if a significant T cell defect were found, would there be increased susceptibility to viral or fungal infections, autoimmune disease, or, possibly, tumors (radiation-induced)? Would it be safe to administer live attenuated vaccines to children born or adults living in space? 34 3. Will simulated gravity in space serve to improve or correct identified defects? Can we intervene therapeutically with the use of adjunctive immunomodulators to correct identifieddefects (e.g., interleukin 2, interferon, cimetidine)? 4. Will wounds heal in space? 5. Is there a time course to the immune dysfunction? This is particularly important given the possibility of prolonged interplanetary spaceflights. Will the abnormafity spontaneously correct itself or, in the extreme, is there a "point of no return" for those who have spent years or generations (continuous or discontinuous) in space? CONCLUSION In an unremarkable region of the night sky lies the Andromeda galaxy, barely visible to the naked
Volume 20 Number 3 March 1989
eye (Fig. 3). To understand what at first may not be obvious requires desire, imagination, vision, and ingenuity. On the basis of these qualities, which are integral to scientific investigation, we believe that dermatologists can play a unique role in the future of manned spaceflight. We do not think that space medicine will be the final dermatologic frontier. Rather it is the inevitable frontier.
Dermatology and space medicine 495
17. 18. 19. 20.
REFERENCES
1. Berry CA. The beginnings of space medicine. Aviat Space Environ Med 1986;57:A58-63. 2. Wilford JN. The pathfinders: manned. In: We reach the moon. New York: Bantam, 1969:79-91. 3. Collins M. Decade's end. In: Lfftoff. New York: Grove Press, 1988:115-61. 4. Taylor GR. Recovery of medically important microorganisms from Apollo astronauts. Aerospace Med 1974; 45:824-8. 5. Vasquez TE, Pretorius HT, Rimkus DS. Space medicine---a review of current concepts. West J Med 1987;147:292-5. 6. Thornton WE, Moore TP, Pool SL, Vanderploeg J. Clinical characterization and etiology of space motion sickness. Aviat Space Environ Med 1987;58:A1-8. 7. Young LR, Oman CM, Watt DGD, Money KE, Lichtenberg BK. Spatial orientation in weightlessness and readaptation to earth's gravity. Science 1984;225:205-8. 8. Thornton WE, Moore TP, Pool SL. Fluid shifts in weightlessness. Aviat Space Environ Meal 1987;58:A8690. 9. Mills FJ, Harding RM. Special forms of flight. IV. Manned spacecraft. Br Med J 1983;287:478-82. 10. Charles JB, Bungo MW. Cardiovascular research in space: consideration for the design of the human research facility of the United States space station. Aviat Space Environ Med 1986;57:1000-5. 11. Atkov OY, Bednenko VS, Fomina GA. Ultrasound techniques in space medicine. Aviat Space Environ Med 1987;58:A69-73. 12. Pool SL, Nicogossian A. Biomedical results of the space shuttle orbital flight test program. Aviat Space Environ Med 1983;54:$41-9. 13. Vorobyov EI, Gazenko OG, Genin AM, Egorov AD. Medical results of Salyut-6 manned space flights. Aviat Space Environ Med 1983;54:$31-40. 14. Merz B. The body pays a penalty for defying the law of gravity. JAMA 1986;256:2040-7. 15. Goldsmith MF. How will humans act as science fiction becomes fact? JAMA 1986;256:2048-52. 16. Alexandre C, Vico L, Pilonchery G, Chapuy MC, Delmas PD, Chappard D. Effects of weightlessness on calcium
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metabolism and hormonal regulation in man (French-US space flight 51 G). Pathol Biol (Paris) 1988;36:144-8. Kimzey SL. The effects of extended spaceflight on hematologic and immunologic systems. J Am Med Worn Assoe 1975;30:218-32. Leach CS, Johnson PC. Influence of spaceflight on erythroldnefics in man. Science 1984;225:216-8. Benton EV, Almasi J, Cassou R, et al. Radiation measurements aboard Spacelab 1. Science 1984;225: 224-6. Satava RM. Surgery in space. Phase I: basic surgical principles in a simulated space environment. Surgery 1988;103:633-7. Nicogossian AE, Pool SL, Leach CS, Moseley E, Rambaut PC. Concepts for NASA longitudinal health studies. Aviat Space Environ Med 1983;54:$68-72. Lapchine L, Moatti N, Gasser G, Richoilley G, Templier