PARADOXICAL PROGRESS

12 May

When  epidemiologists  look  at the rise and  fall of diseases in a global setting over long periods of time, they provide a perspective quite differ- ent from that available to patients and practicing physicians. Such a per- spective suggests a cautious  response to the hyperbole  surrounding the latest ‘‘medical miracles.’’ The analysis of specific examples and general trends in mortality  and morbidity  have led some historians,  epidemiol- ogists,  demographers, and  critics of medicine  to  question  the  role  of medicine throughout history and, therefore, the probable  effect of mod- ern medical technologies  on mortality and morbidity in the foreseeable future.  Indeed,  in looking  closely at the leading causes of death  in the United  States  today,  health  policy advisors  generally  suggest that  the most important focus of attention is no longer the conquest  of disease, but the containment of medical costs.

At the beginning of the twenty-first century, the leading causes of death in America were heart disease, can- cer, stroke, diabetes, accidents, and Alzheimer’s disease. Instead of dying of childhood  diseases, or an emergency appendectomy, Americans  are more likely to spend decades in a nursing home with Alzheimer’s disease or enter an unhappy  middle age sprawl and die of liposuction.  Whether longer lives represent an increase in quality as well as quantity  is open to question, but suicide (which is likely to be underestimated) was number 11 in the listing of the causes of death in the United  States.

The United States devotes more of its economy to healthcare  than other  industrial  countries.  Americans  spent  about  14 percent  of gross domestic  product  on  healthcare,  while other  advanced  nations  spent about  10 percent.  In  2000, healthcare  accounted  for  10.7 percent  of the gross domestic  product  in Switzerland,  10.6 percent  in Germany, 9.5 percent  in France,  and 9.1 percent  in Canada. Medicare  spending, for the elderly and  disabled,  rose 7.8 percent  in 2001, while spending under   Medicaid,   the  federal-state   program   for  low-income  people, increased  by 10.8 percent.  Prescription  drugs  were the fastest-growing category  of healthcare  spending.  In 2001, spending  on drugs exceeded spending  on nursing  homes  and  home  healthcare  combined.  Pharma- ceutical companies say prescription  drugs consumed only about ten per- cent of total  healthcare  spending  in 2001. Spending  for hospitals  and doctors  accounted  for more than  50 percent.

As  measured  by  life span  and  infant  mortality,   however,  most developed nations are healthier than the United States. Moreover, Americans  do not  have more  medical services than  residents  of other nations. In 2001, the United States had 2.7 doctors per thousand people, compared  with a median of 3.1 in the countries  in the Organization for Economic  Cooperation and Development (OECD).  The United  States has 2.9 hospital  beds per thousand people, compared  with the OECD median of 3.9. Germany  has 6.3. Researchers concluded that Americans are charged more for doctors, hospitals, drugs, and, especially, for administrative expenses.

Although  healthcare  spending and access to medical care are hotly contested  issues, some studies seem to suggest that  increased  spending on healthcare  does not  necessarily  lead to  significant  and  measurable improvements  in health. In contrast  to most goods and services, the sup- ply of healthcare (as measured by the numbers of physicians, specialists, diagnostic  and  therapeutic equipment,  and  hospitals)  seems to  drive demand. Many complex economic, political, and cultural factors are involved in patterns  of distribution and usage of healthcare  resources, but  analysts  point  to  major  discrepancies  in  spending  that  are  not reflected in vital statistics. For example, despite major differences between Medicare  spending  for senior  citizens in Miami  and  Minneapolis, life expectancy was essentially the same. Studies that  analyzed the relation- ship between the availability of neonatal intensive-care facilities and specialists and infant mortality  rates reached a similar conclusion. That is, increasing the availability and usage of healthcare  resources increases costs, but does not necessarily result in obvious or measurable  improve- ments in health and longevity.

