Volume 2,  Number 1,  January-March 1996

Dispatches

(Pages 47-54)

Unexplained Deaths Due to Possibly Infectious Causes in the United States:
Defining the Problem and Designing Surveillance and Laboratory Approaches

Many new infectious diseases have been identified in the United States
during the last several decades (1). Among these are AIDS, Legionnaires'
disease, toxic-shock syndrome, hepatitis C, and most recently, hantavirus
pulmonary syndrome; all caused serious illness and death. In each instance,
the disease was recognized through investigation of illness for which no
cause had been identified. Retrospective studies of these and other newly
recognized infectious diseases often identified cases that occurred before
the recognition of the new agent; therefore, a more sensitive detection
system may make the earlier recognition of new infectious agents possible.

Delays in recognizing new infectious agents have often been substantial.
For instance, Legionella pneumophila was established as the cause of
Legionnaires' disease in 1976 after an epidemic in Philadelphia, but
sporadic cases in 1947 and an outbreak in 1957 were retrospectively
identified (2, 3). Similarly, toxic shock syndrome was recognized in late
1979 and early 1980, but retrospective reporting and chart reviews
documented cases as early as 1960 (4). HIV was identified in 1983 (5) yet
retrospective investigations documented AIDS cases in the late 1970s and
possibly as early as 1968 in the United States (6, 7).

The difficulty of identifying unknown etiologic agents is part of the
reason for delays between the occurrence and recognition of new infectious
diseases. Until recently, to identify new infectious agents we relied
primarily on culture techniques. For fastidious bacteria such as Legionella
sp., and new viruses, such as HIV, which have very specific growth
requirements, successful isolation usually required numerous attempts with
various culture systems, often extending over years. Advances in molecular
techniques, including polymerase chain reaction (PCR) amplification and
other DNA- (and RNA-) based techniques (e.g., representational difference
analysis), allow identification and classification of unknown etiologic
agents without having to culture them (8-10) and provide clues concerning
appropriate conditions for subsequent isolation of the agent in culture
(11,12).

A more systematic public health approach for the early detection of unknown
infectious agents is needed. This need was acknowledged in Addressing
Emerging Infectious Diseases Threats: A Prevention Strategy for the United
States, a CDC publication about emerging infections (13). CDC has
established an emerging infections program (EIP) network to conduct special
population-based surveillance projects, develop surveillance methods, pilot
and evaluate prevention strategies, and conduct other epidemiologic and
laboratory studies. In late 1994, CDC funded four programs based at state
health departments and academic institutions in California (Alameda, Contra
Costa, Kern, and San Francisco counties), Connecticut, Minnesota, and
Oregon. Some projects are conducted at all program sites and others,
depending on local interest and expertise, at only one or two sites.

Surveillance for unexplained deaths due to possibly infectious causes
(UDPIC) for early detection of new infectious diseases is one of the core
activities being conducted at all sites. This paper estimates the number of
UDPIC at the EIP programs and summarizes the surveillance and laboratory
approaches that will be used to identify their cause. This is the first
attempt to conduct surveillance for early detection of new infectious
diseases in a large U.S. population.

To estimate the number of deaths that might be identified in surveillance
for UDPIC, we used multiple cause-of-death data for the United States for
1992 from the National Center for Health Statistics (14). The year 1992 was
the most recent for which national data were available at the time of this
study. The analyses of death records were restricted to the EIP program
populations and age group (1-49 years of age) in which surveillance for
UDPIC was planned. Multiple cause-of-death data listed on the National
Center for Health Statistics death record allow for analysis of mortality
data based on the different causes (15). The International Classification
of Diseases, 9th Revision (ICD-9) was used to define UDPIC (16). We
selected 77 codes likely to represent UDPIC when listed on the death record
(Table 1) (17).
 ----------------------------------------------------------------------------------------------------------
 Table 1. Selected codes from Intemational Classification of Diseases, 9th 
revision 
  (ICD-9) used to identify unexplained deaths due to possibly 
infectious causes (UDPIC)
 ----------------------------------------------------------------------------------------------------------
 007.9 unspecified                420.9 other and                      785.6 enlargement of
           protozoal                             unspecified                             lymph nodes
           intestinal disease                 acute pericarditis
 008.5 bacterial                    421.0 acute and subacute        786.0 dyspnea and
          enteritis,                               bacterial                                   respiratory
          unspecified                          endocarditis                              abnormalities
 008.8 intestinal                    421.9 acute endocarditis,         792   nonspecific
           infectious                             unspecified                            abnormal
           due to other                                                                       findings in 
other
           organisms:                                                                         
body substances
           other organism,                                     
           not
 classified
           elsewhere
 009.0 infectious                   422.9 other and                       792.0 cerebrospinal
           colitis,                                  unspecified                              fluid
           enteritis, and                        myocarditis
           gastroenteritis
 009.1 colitis,                        424.9 endocarditis,                  792.1 stool contents
          enteritis, and                        valve unspecified
          