J, Tixador R. Antibiotic activity in space. Drugs Exp Clin Res 1986;12:933-8. Fischer CL, Daniels JC, Levin WC, Kimzey SL, Cobb EK, Ritzmann SE. Effects of the space flight environment on man's immune system. II. Lymphocyte counts and reactivity. Aerospace Meal 1972;43:1122-5. Taylor GR, Neale IS, Dardano JR. Immunological analyses of U.S. space shuttle crewmembers. Aviat Space Environ Med 1986;57:213-7. Cogoli A, Valluchi-Morf M, Mueller M, Briegleb W. Effect of hypogravity on human lymphocyte activation. Aviat Space Environ Med 1980;51:29-34. Cogoli A, Tschopp A, Fuchs-Bislin P. Cell sensitivity to gravity. Science 1984;225:228-30. Bechler B, Cogoli A, Mesland D. Lymphocytes in spaceflight. Naturwissenschaften 1986;73:400-3. Romain PL, Schlossman SF. T and B lymphoeytes. In: Fitzpatrick TB, Eisen AZ, Wolff K, Freedberg IM, Austen KF, eds. Dermatology in general medicine. 3rd ed. New York: McGraw-Hill, 1987:400-10. Patterson JAK, Edelson RL. Interaction of T cells with the epidermis. Br J Dermatol 1982;107:117-22. Talas M, Batkai L, Stoger I, et al. Results of space experiment program "interferon". I. Production of interferon in vitro by human lymphocytes aboard space laboratory Solyut-6 ("interferon r ' ) and influence of space flight on lymphocyte functions of cosmonauts ("interferon III"). Acta Microbiol Hung 1983;30:53-61. Gould CL, Williams JA, Mandel AD, Sonnenfeld G. Effect of flight in mission SL-3 on interferon-gamma production by rats. Physiologist 1985;28:$213-4. Dinarello CA, Mier JW. Lymphokines. N Engi J Med 1987;317:940-5. Clark RAF. Potential roles of fibronectin in cutaneous wound repair, Arch Dermatol 1988;124:201-6. Cogoli A, Tschopp A. Lymphocyte reactivity during spaceflight. Immunol Today 1985;6:1-4.
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Manifesto of space medicine: The next dermatologic frontier Arnold C. Toback, MD, and Steven R. Kohn, MD New York, New York As the fields of astronomy, cosmology,and space travel move rapidly forward, so must space medicine. The manned space program and medical knowledge and support have developed in tandem. Dermatology will play a fundamental role in survival during space flight. This paper reviewspast, present, and future accomplishmentsof the space program as they relate to medicine and characterizes some of dermatology's multiple roles in the future. It further explores the immunologicalterations noted during space flight and the attendant implications for health and well-beingboth in flight and on return to Earth, or to an Earthlike environment. (J AM ACADDERMATOL1989;20:489-95.)
The evolution of life on earth has occurred under the constant and profound force of gravity. When human beings venture into space, an environment of extremely low gravity, some of the basic ground rules of nature change. This change has provided the main impetus to the development of space medicine, which strives to understand the acute and long-term human health problems produced by the space environment. Physicians have been involved with the U.S. space program since its inception, and, to date, seven physician astronauts have flown in space. Medical knowledge pertinent to space flight has developed in tandem with the space program. Despite the opinion of noted physicians and scientists who believed that to send a human being into space was equivalent to a death sentence, l we entered the reaches of outer space when cosmonaut Yuri A. Gagarin flew one revolution around the earth on April 12, 1961. The United States entered the manned space program with the Mercury flights and the successful launch of Alan B. Shepard, Jr., into suborbital flight on May 5, 1961. This and the five Mercury flights that followed demonstrated that human beings were able to
From the Department of Dermatology, College of Physicians and Surgeons of Columbia University. Presented (A.C.T.) in part at the Inaugural Seminar "Skin in Space" of the Space Dermatology Foundation, Houston, Texas, November 5-6, 1987. Reprint requests: Arnold C. Toback, MD, Department of Dermatology, Collegeof Physicians and Surgeons of Columbia University,630 W. 168th St., New York, NY 10032.