Nevertheless,  the cost of healthcare  and the  number  of Americans  without  medical  insurance  are  expected  to increase rapidly.  Some health  policy experts argue  that  debates  about how  states  and  individuals  should  pay  for  medical  care  should  be informed by a healthy skepticism about the cost-effectiveness of medical treatments and  an  understanding that  newer,  more  aggressive,  more expensive care does not  guarantee  better  care, better  health,  or longer life expectancy. For example, studies of the mechanism of heart attacks suggested  that  increasingly  popular  aggressive treatments, like bypass surgery,  angioplasty,  and  the insertion  of stents  (wire cages that  hold plaque  against  an  artery  wall in order  to  maintain  blood  flow) might be useless, as well as dangerous.  Preventive measures, such as giving up smoking,  lowering cholesterol,  and controlling  blood  pressure,  seem to be more significant.  Many  attempts  to show that  opening  a narrowed artery saved lives or prevented heart attacks were unsuccessful, but the call for aggressive intervention  was not affected.

One issue raised by the widespread  misconception  that  the infec- tious diseases have been conquered  is whether interest  in public health and preventive immunizations can be sustained without the threat of epi- demics and direct experience of so-called childhood diseases. In wealthy, industrialized  nations few individuals recall the heavy toll once taken by tuberculosis,  diphtheria, smallpox, measles, and polio. Moreover,  many people mistakenly believe that antibiotics can cure all infectious diseases. Some observers  warn  that  the declining status  of state  and  city public health  departments indicates that,  in the absence of fear, the essential, but  generally  routine  work  of such  institutions is neither  understood nor appreciated.

As Rudolf Virchow (1821–1902), the founder of cellular pathology,  warned  his bacteria-hunting colleagues, simplistically attri- buting contagious diseases to bacteria ‘‘hinders further research and lulls the conscience to sleep.’’ At the turn of the century, fear of biological ter- rorism  and  the threat  of newly emerging diseases stimulated  concerns about the ability of industrialized nations to respond to particularly viru- lent, contagious,  and unfamiliar  infectious diseases. According to public health experts, concern did not necessarily lead to funding and planning.

Understanding the tensions  that  result from changing  patterns  of health,  disease, and demography, and the differences in patterns  found in the wealthy nations and impoverished nations requires familiarity with history,  geography,  ecology, and  economics,  as well as knowledge  of medicine and science. The global spread of AIDS, which has devastating villages and  cities in  Africa  where  the  disease  may  have  originated, revealed the necessity for a global and historic  perspective.  AIDS  first appeared  as a diagnostic  entity  in 1981 when the Centers  for Disease Control  began to report  that  strange clusters of illnesses usually associ- ated  with  a severely compromised  immune  system were appearing  in previously  healthy  gay men in New York  and  Los  Angeles.

In  1984, the causative agent, a retrovirus  referred to as the human  immunodefi- ciency virus (HIV), was identified. Within five years of the first reports, the United States Public Health  Service estimated that more than a mil- lion American were infected with HIV. Further studies of HIV suggested that the virus had not simply appeared  in the 1980s, but had been incu- bating as a silent epidemic in areas of the world where the deaths of chil- dren and young adults from fever and diarrheal  diseases were not at all uncommon. Presumably,  other  still unrecognized  diseases and  patho- gens remain  submerged  among  the fevers of unknown  origin  (FUOs) in the developing world.

Unlike Thomas McKeown (1911–1988), the eminent social philoso-pher  of medicine,  who  contended  that  medical  intervention had  little effect on mortality  rates and  minor  consequences  for morbidity,  some medical  historians  believe that  public  health  measures  played  a  very significant role in the control of infectious diseases during the nineteenth century.  Some critics of modern  medicine  have  argued  that  the  term