gastroenteritis
          of presumed
          infectious
 origin
 009.2 infectious                   425.4 other primary                  792.2 semen
          diarrhea                               cardiomyopathies
 009.3 diarrhea of                 425.9 secondary                      792.3 amniotic fluid
          presumed                            cardiomyopathy,
          infectious origin                   unspecified
 027.9 unspecified                446.6 thrombotic                       792.4 saliva
          zoonotic                              microangiopathy
          bacterial disease
 038.9 unspecified                465.0 acute                              792.9 other 
nonspecific
          septicemia                           laryngopharyngitis                    
abnormal findings
                                                                 
                                  in body
                                                           
                                                                                                   substances
 041.9 bacterial                     465.8 acute upper                    795   nonspecific
          infection                                respiratory                              abnormal
          in conditions                          infections of                            histologic and
          classified                               multiple or                               immunologic
          elsewhere and of                    unspecified sites:                    findings
          unspecified site:                     other multiple sites
          bacterial
          infection,
          unspecified
 046.9 unspecified slow          465.9 acute upper                    795.3 nonspecific
          virus                                     respiratory                               positive
 culture
          infection of the                      infections of                             
findings
          central                                  multiple or                
          nervous system                     unspecified sites:
                                                      unspecified site
 047.9 unspecified viral           466.0 acute bronchitis              795.4 other
          meningitis                                                                            nonspecific
                                                                                                     abnormal
                                                                                                     histologic
                                                                                                     findings
 049.9 unspecified                  466.1 acute bronchiolitis           795.7 other
          non-arthropodborne                                                              nonspecific
          viral diseases of                                                                    immunologic
          central nervous                                                                     findings
          system
 057.9 viral exanthem,             480.9 viral pneumoma,              796.4 other
          unspecified                            unspecified                               nonspecific
                                                                                                      abnormal
                                                                                                      findings:
                                                                                                      other abnormal
                                                                                                      clinical
 findings
 079.9 viral infection in            482.9 bacterial pneumonia,       798   sudden death,
          conditions classified               unspecified                             cause unknown
          elsewhere and of
          unspecified site:
          unspecified viral
          and
 chlamydial
          infection
 099.0 venereal disease,          485 bronchopneumonia,           798.1 instantaneous
          unspecified                         organism unspecified                  death
 136.9 other and                      486 pneumonia, organism        798.2 death occurring
          unspecified                          unspecified                                in less than 24
          infectious and                                                                       hours from the
          parasitic                                                                               onset of
          diseases:                                                                              symptoms, not
          unspecified                                                                           otherwise
          infectious and                                                                        explained
          parasitic diseases
 283.1 non-autoimmune            511.9 unspecified pleural         798.9 unattended
          hemolytic anemias                   effusion                                  death
 284.8 other specified               518.4 acute edema of lung,      799    other 
ill-defined
          aplastic anemias                      unspecified                              and
 unknown 
                                                                                                      causes
 of morbidity
                                                                                                      
and mortality
 286.6 defibrination                   518.8 other diseases of            799.0 asphyxia
          syndrome                                lung
 287.3 primary                          519.9 unspecified disease        799.1 respiratory
          thrombocytopenia                    of respiratory system               failure