work, think, and survive during a relatively brief sojourn into space; the longest flight in the Mercury series was 341A hours. The Gemini program was developed in preparation for the challenge of landing human beings on the moon, and it was notable for the first space walk by an American, Edward H. White II. It was shown that teams of two astronauts could survive more prolonged flights and perform exceptionally complex flight maneuvers. Although the astronauts were believed to be in "perfect health ''2 on return from their flights, the first subtle changes of space on the human body became apparent. The Apollo phase of the space program took human beings to the moon's surface and back again. Tragically, Apollo 1 wa~ also the setting for the first fatality in the space program, in which astronauts Grissom, White, and Chaffee died on the launch pad in a capsule fire. This disaster led to major modifications in materials and in the atmosphere in the capsule at launch for Apollo and future space craft? Other near disasters followed, most notably during the Apollo 13 mission, whose flight culminated in a race against decreasing air supply and lack of fuel to return the astronauts to Earth, during which one astronaut had a urinary tract infection caused by Pseudomonas aeruginosa. 4 It was clear, however, that three-person crews could survive not only a prolonged space flight but could visit the moon, function in its gravitational field (one sixth of the force of Earth's), and return without suffering any severe consequences. Americans made a total of six successful lunar landhags. 489
490 Tobaek and Kohn Sk-ylab was developed as the first U.S. laboratory in space. Before Skylab, medical data were obtained by preflight and postflight examinations. It was now possible to study the medical effects of extended space flight (up to 84 days). The present workhorse of the U.S. space program is the Space Transportation System (STS), the "shuttle." The shuttle carries astronauts into space for variable lengths of time, usually for 5 to 9 days. Studies can be performed in the on-board space laboratory (Spacelab), data interpreted on landing, and additional, more discerning questions addressed on subsequent flights. ADVERSE EFFECTS OF SPACE FLIGHT
The adverse effects of space flight were noted as early as Gemini. The first hint of cardiovascular deconditioning was seen, as well as the loss of exercise capacity, bone density, and red cell mass. The space adaptation syndrome, or space motion sickness, occurs in 40% to 50% of all astronauts), 6 Within the first few minutes to hours of flight, affected persons develop sudden, brief episodes of vomiting, usually unaccompanied by nausea and associated with an almost universal loss of appetite. 6 Malaise, irritability, lack of initiative, somnolence, and a mild, nonspecific headache are common. Symptoms plateau over hours and typically resolve suddenly and dramatically between 30 and 48 hours. No correlation has been found with earth-bound motion sickness; some of the astronauts who were most resistant to provocative tests of motion sickness before flight suffered most in flight. Seemingly just a nuisance, this syndrome may lead to an important lapse of productivity, which may be especially significant during a short flight. At present there is no definitive therapy, although the use of scopolamine/dexedrine combinations appear to lessen symptoms. The cause may involve discordant neurovestibular input, with misinterpretation of signals sent from graviceptors in the inner ear to the central nervous system.7 Cardiovascular changes begin to occur simultaneously with weightlessness. A fluid shift of 1.5 to 2 L from the lower to the upper portion of the body occurs during the first hours of flight? This causes facial edema, distended head and neck veins, and "bird legs" from decreased calf girth. Diuresis occurs but diminishes during the first 6 days as the intake of fluid lessens from decreased thirst? In fact, diuresis starts before flight while the astronaut
Journal of the American Academy of Dermatology
