Lawrence B. Schonberger

Chronic Fatigue Syndrome: A Working Case Definition

The chronic Epstein-Barr virus syndrome is a poorly defined symptom complex characterized primarily by chronic or recurrent debilitating fatigue and various combinations of other symptoms, including sore throat, lymph node pain and tenderness, headache, myalgia, and arthralgias. Although the syndrome has received recent attention, and has been diagnosed in many patients, the chronic Epstein-Barr virus syndrome has not been defined consistently. Despite the name of the syndrome, both the diagnostic value of Epstein-Barr virus serologic tests and the proposed causal relationship between Epstein-Barr virus infection and patients who have been diagnosed with the chronic Epstein-Barr virus syndrome remain doubtful. We propose a new name for the chronic Epstein-Barr virus syndrome--the chronic fatigue syndrome--that more accurately describes this symptom complex as a syndrome of unknown cause characterized primarily by chronic fatigue. We also present a working definition for the chronic fatigue syndrome designed to improve the comparability and reproducibility of clinical research and epidemiologic studies, and to provide a rational basis for evaluating patients who have chronic fatigue of undetermined cause.

Pandemic versus Epidemic Influenza Mortality: A Pattern of Changing Age Distribution

Almost all deaths related to current influenza epidemics occur among the elderly. However, mortality was greatest among the young during the 1918-1919 pandemic. This study compared the age distribution of influenza-related deaths in the United States during this centurys three influenza A pandemics with that of the following epidemics. Half of influenza-related deaths during the 1968-1969 influenza A (H3N2) pandemic and large proportions of influenza-related deaths during the 1957-1958 influenza A (H2N2) and the 1918-1919 influenza A (H1N1) pandemics occurred among persons <65 years old. However, this group accounted for decrementally smaller proportions of deaths during the first decade following each pandemic. A model suggested that this mortality pattern may be explained by selective acquisition of protection against fatal illness among younger persons. The large proportion of influenza-related deaths during each pandemic and the following decade among persons <65 years old should be considered in planning for pandemics.

The impact of influenza epidemics on mortality: introducing a severity index.

OBJECTIVES The purpose of this study was to assess the impact of recent influenza epidemics on mortality in the United States and to develop an index for comparing the severity of individual epidemics. METHODS A cyclical regression model was applied to weekly national vital statistics from 1972 through 1992 to estimate excesses in pneumonia and influenza mortality and all-cause mortality for each influenza season. Each season was categorized on the basis of increments of 2000 pneumonia and influenza excess deaths, and each of these severity categories was correlated with a range of all-cause excess mortality. RESULTS Each of the 20 influenza seasons studied was associated with an average of 5600 pneumonia and influenza excess deaths (range, 0-11,800) and 21,300 all-cause excess deaths (range, 0-47,200). Most influenza A(H3N2) seasons fell into severity categories 4 to 6 (23,000-45,000 all-cause excess deaths), whereas most A(H1N1) and B seasons were ranked in categories 1 to 3 (0-23,000 such deaths). CONCLUSIONS From 1972 through 1992, influenza epidemics accounted for a total of 426,000 deaths in the United States, many times more than those associated with recent pandemics. The influenza epidemic severity index was useful for categorizing severity and provided improved seasonal estimates of the total number of influenza-related deaths.

Acquired immunodeficiency syndrome (AIDS) associated with transfusions.

Of 2157 patients with the acquired immunodeficiency syndrome (AIDS) whose cases were reported to the Centers for Disease Control by August 22, 1983, 64 (3 per cent) with AIDS and Pneumocystis carinii pneumonia had no recognized risk factors for AIDS. Eighteen of these (28 per cent) had received blood components within five years before the onset of illness. These patients with transfusion-associated AIDS were more likely to be white (P = 0.00008) and older (P = 0.0013) than other patients with no known risk factors. They had received blood 15 to 57 months (median, 27.5) before the diagnosis of AIDS, from 2 to 48 donors (median, 14). At least one high-risk donor was identified by interview or T-cell-subset analysis in each of the seven cases in which investigation of the donors was complete; five of the six high-risk donors identified during interview also had low T-cell helper/suppressor ratios, and four had generalized lymphadenopathy according to history or examination. These findings strengthen the evidence that AIDS may be transmitted in blood.

Iatrogenic Creutzfeldt–Jakob disease at the millennium

Article abstract The causes and geographic distribution of 267 cases of iatrogenic Creutzfeldt–Jakob disease (CJD) are here updated at the millennium. Small numbers of still-occurring cases result from disease onsets after longer and longer incubation periods following infection by cadaveric human growth hormone or dura mater grafts manufactured and distributed before the mid-1980s. The proportion of recipients acquiring CJD from growth hormone varies from 0.3 to 4.4% in different countries, and acquisition from dura mater varies between 0.02 and 0.05% in Japan (where most cases occurred). Incubation periods can extend up to 30 years, and cerebellar onsets predominate in both hormone and graft recipients (in whom the site of graft placement had no effect on the clinical presentation). Homozygosity at codon 129 of the PRNP gene is over-represented in both forms of disease; it has no effect on the incubation period of graft recipients, but may promote shorter incubation periods in hormone cases. Knowledge about potential high-risk sources of contamination gained during the last quarter century, and the implementation of methods to circumvent them, should minimize the potential for iatrogenic contributions to the current spectrum of CJD.