 287.5 thrombocytopenia,          558   other and                       799.3 debility,
          unspecified                              unspecified                             unspecified
                                                         noninfectious
                                                         gastroenteritis
                                                         and colitis
 320.9 meningitis due to             780.6 pyrexia of unknown         799.4 cachexia
          unspecified                              origin
          bacterium
 322.9 meningitis,                      782.1 rash and other                799.8 other
          unspecified                              nonspecific skin                        ill-defined
                                                         eruption                                    conditions
 323.9 unspecified cause           782.7 spontaneous                   799.9 other unknown
          of encephalitis                          ecchymoses                            and 
unspecified
                                                                                                        
cause
 357.0 acute infective                 785.5 shock without
          polyneuritis                               mention of trauma
 ----------------------------------------------------------------------------------------------------------

Analyses for UDPIC were restricted to previously healthy persons 1 to 49
years of age by excluding persons outside this age-group and those who had
any of the following ICD-9 codes as an underlying cause of death: 140 to
239.9, neoplasms; 250.0 to 250.9, diabetes mellitus; 279.0 to 279.9,
disorders involving the immune mechanism; 295.5, other disease of spleen;
800 to 999.9, injury and poisoning; E800 to E998, supplementary
classification of external causes of injury and poisoning. Patients with
HIV disease listed anywhere on the death record were also excluded (codes
042, 042.0, 042.1, 042.2, 042.9, 043, 043.0, 043.1, 043.2, 043.3, 043.9,
044, 044.0, 044.9, and 795.8) (18).

Deaths meeting the study criteria were identified along with patient age,
gender, race (black, white, and other), and autopsy status for the four
EIPs (aggregate and by EIP program). To determine rates of UDPIC, we used
1992 census estimates for the four EIP programs (19).

In 1992, 744 UDPIC were identified among previously healthy persons 1 to 49
years of age in the four EIP sites. These deaths accounted for 14% of all
deaths (n = 5,304) among persons 1 to 49 years of age in hospitals and
emergency rooms. Most of the 744 UDPIC occurred among male patients (60%)
and whites (72%) (Table 2). Overall rates among blacks were almost four
times as high as those among whites (29.5 vs. 7.7 per 100,000). By site,
overall rates ranged from 5.6 (in Minnesota) to 14.5 (in California) per
100,000 population. These geographic differences could be accounted for
only in part by differences in the proportions of blacks by site. In
Minnesota and Oregon the proportions of blacks were 2.8% and 1.9%,
respectively, whereas in California and Connecticut the proportions were
14.7% and 12.4%, respectively.

Figure 1 shows the age-specific rates of UDPIC for persons 1 to 49 years of
age. Persons 1 to 24 years of age accounted for only 19% of deaths, while
persons 40 to 49 years of age accounted for 50%.

[Image]
Figure 1. Age-specific rates of unexplained deaths due to possibly
infectious causes (UDPIC) among previously health persons 1 to 49 years of
age in the four emerging infections program sites, 1992.

Of selected ICD-9 codes (Table 1), the six disease classifications (and
codes) accounting for the most of the UDPIC are shown in Table 3. A
selected ICD-9 code was listed as the underlying cause of death in 253
(34%) of 744 UDPIC. Autopsies were performed in 293 (39%) of the 744 UDPIC.

Two approaches for surveillance were proposed as a basis for the EIP
project. In the first, clinicians will be asked to report unexplained
deaths and serious illnesses from possibly infectious causes. In the
second, death certificate databases will be used to select patients with
ICD-9 codes likely to represent UDPIC. The first approach allows
prospective collection of data and specimens for deaths and serious
illnesses. In the second approach, UDPIC will be identified retrospectively
through information on death certificates.
 ----------------------------------------------------------------------------------------------------------

   Table 2. Unexplained deaths due to possibly infectious causes (UDPIC)
   among previously healthy persons by emerging infection program (EIP)
                                site, 1992
 -----------------------------------------------------------------------------------------------------------
                                  Rate (per 100,000 population aged 1-49 years)
                          -------------------------------------------------
--------------------------------
                                                      Gender               Race
                                    ---------------------------------------
--------------------------------
                        No. of
 EIP site           UDPIC   Overall   Female  Male   Black  White    Other
 --------------------------------------------------------------------------
--------------------------------
 California*          316       14.5      10.8    18.5     34.0    12.2       8.9
 Connecticut        83       14.2      10.5    18.5     37.9    11.4        --
 Minnesota           189        5.6        4.8      6.6     11.0     5.4        9.5
 Oregon               156        7.2        6.9      7.7     21.8     7.0        7.8
 Total                   744        8.9        7.4    10.9     29.5     7.7        8.7
 --------------------------------------------------------------------------
--------------------------------
 *Alameda, Contra Costa, and San Francisco counties.
 New Haven County.
---------------------------------------------------------------------------
--------------------------------
--------------------------------------------------------------------------
--------------------------------
-
 Table 3. Of selected ICD-9 codes, disease classifications accounting for
 most unexplained deaths due to possibly infectious causes (UDPIC) in the
                          four study sites, 1992
--------------------------------------------------------------------------
--------------------------------