is in the prelaunch reclining position, sometimes for many hours. Usually, heart rate, systolic blood pressure, and pulse pressure are elevated in flight, whereas diastolic blood pressure is decreased compared with preflight pressure. I~ Stroke volume and cardiac output are increased during the first month of flight, then remain constant. Echocardiograms before, during, and after flight have revealed decreased right ventricular volume throughout the flight, whereas left ventricular volume initially increases the first day, then decreases beginning the second day and continuing thereafter? On return to Earth, cardiac output and stroke volume are both decreased, most likely reflecting reduced blood volume. 1~ Although orthostatic hypotension is common, recently it has been lessened by prelanding fluid intake, as well as by the use of the positive pressure flight garment (the G-suit)J 2,13 Generally, the longer the flight, the longer it takes for complete readaptation to the Earth's environment. On return from the 237-day Soviet flight, the cosmonauts barely could move. TM In fact, there was speculation that if the flight duration had been significantly longer, the cosmonauts might not have been able to withstand the stress of reentry. In-flight exercise of up to 3 hours/day does not appear to stop all cardiac deconditioning effects but does seem to shorten the period of readaptation. 1~ Weightlessness greatly reduces the muscular force required to maintain an upright posture. When the stress of gravity on the vertebral disks is removed, astronauts become taller. Muscle atrophy occurs in space, with attendant negative nitrogen balance. 5 Soviet cosmonauts wear "penguin suits" of elastic material on long flights to provide constant compressing force on the spine, which necessitates continued muscular work by the weight-bearing muscles. In general, as with the heart, exercise programs reduce but do not prevent muscular atrophy. Bone loss and negative calcium balance,* with loss of 3.2% to 8% of bone calcium and continual excretion of calcium both in urine and stool, have been noted on flights longer than 2 weeks. This loss appears proportionate to mission length. On the astronaut's return to Earth, bone loss reverses, but *An overviewof bonedcmineralizationin space flight. In: Final report phase III: research opportunitiesin bone dcmineralization[NASA contractor report 3795]. NASA Office of Space Science and Applications, 1984:5-24,
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bone mineral content probably does not return to baseline. Whether bone loss will be irreversible on extended flights is not known. In-flight exercise has been shown to slow, but not halt, calcium loss. The cause, whether hormonal or otherwise, has not been fully elucidated. Evidence suggests that blood parathyroid hormone and 1,25-dihydroxyvitamin D levels are normal during space flight. 1~ Red blood cell loss was discovered on Gemini, during which it averaged 9% for a period of 30 to 60 days (range, 2%-21%). 17For unknown reasons, red blood cell loss stabilizes on long flights. Hemolysis caused by the high oxygen content in the capsule was suspected initially but has been subsequently refuted. Serum erythropoietin levels are not decreased in flight, although average absolute values were always lower than preflight levels.18 Further, erythmpoietin levels showed no increase in response to the red cell loss. Red blood cells may undergo splenic sequestration or suppression of bone marrow red blood cell production may occur. All hematologic values normalize on the astronauts' return to Earth, but the process may take days to weeks? Excess radiation exposure has not yet been a problem. 19 Above Earth's atmospheric protection, cosmic rays and charged particles either from deep space or from our sun are encountered. The potential for future problems exists when space flight is extended into and through the radiationrich Van Allen belts encircling the earth. The greatest exposure has been 8.0 rem (Skylab 4), ~9 well below the accepted safe limit of 25 rem/ mission? Because charged particles may be extremely penetrating, complete protection is now technologically impossible. HEALTH MAINTENANCE FACILITY The permanent presence of human beings in space is no longer a fantasy. The Soviets have had space station Mir in orbit since 1986. In 1984 President Reagan mandated the development of the U.S. space station, which will be called Freedom (Fig. 1). Hardware for the space station is slated to be launched by 1994, with a completion date set for early 1996.* The space station will consist of crews of 6 to 8 *Space station development plan. Submitted to the Committee on Science, Space, and Technology, US House of Representatives. NASA, 1987:46.