The Impact of Influenza Epidemics on Hospitalizations

The traditional method for assessing the severity of influenza seasons is to estimate the associated increase (i.e., excess) in pneumonia and influenza (P&I) mortality. In this study, excess P&I hospitalizations were estimated from National Hospital Discharge Survey Data from 26 influenza seasons (1970-1995). The average seasonal rate of excess P&I hospitalization was 49 (range, 8-102) /100,000 persons, but average rates were twice as high during A(H3N2) influenza seasons as during A(H1N1)/B seasons. Persons aged <65 years had 57% of all influenza-related hospitalizations; however, the average seasonal risk for influenza-related P&I hospitalizations was much higher in the elderly than in persons aged <65 years. The 26 pairs of excess P&I hospitalization and mortality rates were linearly correlated. During the A(H3N2) influenza seasons after the 1968 pandemic, excess P&I hospitalizations declined among persons aged <65 years but not among the elderly. This suggests that influenza-related hospitalizations will increase disproportionately among younger persons in future pandemics.

The Guillain–Barré Syndrome and the 1992–1993 and 1993–1994 Influenza Vaccines

BACKGROUND The number of reports of influenza-vaccine-associated Guillain-Barré syndrome to the national Vaccine Adverse Event Reporting System increased from 37 in 1992-1993 to 74 in 1993-1994, arousing concern about a possible increase in vaccine-associated risk. METHODS Patients given a diagnosis of the Guillain-Barré syndrome in the 1992-1993 and 1993-1994 influenza-vaccination seasons were identified in the hospital-discharge data bases of four states. Vaccination histories were obtained by telephone interviews during 1995-1996 and were confirmed by the vaccine providers. Disease with an onset within six weeks after vaccination was defined as vaccine-associated. Vaccine coverage in the population was measured through a random-digit-dialing telephone survey. RESULTS We interviewed 180 of 273 adults with the Guillain-Barré syndrome; 15 declined to participate, and the remaining 78 could not be contacted. The vaccine providers confirmed influenza vaccination in the six weeks before the onset of Guillain-Barré syndrome for 19 patients. The relative risk of the Guillain-Barré syndrome associated with vaccination, adjusted for age, sex, and vaccine season, was 1.7 (95 percent confidence interval, 1.0 to 2.8; P=0.04). The adjusted relative risks were 2.0 for the 1992-1993 season (95 percent confidence interval, 1.0 to 4.3) and 1.5 for the 1993-1994 season (95 percent confidence interval, 0.8 to 2.9). In 9 of the 19 vaccine-associated cases, the onset was in the second week after vaccination, all between day 9 and day 12. CONCLUSIONS There was no increase in the risk of vaccine-associated Guillain-Barré syndrome from 1992-1993 to 1993-1994. For the two seasons combined, the adjusted relative risk of 1.7 suggests slightly more than one additional case of Guillain-Barré syndrome per million persons vaccinated against influenza.

Reye's Syndrome in the United States from 1981 through 1997

BACKGROUND Reyes syndrome is characterized by encephalopathy and fatty degeneration of the liver, usually after influenza or varicella. Beginning in 1980, warnings were issued about the use of salicylates in children with those viral infections because of the risk of Reyes syndrome. METHODS To describe the pattern of Reyes syndrome in the United States, characteristics of the patients, and risk factors for poor outcomes, we analyzed national surveillance data collected from December 1980 through November 1997. The surveillance system is based on voluntary reporting with the use of a standard case-report form. RESULTS From December 1980 through November 1997 (surveillance years 1981 through 1997), 1207 cases of Reyes syndrome were reported in patients less than 18 years of age. Among those for whom data on race and sex were available, 93 percent were white and 52 percent were girls. The number of reported cases of Reyes syndrome declined sharply after the association of Reyes syndrome with aspirin was reported. After a peak of 555 cases in children reported in 1980, there have been no more than 36 cases per year since 1987. Antecedent illnesses were reported in 93 percent of the children, and detectable blood salicylate levels in 82 percent. The overall case fatality rate was 31 percent. The case fatality rate was highest in children under five years of age (relative risk, 1.8; 95 percent confidence interval, 1.5 to 2.1) and in those with a serum ammonia level above 45 microg per deciliter (26 micromol per liter) (relative risk, 3.4; 95 percent confidence interval, 1.9 to 6.2). CONCLUSIONS Since 1980, when the association between Reyes syndrome and the use of aspirin during varicella or influenza-like illness was first reported, there has been a sharp decline in the number of infants and children reported to have Reyes syndrome. Because Reyes syndrome is now very rare, any infant or child suspected of having this disorder should undergo extensive investigation to rule out the treatable inborn metabolic disorders that can mimic Reyes syndrome.

Chronic wasting disease and potential transmission to humans.

Chronic wasting disease (CWD) of deer and elk is endemic in a tri-corner area of Colorado, Wyoming, and Nebraska, and new foci of CWD have been detected in other parts of the United States. Although detection in some areas may be related to increased surveillance, introduction of CWD due to translocation or natural migration of animals may account for some new foci of infection. Increasing spread of CWD has raised concerns about the potential for increasing human exposure to the CWD agent. The foodborne transmission of bovine spongiform encephalopathy to humans indicates that the species barrier may not completely protect humans from animal prion diseases. Conversion of human prion protein by CWD-associated prions has been demonstrated in an in vitro cell-free experiment, but limited investigations have not identified strong evidence for CWD transmission to humans. More epidemiologic and laboratory studies are needed to monitor the possibility of such transmissions.

A Novel Human Disease with Abnormal Prion Protein Sensitive to Protease

To report a novel prion disease characterized by distinct histopathological and immunostaining features, and associated with an abnormal isoform of the prion protein (PrP) that, contrary to the common prion diseases, is predominantly sensitive to protease digestion.