                                                            UDPIC with ICD-9 code included on death
                                                                          record by age group (%)
                                                            ----------------------------------------
--------------

 Disease classification (ICD-9)*             1-49 yr;      1-14 yr;    15-39 yr;     40-49 yr;
                                                            n = 744      n = 75      n = 295       n = 374
 --------------------------------------------------------------------------
--------------------------------
 Respiratory failure (799.1)               205 (28)     14 (19)     91 (31)      100 (27)
 Unspecified septicemia (038.9)        108 (14)       8 (11)     42 (14)        58 (16)
 Pneumonia, organism unspecified
 
(486)                                              101 (14)       7 (9)       33 (11)        61 (16)
 Other primary cardiomyopathy
 
(425.4)                                             84 (11)       5 (7)        26 (9)         53 (14)
 Shock without mention of trauma
 (785.5)                                             83 (11)     10 (13)       29 (10)       44 (12)
 Other unknown or unspecified
 
(799.9)                                             75 (10)       9 (12)       35 (12)       31 (8)
 Totals                                            505 (68)     39 (52)     193 (65)      273 (73)
 -------------------------------------------------------------------------
--------------------------------
 *More than one of these disease classifications (ICD-9 code) may be
 listed on a death record.
 UDPIC with at least one of the six disease classifications included on
 the death record.
 --------------------------------------------------------------------------

Clinicians in the EIP areas have been asked to report by telephone to EIP
program surveillance personnel all previously healthy persons 1 to 49 years
of age who are hospitalized (or admitted to an emergency room) with a
life-threatening illness with hallmarks of an infectious disease for which
no cause is identified. Inclusion and exclusion criteria are shown below.

Inclusion criteria

  1. 1 to 49 years of age
  2. Admitted to a hospital or emergency room with life-threatening illness
     of potentially infectious etiology
  3. No cause for illness identified by preliminary testing

Exclusion criteria

  1. Preexisting chronic medical condition: malignancy; HIV infection;
     chronic cardiac, pulmonary, renal, hepatic or rheumatologic disease;
     or other known underlying chronic illness (e.g., diabetes mellitus)
  2. Immunosuppressive therapy
  3. Trauma
  4. Toxic ingestion or exposure
  5. Nosocomial infection

Clinicians and pathologists in the four EIP programs were informed of the
surveillance system through a combination of mailings, oral presentations,
and posters.

Classifying patients as having one or more infectious disease-related
syndrome(s) as listed below should help identify groups of patients with
similar illnesses for laboratory testing.

  1. Acute abdominal symptoms (e.g, diarrhea, pain, nausea/vomiting) and
     history of (h/o) fever
  2. Arthritis or osteomyelitis and h/o fever
  3. Blood cell dyscrasia or coagulopathy and h/o fever
  4. Conjunctivitis, keratitis, endophthalmitis, or periocular infection
     and h/o fever
  5. Endocarditis, myocarditis, pericarditis and h/o fever
  6. Hepatitis or hepatic insufficiency/failure and h/o fever
  7. Meningitis, encephalitis, encephalopathy, dementia, or other
     neurologic syndrome with or without a h/o of fever
  8. Rash, skin or mucosal membrane lesions, cellulitis, myositis,
     lymphadenitis, or lymphangitis and h/o of fever
  9. Renal insufficiency/failure and h/o of fever
 10. Respiratory failure, pulmonary infiltrates, or other pleuropulmonary
     manifestation and h/o of fever
 11. Shock or sepsis and h/o of fever or hypothermia
 12. Other

Information about exposures (e.g., travel or contact with animals or
insects) resulting in infectious diseases will be collected. For patients
who are still alive or have died recently, clinical and pathology
laboratories will be asked to save clinical specimens (including biopsied
tissues) obtained during clinical care and diagnostic evaluation. Range of
specimens will vary but be appropriate for the given illness and organ
systems affected. These specimens will be collected, divided into aliquots,
and stored. Autopsies will be encouraged. With the exception of pathology
specimens, specimens will be initially banked at the EIP sites. Fixed or
frozen tissue specimens (premortem and postmortem) will be sent directly to
CDC for examination. A CDC pathologist will be available to consult with
the local pathologist and to discuss preparation and transport of tissues.
Pathology results are expected to guide further laboratory testing on
specimens.