‘‘healthcare’’ is a misnomer.  Many wealthy countries  actually have cre-ated  what  should  more  accurately  be called an  ‘‘illness subeconomy’’ that  consumes  a  substantial and  increasing  share  of  gross  domestic product  in order  to deal with chronic illness. Many  scholars agree that there is little evidence that  therapeutic medicine affected mortality  and morbidity  rates.  McKeown’s  work,  summarized  in The Modern  Rise of  Population  (1976),  challenged  then  prevailing  assumptions   about the  relationship   between  medical  practice  and  changing  patterns   of mortality  and  morbidity.   Between  1800 and  2000, life expectancy  at birth  rose  from  about  30 years  to  a  global  average  of  67 years.  In the wealthy,  industrialized  nations,  life expectancy  at  birth  was more than  75  years.  Although   patterns   of  morbidity   and  mortality   have undergone  remarkable changes in this relatively brief period  of human history,  major  differences  in  patterns   of  disease  and  life expectancy separate  the wealthy  nations  from  developing  nations.  Moreover,  the so-called  developing  world  accounts  for  about  80 percent  of  global population. In  Africa  and  other  parts  of the  developing  world,  over 60 percent  of deaths  are caused by communicable  diseases. In Europe only eight percent  of deaths  are due to communicable  diseases.

Perhaps  the fears generated  by AIDS will reverse the tendency of the  wealthy  nations  to  assume  that  the  infectious  diseases have  been conquered  and  that  the  contagious  diseases  of third  world  countries are  inconsequential. AIDS  has  made  it clear  that  the  most  powerful chemotherapeutic agents are ultimately powerless against the onslaught of germs if the natural immunological  defenses cannot participate in the battle.  Expensive, complex new drug regimens have transformed AIDS from  a fatal  disease to  a chronic  disease, at  least  for  those  who  can afford  therapy,  but  the remedies themselves are not  without  risks and adverse effects. Of course,  in much  of the world old enemies, such as tuberculosis,  malaria,  measles, cholera, and, above all, poverty and mal- nutrition, have not given up their role as ‘‘million-murdering  death.’’ Medical errors have become the subject of extensive studies and of sharp debates since the 1990s. Although  the Hippocratic texts reveal an appreciation of the problem of medical errors and the fact that medical interventions frequently  led to unintended adverse effects, recent critics of modern  medical practice have diagnosed  what they called a ‘‘terrify- ing epidemic of medical mistakes.’’ In 1999, the Institute  of Medicine of the National Academy of Sciences published a report  entitled To Err is Human,  which estimated  that  about  100,000 Americans  died annually as  a  result  of  medical  mistakes  that  occurred  in  hospitals,  including about   seven  thousand  deaths   attributed  to  medication   errors   and adverse  drug  reactions.  Some experts  are sure that  these numbers  are underestimates.

Adverse  drug  reactions  are  compounded by unanticipated inter-actions  between drugs,  dietary  supplements,  and  foods,  and  the prob- ability  that  toxic  reactions  to  particular drugs  will not  be  detected until large numbers  of people have taken  a new drug  for a significant amount  of time. Pharmaceutical companies and researchers have coined a new term, theranostics  (diagnostics þ therapy) to suggest a strategy for combining  diagnostic  tests with targeted  drug therapy.  Diagnostic  tests that could identify patients most likely to be helped or damaged by new medications would be combined with drug therapy that targets a specific gene or protein.  Since the turn  of the century,  several such tests have been  developed  for  use  in  the  diagnosis  and  treatment of  leukemia, breast cancer, colorectal cancer, and lung cancer. Skeptics note that, although  ‘‘personalized medicine’’ is an admirable goal, drug companies are more likely to pursue drugs that  treat  many people than  drugs that are specific to much smaller groups of patients.  Advocates  of theranos- tics argue that  increased efficacy and safety would stimulate  the devel- opment  and  approval  of many  more  new drugs  for  chronic  diseases and infectious diseases as well as cancers.