Dermatology and space medicine 491 persons; eventually up to 20 crew members are anticipated. The mission duration will average 3 to 6 months. It is unlikely that a practicing physician will be a member of each crew. The approach to medical care aboard the space station uses the truly futuristic construct of the health maintenance facility. The general goals of such a facility include maintaining crew health, preempting the need for in-flight rescues, and stabilizing an ill patient until rescue is effected, t5 This self-contained facility, with the constrictions imposed by a weight limit of 1200 pounds and a size limit of 53 cubic feet, is being developed to assist in diagnosis and treatment of a variety of medical problems. If a medical problem cannot be resolved on board and a rescue is necessary, it will take anywhere from 14 to 28 days for the rescue completion, at an estimated cost of $125 to $175 million, t5 Three classes of illness have been defined to facilitate the development of computerized protocols. Class 1 concerns minor medical illnesses such as respiratory infection and headaches. Class 2, for which the heakh maintenance facility is geared, consists of potentially life-threatening illnesses such as renal stones, blunt head trauma, decompression sickness, diverticulitis, and appendicitis (medical management). Class 3 illnesses, which are acutely life-threatening and probably not survivable on a space station, include massive burns, severe head trauma, and massive myocardial infarction. In these situations, proper storage of space suit-clad human remains is the end point. Instruments for minor surgery are being developed, as well as surgical tables and intravenous drug delivery systems that do not depend on gravity flow. The skills required of a space surgeon will differ from those needed by an Earth surgeon.2~Even the clearing of air from a syringe will not be a simple maneuver, inasmuch as tapping or shaking the syringe leads to the dispersion rather than the separation of air into solution, CUTANEOUS CONDITIONS "Rash" and contact dermatitis have been noted in flight in at least three instances, but diagnosis or implicated agents have not been verified.21 Additionally, at least one astronaut has had a "boil," and skin irritation from fiberglass exposure occurred in three others? ~ Subclinical tinea pedis caused by Trichophyton mentagrophytes and tinea cruris caused by 71. rubrum, respectively, were noted before flight in two Apollo astronauts. 4
492
Toback and Kohn
Journal of the American Academyof Dermatology
Fig. 1. Artist's rendering of the planned U.S. space station. (Courtesy NASA.) Fig. 2. Primary irritant contact dermatitis caused by electrode patch of electrocardiographic monitoI on the chest wall of Mission SpeciaIist D. Lind during U.S. shuttle flight 51-B. (Courtesy NASA.) Fig. 3. Astrophotograph of the Andromeda galaxy (M31; NGC 224). Extensive fissuring of the fingertips of astronauts occurred aboard Skylab, as well as one case of primary irritant contact dermatitis caused by the chest wall electrode patch of an electrocardiographic monitor (W. Thornton, MD, personal communication, November 6, 1987) (Fig. 2). Nasal and oral carriage of Staphylococcus aureus was found repeatedly in Apollo 13, 14, and 15 astronauts. It was further shown by phage-typing techniques that intercrew transfer of S. aureus is a common occurrence during spacecraft. 4 Just as we have discovered and defined uniquely tropical diseases, so will there be cutaneous conditions unique to the environment of space. Known dermatologic diseases that may affect an astronaut's skin in space may occur in unusual or uncharacteristic ways, particularly those that depend on gravity (e.g., the acz.entuation of the appearance of distal lesions in lower extremity