Clinical and epidemiologic data will be periodically reviewed locally at
each EIP and at CDC in aggregate. Each EIP will identify UDPIC not reported
through the clinician-based system by using state-based (rather than
national) electronic data systems to reduce delays in relaying information.
When deaths not reported through the clinician-based system are identified,
the medical chart will be reviewed, the patient's illness will be
classified by syndrome and information available in the medical record
concerning exposures will be collected. Samples of specimens will be
obtained at autopsy. Deaths will be handled as in the clinician-based
system with regard to periodic review and laboratory testing, although it
is expected that fewer clinical specimens will be available from patients
whose deaths were not reported through the clinician-based system.

Additional reference level laboratory tests for known pathogens will be
done in state health laboratories and CDC. CDC will test for previously
unrecognized infectious agents.

Initial identification of unrecognized etiologic agents at CDC will
primarily rely on serology, immunohistochemistry, and nucleic acid probes.
When a sufficient number of patients with similar illnesses are identified,
a customized strategy for laboratory testing will be designed. Serology and
immunohistochemistry will be used to narrow the scope of possible
etiologies. Nucleic acid probes will be used with PCR to amplify from
clinical specimens specific fragments of genetic material that can be
sequenced and used for phylogenetic comparisons to known infectious agents.
Clinicians who reported cases will be informed of laboratory results, but
information will usually not be available in time to affect treatment of
individual patients.

Until now, unexplained deaths and serious illnesses due to possibly
infectious causes have not been addressed as a specific public health
problem. The data obtained in the first phase of this project suggest that
UDPIC in previously healthy persons account for 13% of hospitalized deaths
among persons 1 to 49 years old in the EIP sites. Experience in recent
years with new infectious diseases suggests that systematic study of UDPIC
and similarly unexplained serious illnesses may allow earlier detection of
emerging infections. This has been made more feasible by newly developed
nucleic acid-based methods for identification of unknown etiologic agents.

Use of the 1992 National Center for Health Statistics multiple
cause-of-death data to estimate the number of UDPIC has its limitations.
The most important is in the selection of ICD-9 codes to identify these
deaths. Even with codes such as 038.9 ("unspecified septicemia"), which
seem relevant, without reviewing the medical record it is impossible to
know if the cause of the septicemia was known by the clinician but not
specified or was nosocomial. Codes representing potentially infectious
deaths (e.g., 799 for "other ill-defined and unknown causes of morbidity
and mortality") might also be assigned to noninfectious deaths. Another
critical limitation is failure to identify deaths that are, in fact,
unexplained but have been given an incorrect diagnosis.

For several reasons, our surveillance is limited to persons 1 to 49 years
of age who have been healthy. The 1-year lower age limit was selected to
avoid confusion with congenital problems in infants but include most
children in day-care, where infectious diseases are common and a new
infectious disease might spread rapidly. The upper age limit was set to
exclude an expected increased proportion of unexplained deaths from
noninfectious causes in persons 50 years and older. Many of the recently
recognized life-threatening infectious diseases would have been detected
among previously healthy persons in this age-group. Previously healthy
persons might also be considered better sentinels for new infectious
diseases because of their generally more vigorous interaction with people
and higher likelihood of exposure to infections (e.g., travel or contact
with animals or insects). However, restricting surveillance to previously
healthy persons is likely to decrease the sensitivity of our system.

Patients who are immunocompromised whether from HIV infection, malignancy,
or immunosuppressive therapy and many patients with other chronic
illnesses, are more susceptible to known and unknown infectious diseases.
New infectious diseases first identified in persons who are
immunocompromised or have chronic illnesses have subsequently been found to
also cause infection in persons with normal immune systems (20, 21).
Although sensitivity could be improved by including these populations in
surveillance, available resources and a concern that laboratory evaluation
would be complicated by the broader range of infectious possibilities
compelled us to focus on previously healthy persons.