Despite   sophisticated  diagnostic   imaging,   there   is  compelling evidence that many errors occur in diagnosis, surgery, and prescriptions. A report  published in 2004 found that  out of some sixty-four thousand patients  who  had  undergone  appendectomies between  1987 and  1998 about  15 percent did not have appendicitis.  Among the female patients in this group about  23 percent of the appendectomies were unnecessary. Researchers found that cardiologists missed evidence of significant heart disease about a third of the time. Similar errors were found in reviews of radiologists examining mammograms. Cynics say that the true extent of medical  errors  is impossible  to  measure  because  serious  mistakes  are buried with the patient, as demonstrated by studies of randomly  selected autopsies.  Nevertheless,  biomedical  scientists  continue  to  believe that further  advances  in  technology  will provide  more  sophisticated and accurate  diagnostic  information. Skeptics  insist  that  techniques  that work  in the laboratory do not  necessarily work  under  more  complex, less structured conditions.

As demonstrated in the controversy  that  erupted  when salvarsan was used to treat syphilis, evaluating the safety and efficacy of any drug or medical innovation  entails many difficulties, scientific and  political. Indeed,  the passage of time and  rigorous  statistical  analyses are likely to demonstrate that various ‘‘miracle drugs’’ are dangerous, ineffective, or no more effective than  older remedies. Worse yet, some drugs pose dangers  not  only to  the patients  for  whom  they were prescribed,  but also  for  their  future  children,  as demonstrated by the  tragic  cases of thalidomide  and  diethylstilbesterol  (DES).  DES,  a synthetic  estrogen, was widely prescribed  from  the  1940s to  the  1970s, in  the  mistaken belief that  it would  prevent  miscarriages.  Not  only did  DES  increase the  risk of complications  during  pregnancy,  it caused  a rare  form  of cancer  in  DES  daughters,   reproductive disorders  in  both  DES  sons and  daughters,   and  increased  the  risk  of  various  cancers  in  women who had taken  the drug.

During the 1950s, thalidomide  entered the German pharmaceutical market  as a remedy for insomnia,  tension,  and  morning  sickness. The drug  was described  as  more  effective and  safer  than  barbiturates. It was so commonly  used to sedate children  that  it was often referred  to as the West German  baby-sitter.  By 1960, when the drug  was already available  in about  fifty countries,  members  of the German  Society for Pediatric   Medicine   were  discussing  a  suspiciously   high  number   of unusual   birth   defects.  Ultimately,   researchers   estimated   that   about ten  thousand children  were  born  with  abnormalities of  the  internal organs as well as deformities of the arms, legs, hands, and feet that were grouped   together   as  phocomelia   (from  the  Greek   for  seal þ limb). Widukind  Lenz (1919–1995), a pediatrician  and  professor  at the Uni- versity  of  Hamburg, became  particularly interested  in  possible  links between phocomelia  and  thalidomide. In 1961, he reported  his suspi- cions about  ‘‘a frightening increase in deformities’’ and suggested a link between the birth  defects and a new drug.

Eventually,  thalidomide   was  identified  as  a  powerful  teratogen (an  agent  that  causes  malformations in an  embryo  or  fetus) and  the cause of the worldwide  epidemic of phocomelia.  Because of the work of Frances  Kathleen  Oldham  Kelsey (1914–), a medical officer at  the Food   and  Drug  Administration, less than  20 cases  occurred  in  the United  States.  The  Pure  Food  and  Drug  Act of 1906 established  the regulatory  agency that  became  the Food  and  Drug  Administration in order to protect consumers from dangerous  foods, drugs, and cosmetics. In 1937, for example, the Masengill Company  prepared  a liquid form of sulfanilamide  by dissolving  the  drug  in diethylene  glycol, which  is a sweet,  but  highly  toxic  liquid.  About  240 gallons  of  ‘‘sulfanilamide elixir’’ were distributed, without  any tests for safety,  and  at  least 107 people died. This tragedy  created  demands  for federal regulations  that would  prevent  the  marketing  of unsafe  pharmaceutical products.  On June  15, 1938, President  Franklin D.  Roosevelt  signed  into  law  the Food,  Drug  and Cosmetic Act.