palpable purpura in systemic vasculitis). Some conditions will be exacerbated by the space environment. As aforementioned, postflight increases in S. aureus, as well as r-hemolytic streptococcus carriage, have been noted consistently.4 Sequential microbiologic analysis of the Skylab facility showed an accumulation of bacteria and yeast specific for each of the preceding groups of astronauts, all cohabiting within the same environment. 4 Since bathing is difficult, we may see more pyoderma, which may be particularly troublesome because of the recent demonstration of antibiotic resistance of certain bacteria during spaceflight.22 In contrast, some dermatologic conditions may be improved by the space environment (e.g., stasis dermatitis). Researchers in dermatologic space medicine may use known research techniques to ask and answer questions pertinent to space habitation and Earth-based physiology. For example, the tools of
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Dermatology and space medicine 493
Table I. Comparison of T cell reactivity before and after fright Flight Mission
Soyuz 6,7,8 Apollo 7-13 Skylab II,III,IV ASTP Salyut 4 Salyut 6 Salyut 6 STS 1 STS 2 STS 3 STS 4 STS 5 STS 6 STS 8 STS 41B STS 41C STS 41D
duration (days)
T cell reaetlvity
5 6-12 28,59,84
Decreased No change Decreased
9 30,63 96 140 2 2 8 7 5 5 6 8 7 6
Decreased Decreased No change Decreased Decreased Decreased Decreased Decreased Decreased Decreased Decreased Decreased Decreased Decreased
Modified from Taylor GR, Neale LS, Dardano JR. Aviat Space Environ Med 1986;57:213; Cogoli A, Tschopp A. Experiment A08/ 32/CH: "Effect of spaceflight on lymphocyte activation." Proceedings of a workshop held at DFVLR-Instititute of Aerospace Medicine, Cologne, Germany, March 9-t 1, 1983:57-61. ASTP, Apollo-Soyuz Test Projot; STS, Space Transportation System
(Shut,e).
photobiology may prove to be valuable in answering the therapeutic dilemma of calcium loss in space as well as on Earth. T CELL FUNCTION Studies during the Apollo flights revealed an unexpected alteration of T cell function, whereas B cell function appeared intact. 23 Numerous confirmatory studies have been performed on subsequent flights. Table I presents a brief summary of spaceflight and T lymphocyte function. These studies are based on the lymphocytes extracted from blood that was drawn before and immediately after flight. Most studies measured the response of T cells in vitro to mitogen stimulation (PHA or ConA, which are selective T lymphocyte stimulators), with subsequent determination of DNA or R N A synthesis.*, 24,25 *Cogoli A, Tschopp A. Experiment AO8/32/CH: "Effect of spaceflight on lymphocyte activation," Proceedings of a workshop held at DFVLR-Institute of Aerospace Medicine. Cologne, Germany, March 9-11, 1983:57-61.
Table II. Areas of potential dermatologic research of the immune system during spaceflight T lymphocyte Primary sensitization: DNCB, SADBE, urushiol Anamnestic response Antigens known to produce positive reactions to patch tests; skin test (Candida. mumps) Lymphokine release: MAF/MIF Surface receptor expression: T cell antigen, I1-2 Production of I1-2 Response to exogenous 11-2 Tumor rejection Graft rejection T cell subsets in biopsy specimens of patch-tested skin Macrophage/Langerhans cells Quantifications during and after flight Functional evaluation Antigen uptake II-1 release In-flight response to exogenous MAF/MIF B lymphocyte Primary sensitization with vaccine Antibody response during and after flight Anamnestic response to booster vaccination Antibody response during and after fright Keratinocyte ETAF production TdT expression by immature thymocytes in the presence of keratinocytes Interferon Production after tumor/viral challenge Clinical response to exogenous interferon Wound healing Time course Response to bio-occlusive dressings (e.g., Duoderm, Vigilon, Tegaderm) Tensile strength of healing wounds DNCB, Dinitrochlorobenzene; SADBE, squaric acid dibutyl ester; 1l, interleukin; MAF, macrophage activating factor; MIF, migration inhibiting factor; ETAF, epidermal cell--derived thymocyte-activating factor; TdT, terminal deoxynucleotidyl transferase.