Clinician-based and death certificate based systems for surveillance and
laboratory evaluation are being used in combination because of their
complementary strengths and weaknesses. The notable strengths of the
clinician-based system are the contribution of clinicians and the
timeliness of reporting. Because of their training and their relationship
with patients, clinicians can recognize unusual and potentially new
infections. This system also offers opportunities to collect and store
clinical specimens (pre-mortem and postmortem) that would not normally be
saved, in addition to providing systematic and timely collection of
exposure information that might not be available in the medical record.
This system might also increase the likelihood of an autopsy. However,
reporting is time-consuming and is not likely to affect the patient's care,
which may lower the sensitivity of this approach.

The primary strengths of the death certificate based system are its
completeness and relative ease, once the data are electronically available.
The completeness may make it sensitive for detection of new infections
resulting in death (but assumes that the correct ICD-9 codes are selected
and that they are coded accurately). Sensitivity is important because, to
be effective, the combined approaches should detect relatively rare
illnesses (e.g., in the range of one case per 100,000 to 1,000,000
population per year). The main disadvantages of this system are the
vagaries of ICD-9 classification: codes are not designed to identify new
infectious diseases and are assigned by persons not directly familiar with
the case. The list of ICD-9 codes used to identify UDPIC is likely to be
modified on the basis of information collected in this system and in the
clinician-based system. Another problem is the delay in getting information
on the death certificate into the database for review, which makes this
system relatively slow. Further, the only clinical specimens likely to be
available for laboratory evaluation are those collected at autopsy.

The goal of our project is early detection of new life-threatening
infectious diseases. However, it is likely that in the process, we will
identify cases in which known, but poorly recognized, infectious diseases
are responsible, either because the diagnostic tests being used clinically
are of poor sensitivity or because the diagnosis was unexpected by
clinicians. Findings concerning such cases may be useful in identifying
areas in which better diagnostic capabilities are needed and in improving
estimates of infectious disease prevalence (22). A population-based bank of
clinical specimens will be invaluable in current and future testing for
newly recognized etiologic agents and for developing diagnostic tests. This
project will better clarify surveillance strategies and help standardize
nucleic acid-based techniques for identification of previously unknown
etiologic agents. Through it, we expect to build U.S. capacity for
detecting and responding to newly recognized infectious diseases not only
at the EIP sites but elsewhere, nationally and internationally.

Bradley A. Perkins,* Jennifer M. Flood, Richard Danila, Robert C.
Holman,* Arthur L. Reingold, Laura A. Klug,* Michael Virata, Paul R.
Cieslak, Sherif R. Zaki,* Robert W. Pinner,* Rima F. Khabbaz,* and the
Unexplained Deaths Working Group#

*National Center for Infectious Diseases, Centers for Disease Control and
Prevention, USA, Atlanta, Georgia; School of Public Health, University of
California at Berkeley, California, USA;

Minnesota Department of Health, Minneapolis, Minnesota, USA; Yale
University School of Medicine, New Haven, Connecticut, USA; Oregon
Department of Human Resources, Portland, Oregon, USA

#The Unexplained Deaths Working Group: Grechen Rothrock, University of
California at Berkeley; Duc Vugia, California Department of Health
Services; James Hadler, Matt Cartter, Connecticut Department of Public
Health and Addiction Services; James Meek, Robin Ryder, Mark Wilson, Yale
University School of Medicine; Michael Osterholm, Kristine L. MacDonald,
Jean Rainbow, Norman Crouch, Kathy LeDell, Minnesota Department of Health;
David Fleming, Katrina Hedberg, Oregon Health Division; Don Brenner, Mark
Eberhard, James Olson, Pierre Rollin, R. Gibson Parrish, CDC.