Despite claims by the manufacturer, Richardson-Merrell Inc., that no adverse effects occurred  when thalidomide  was taken  for insomnia, nervous  tension,   asthma,   and  relief  of  nausea   in  early  pregnancy, Kelsey  delayed   approval   of  thalidomide   by  repeatedly   requesting addition  tests and information. Merrell was seeking approval  of thalid- omide as a sleeping aid, but  Kelsey noted  that  the drug  did not  make experimental  animals sleepy. Despite evidence from England  that  some patients  taking  thalidomide  experienced  serious effects on the nervous system that  resulted in tingling, numbness,  and burning  in their fingers and toes, Kelsey’s supervisors  and the drug manufacturer exerted con- siderable  pressure  on  her  to  expedite  approval.  According  to  a 1962 report  read into the Congressional  Record  by Senator  Estes Kefauver, Merrell continued  to call for routine  approval  and appealed to Kelsey’s superiors.   Moreover,   even  without   approval,   the  law  at  the  time allowed Richardson-Merrell Inc. to enlist hundreds  of American  doc- tors  to  carry  out   ‘‘clinical  trials’’  of  thalidomide   on  their  private patients. After the relationship between thalidomide and phocomelia became public knowledge,  Merrell revoked  its application and eventu- ally withdrew the drug from experimental  use. The thalidomide  tragedy was one  of the factors  that  stimulated  the passage  of legislation  that gave  the  FDA   additional  authority  to  regulate  the  introduction  of new drugs.

An experienced researcher  in pharmacology when she began work at the FDA  in 1960, Kelsey had  earned  a master’s degree in pharma- cology from McGill University, Montreal (1934), a Ph.D. (1938) in phar- macology, and a medical degree (1950) from the University of Chicago. While teaching  at  the University,  she married  fellow faculty  member, Dr. Fremont Ellis Kelsey. The Kelseys moved to South  Dakota where Frances  Kelsey  practiced  medicine  and  taught  pharmacology.  When her husband  accepted a position  in Washington, DC, Kelsey was hired by  the  Food   and  Drug  Administration.

In  1962,  after  thalidomide was taken off the market by many European nations,  Kelsey was lauded for  preventing   thalidomide   birth  defects  in  thousands  of  American infants.  She received the Distinguished  Federal  Civilian Service Award from  President  John  Fitzgerald  Kennedy  (1917–1963). The  engraving on her presidential  award reads, ‘‘Her exceptional judgment  in evaluat- ing a new drug for safety for human  use has prevented a major tragedy of  birth  deformities  in  the  United  States.  Through   high  ability  and steadfast  confidence in her professional  decision she has made an out- standing  contribution to the protection of the health  of the American people.’’ The  Washington Post  called Kelsey a ‘‘heroine’’ and  praised her for the ‘‘skepticism and  stubbornness’’  that  prevented  a potential American  tragedy.  The  New York  Times praised  Kelsey  for  leading ‘‘a two-year  battle  with the makers  of thalidomide.’’  In 2000, Kelsey, who was still working  in the FDA’s  Center  for Drug  Evaluation and Research,  was inducted  into  the  National Women’s Hall  of Fame  in Seneca Falls,  New York.

Germany’s  federal  prosecutor  filed a criminal  indictment  against the  manufacturer of  thalidomide   in  1967. The  complex  and  contro- versial trial  did  not  end  until  a negotiated  settlement  was reached  in 1970. Prosecutors  agreed  to  drop  charges  against  the  company,  and protect  the  company  and  individual  defendants  from  future  criminal or civil liability,  in exchange for an agreement  establishing  a fund  for thalidomide  children. The judges explained that  it was more important to improve  methods  of drug development  in the future  than  to punish those associated  with marketing  thalidomide.