Two studies have been performed on the shuttle with the use of in-fright analysis? ~,~7 The first involved lymphocytes that were drawn before the flight and exposed to mitogen in fright. Compared with ground controls, lymphocyte activation was only 3% of normal. All cells were viable, and cell-to-cell aggregation was seen in flight) 6 To further elucidate this T cell phenomenon, lymphocytes obtained from the astronauts before, during, and after flight were mitogenically stimulatedY In-flight lymphocyte activity was depressed
Journal of the AmericanAcademyof Dermatology
494 Toback and Kohn by 90% and returned to normal by 13 days after flight. As part of this same study, lymphocytes obtained immediately before launch were mitogenically stimulated in flight. Half these cells were centrifuged in flight at 1 G. The unspun lymphocyte response to mitogen was markedly depressed but improved with centrifugation. Interestingly, the centrifuged group still showed decreased activity compared with that of the control group indicating an unknown component to the weightless state or shuttle environment. T cells are an essential component of the immune system. They are the critical ceUs in that portion of the immune response known as cellmediated immunity, and they are involved in the regulation of B cell function and antibody-directed cell-mediated eytotoxicity?8 It is clear that the skin is intimately involved with the immune system, specifically with T cells. 29 The skin is accessible, abundant, relatively easy to follow clinically, and eminently harvestable. These characteristics enable dermatologists to devise experiments addressing two important questions about the immune system and, more broadly, about the survival and well-being of human beings in space: 1. What is the extent of immune dysfunction? 2. What will be the clinical implications of the dysfunction? To approach these questions we propose studies summarized in Table II, which may help to elucidate the reported T cell abnormalities of space flight. Simple patch testing with known contact sensitivity-producing allergens requires a number of systems to function correctly and synchronously to produce a positive response. We are presently preparing with the National Aeronautics and Space Administration (NASA) a.patch test study to be performed in flight as a gross clinical screen of cell-mediated immunity. This table also enumerates studies to assess the function of macrophage/ Langerhans cells, B cells, and keratinocytes, all of which interact with or are influenced by T lymphocytes. Macrophages and their circulating form, monocytes, may be involved in the observed T cell abnormalities inasmuch as decreased circulating monocytes have been found in shuttle crew members who also exhibited poor T cell blast transformation?4 Studies of interferon in space have shown mark-
edly increased in vitro lymphocyte production of aria-interferon, whereas gamma-interferon production by spleen cells of rats is decreased?~3~Interferons have a variety of functions, including inhibition of viral replication and enhanced killing of tumor ceils?2 The possible clinical relevance of these changes might be explored by measuring the production of interferons with viral or tumor challenge in laboratory animals in space. If production is inhibited or clinical consequence is clearly shown, the response to exogenous interferon could be therapeutically important. To date no astronaut in the American spaceflight program has sustained significant in-flight injury that has required extensive wound healing (W. Thornton, MD, personal communication, November 6, 1987). However, because we know that macrophages and lymphocytes are important in the healing process, 33 assessment of wound healing in space should be pursued. If abnormalities in the immune system are uncovered on the basis of these study prototypes, the following questions would need to be answered. 1. Will space travelers be immunosuppressed? Is so, will all space travelers be immunosuppressed or are certain subgroups at risk? 2. If immunosuppression is found, what will be the potential clinical consequences? For example, if a significant T cell defect were found, would there be increased susceptibility to viral or fungal infections, autoimmune disease, or, possibly, tumors (radiation-induced)? Would it be safe to administer live attenuated vaccines to children born or adults living in space? 34 3. Will simulated gravity in space serve to improve or correct identified defects? Can we intervene therapeutically with the use of adjunctive immunomodulators to correct identifieddefects (e.g., interleukin 2, interferon, cimetidine)? 4. Will wounds heal in space? 5. Is there a time course to the immune dysfunction? This is particularly important given the possibility of prolonged interplanetary spaceflights. Will the abnormafity spontaneously correct itself or, in the extreme, is there a "point of no return" for those who have spent years or generations (continuous or discontinuous) in space? CONCLUSION In an unremarkable region of the night sky lies the Andromeda galaxy, barely visible to the naked
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eye (Fig. 3). To understand what at first may not be obvious requires desire, imagination, vision, and ingenuity. On the basis of these qualities, which are integral to scientific investigation, we believe that dermatologists can play a unique role in the future of manned spaceflight. We do not think that space medicine will be the final dermatologic frontier. Rather it is the inevitable frontier.
Dermatology and space medicine 495
17. 18. 19. 20.
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