References

  1. Institute of Medicine. Emerging infections: microbial threats to
     health in the United States. Washington, DC: National Academy Press,
     1992.
  2. McDade JE, Brenner DJ, Bozeman FM. Legionnaires' disease bacterium
     isolated in 1947. Ann Intern Med 1979;90:659-61.
  3. Osterholm MT, Chin TDY, Osborne DO, et al. A 1957 outbreak of
     Legionnaires' disease associated with a meat packing plant. Am J
     Epidemiol 1983;117:60-7.
  4. Osterholm MT, Forfang JC. Toxic-shock syndrome in Minnesota: results
     of an active-passive surveillance system. J Infect Dis
     1982;145:458-64.
  5. Barre-Sinoussi F, Chermann JC, Rey F, et al. Isolation of a
     T-lymphotropic retrovirus from a patient at risk for acquired
     immunodeficiency syndrome (AIDS). Science 1983;220:868-71.
  6. CDC Task Force on Kaposi's Sarcoma and Opportunistic Infections.
     Epidemiologic aspects of the current outbreak of Kaposi's sarcoma and
     opportunistic infection. N Engl J Med 1982;306:248-52.
  7. Garry RF, Witte MH, Gottlieb A, et al. Documentation of an AIDS virus
     infection in the United States in 1968. JAMA 1988;260:2085-7.
  8. Relman DA, Loutit JS, Schmidt TM, Falkow S, Tompkins LS. The agent of
     bacillary angiomatosis: an approach to the identification of
     uncultured pathogens. N Engl J Med 1990;323:1573-80.
  9. Nichol ST, Spiropoulou CF, Morzunov S, et al. Genetic identification
     of a hantavirus associated with an outbreak of acute respiratory
     illness. Science 1993; 262:914-7.
 10. Chang Y, Cesarman E, Pessin MS, et al. Identification of
     herpesvirus-like DNA sequences in AIDS-associated Kaposi's sarcoma.
     Science 1994;266:1865-9.
 11. Koehler JE, Quinn FD, Berger TG, LeBoit PE, Tappero JW. Isolation of
     Rochalimaea species from cutaneous and osseous lesions of bacillary
     angiomatosis. N Engl J Med 1992;327:1625-31.
 12. Elliot LH, Ksiazek TG, Rollin PE, et al. Isolation of the causative
     agent of hantavirus pulmonary syndrome. Am J Trop Med Hyg
     1994;51:102-8.
 13. Centers for Disease Control and Prevention. Addressing emerging
     infectious disease threats: a prevention strategy for the United
     States. Atlanta: U.S. Department of Health and Human Services, Public
     Health Service, 1994.
 14. National Center for Health Statistics. Public use data tape
     documentation. Multiple cause of death for ICD-9 1992 data.
     Hyattsville, MD: U.S. Department of Health and Human Services, 1994.
 15. Israel RA, Rosenberg HM, Curtin LR. Analytical potential for multiple
     cause-of-death data. Am J Epidemiol 1986;124:161-79.
 16. World Health Organization. Manual of the international statistical
     classification of diseases, injuries, and causes of death, based on
     the recommendations of the Ninth Revision Conference, 1975, and
     adopted by the twenty-ninth World Health Assembly. Vol. 1. Geneva:
     World Health Organization, 1977.
 17. Chamblee RF, Evans MC. TRANSAX, the NCHS system for producing multiple
     cause-of-death statistics, 1968-78. Washington, D.C.: US Government
     Printing Office, 1986. DHHS Pub No. [PHS] 86-1322).
 18. National Center for Health Statistics. Vital statistics of the United
     States 1987, Vol. II, mortality, part A, technical appendix.
     Washington, D.C.: U.S. Department of Health and Human Services, Public
     Health Service, 1990. (DHHS Pub No. (PHS) 90-1101).
 19. U.S. Bureau of Census. Intercensal estimates of the population of
     counties by age, sex and race: 1970-1992 (machine-readable data file).
     Washington, DC: U.S. Bureau of Census, 1995.
 20. MacKenzie WR, Hoxie NJ, Proctor ME, et al. A massive outbreak in
     Milwaukee of Cryptosporidium infection transmitted through the public
     water supply. N Engl J Med 1994;331:161-7.
 21. Tappero JW, Koehler JE, Berger TG, et al. Bacillary angiomatosis and
     bacillary splenitis in immunocompetent adults. Ann Intern Med
     1993;118:363-5.
 22. Pinner RW, Teutsch S, Simonsen L, et al. Trends in infectious diseases
     mortality in the United States. JAMA 1996;275:189-93.