Attempts  to  balance  the  need  to  make  drugs  available  with  the need to  prevent  the adoption of drugs  that  are  potentially  dangerous remain problematic. In the 1980s, cancer and AIDS activists demanded more rapid access to new drugs. For patients  with deadly diseases, they argued,  the benefits of new drugs outweighed  any potential  risks. The problem  of adverse,  unexpected  interactions between  drugs,  however, is particularly likely to affect people with severe and  chronic  diseases. Regulatory agencies typically cite the need for constant  vigilance to pre- vent  future  thalidomide-like tragedies,  while critics of the  long,  slow, and  increasingly  expensive  process  of  drug  approval   insist  that  new life-saving  remedies  are  held  hostage   by  cold-hearted   bureaucrats. Few are likely to remember how Frances Kelsey, serving as a bureaucrat and a ‘‘gatekeeper’’ prevented widespread distribution of thalidomide  in the  United  States.  Complicating  the  argument  is the  realization  that even a drug like thalidomide, with its notorious reputation as a terato- genic agent,  may have some value in the treatment of certain  diseases, including   leprosy,  certain   AIDS-related  conditions   such  as  painful mouth ulcers and severe body wasting, arthritis  and other inflammatory disorders,   Crohn’s   disease,   multiple   sclerosis,  Alzheimer’s  disease, multiple myeloma, myelodysplastic syndrome (also known as pre- leukemia), and other cancers. Thalidomide seemed to block the normal development  of fetal limbs by preventing  angiogenesis  (the growth  of new blood vessels). Obstructing angiogenesis is one of the strategies that might be valuable  as a treatment for certain cancers, because like fetal limbs, tumors  need new blood  vessels in order  to grow.

Organizations representing  the surviving, adult  victims of thalido-mide objected to attempts  to rehabilitate this highly controversial, tera- togenic  drug.  When  thalidomide   was  licensed  for  use  in  the  United States  in  1998, members  of  the  Thalidomide Victims  Association  of Canada   (TVAC)  adopted   the  unequivocal  position  that  they  would ‘‘never accept a world with thalidomide  in it.’’ Even the remote  possi- bility that  a drug might help victims of deadly or debilitating  diseases, they  warned,  could  lead  to  reckless,  irresponsible,   and  unregulated usage,  and  the  possibility  of fetal  exposure  to  thalidomide  as well as nerve damage in adults. Rather  than allowing the possibility of another generation  of thalidomide  victims, the Association  argued  for research that  would  lead  to  development   of  thalidomide   analogs  that  would not have its teratogenic effects. However, the potential  anticancer effects of  thalidomide   and  its  derivatives  might  involve  the  same  pathways that  cause  phocomelia.  Victims of thalidomide  urged  the  mandatory inclusion  of  a  picture  of  a  thalidomide   baby  and  other  educational materials  in all packages  of thalidomide  and the prominent use of that name along with any new trade  names.

Both the idea of progress  and the role of medicine become prob-lematic when morbidity  and mortality  are analyzed  in terms of a tran- sition   from   the   old   epidemic,   infectious   diseases   to   diseases   of affluence and diseases of medical progress, and when patients  find their rising expectations  for cure and comfort  increasingly frustrated. Many scientists and physicians would agree with what Benjamin Franklin said in 1772: ‘‘It appears that the doctrines of life and death in general are yet but  little  understood.’’  Healthcare controversies  have  been  addressed judiciously in professional journals and the scholarly literature, and passionately  in popular  books, magazines, and TV talk shows. Another five hundred  pages would hardly  begin to address  these problems,  but perhaps even a bare survey of the history of medicine will provide some of the facts and concepts  that  every person  needs to know in order  to appreciate  the complex relationships among  disease, health,  medicine, and  society.  The  biomedical  sciences are  certainly  entering  a new era in the development  of vaccines and  therapeutic agents. But as always, there  are  no  remedies without  risk.  Therefore,  the  words  of the  wise doctors  of Salerno  still provide an appropriate conclusion  to any con- siderations  of the history of medicine:

And here I cease to write, but will not cease To wish you live in health,  and die in peace; And ye our Physicke rules that  friendly read, God  grant  that  Physicke you may never need.

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