HISTORICAL ARTICLE What Caused the Epidemic of Pneumocystis Pneumonia in European Premature Infants in the Mid-20th Century?

An epidemic of interstitial pneumonia principally involving premature infants occurred in Germany and nearby European countries between the 1920s and 1960s. Fatalities were due to Pneumocystis. Because the principal defenses against Pneumocystis are T cells, an acquired T-cell deficiency was postulated. A number of potential causes including malnutrition were considered. All were implausible except for a retrovirus that was benign in adults but virulent in premature infants. Furthermore, we suspect that the virus was imported into Germany from former German African colonies. Premature infants were vulnerable because of the developmental status of their T cells. Given the practices in that part of Europe at that time, the virus was most likely transmitted by contaminated blood transfusions and subsequent contamination of reusable needles and syringes used in injections. Although the epidemic ended 4 decades ago, a search for the postulated retrovirus can be conducted if tissues from affected infants are available. Pediatrics 2005;115:e725–e736. URL: www.pediatrics.org/ cgi/doi/10.1542/peds.2004-2157; Africa, Europe, retrovirus, premature infants, T cells, Pneumocystis pneumonia. ABBREVIATIONS. CMV, cytomegalovirus; HTLV-1, human Tcell lymphotropic virus type 1; Ig, immunoglobulin; STLV, simian T-cell leukemia virus; MHC, major histocompatibility complex; TcR, T-cell antigen receptor. An epidemic of interstitial pneumonia struck premature (preterm) infants in Germany and surrounding countries during the mid-20th century.1–8 Fatalities were due to Pneumocystis.1–3 Pneumocystis pneumonia was also reported in malnourished, orphaned infants during that period.1 Many physicians assumed that the pneumonias in premature infants were also secondary to malnutrition. However, when the epidemic intensified and peaked in Europe during the 1950s, malnutrition was rare. Since the epidemic ceased, much information emerged concerning Pneumocystis, the defense by T cells against Pneumocystis and other opportunistic agents, the causes of T-cell deficiencies including human retroviruses, and the developmental status of T cells in newborn infants. Furthermore, certain clinical practices common in premature nurseries in which the epidemic was centered and hitherto unpublished observations of the histopathology of the lymphoid system in some fatal cases were considered. This information permitted the formation of a hypothesis concerning the genesis of the epidemic that has not appeared in peer-reviewed articles. We propose that premature infants developed a T-cell deficiency because of a retrovirus imported from previous German African colonies. PNEUMOCYSTIS EPIDEMIC IN EUROPEAN PREMATURE INFANTS The epidemic was heralded by sporadic cases of fatal interstitial plasma cell pneumonia in German premature infants during the 1920s through the early 1940s4–8 (Table 1). Although epidemiologic methods were not sophisticated at that time, it is clear from the reports that although the epidemic progressively intensified and spread throughout Germany and into nearby European countries by the early 1950s,1–3,9–11 it continued to occur predominantly in Germany and nearby German-speaking countries or regions (Table 1). The epidemic peaked between 1955 and 1959 (Table 1) and quickly subsided during the early 1960s.3,9,10 At the height of the epidemic in the 1940s and 1950s, numerous premature infants in many countries were affected. Many thousands of cases occurred in Germany.1,3,9,10 Some 2000 cases were reported in Czechoslovakia in 4 years.9 In 7 years, there were 200 cases in the University Children’s Hospital in Helsinki, Finland.12 During 1941–1949, 707 cases occurred in the German-speaking part of Switzerland, whereas no cases occurred in other sections of that country.13 Of 1104 premature infants born in 1959–1963 at the University of Szeged in Szeged, Hungary, 232 (21%) developed interstitial pneumonia.11 The frequency of interstitial pneumonia increased with decreasing birth weight (birth weight 2001–2500 g: 6%; birth weight 1501–2000 g: 21%; birth weight 1500 g: 41%).11 Males and females were affected equally. In most reports, the first signs of the pneumonia, rapid and labored respiration, began several weeks after discharge from the hospital nursery. The mortality rate was 20% to 30%.2,9,13 In 1942, Pneumocystis was identified in the lungs of 2 Dutch infants with fatal interstitial pneumonia, but no disease was attributed to the microorganism.14 Then in 1951, Vanek and Jirovec15,16 in CzechoslovaFrom the *University of Texas Medical Branch, Galveston, Texas; ‡Johns Hopkins University Bloomberg School of Public Health, Baltimore, Maryland; and §Expert Health Data Programming, Inc, Seattle, Washington. Accepted for publication Dec 13, 2004. doi:10.1542/peds.2004-2157 No conflict of interest declared. Address correspondence to Armond S. Goldman, MD, Department of Pediatrics, University of Texas Medical Branch, Galveston, TX 77555-0369. E-mail: [email protected] or [email protected] PEDIATRICS (ISSN 0031 4005). Copyright © 2005 by the American Academy of Pediatrics. www.pediatrics.org/cgi/doi/10.1542/peds.2004-2157 PEDIATRICS Vol. 115 No. 6 June 2005 e725 by guest on March 30, 2017 Downloaded from kia reported that interstitial plasma cell pneumonia in some premature infants was due to Pneumocystis. Moreover, they recognized Pneumocystis in photomicrographs of lungs of premature infants with interstitial pneumonia published in 1938.6,7 Afterward, many cases of fatal Pneumocystis pneumonia in European premature infants were recognized.1–3,9,10 According to Gajdusek,1 there were at least 111 separate publications from Germany, 33 from Czechoslovakia, 21 from Italy, 13 from Finland, 10 from France, 9 from Austria, and 6 from Hungary during the decade after the report by Jirovec and Vanek1 (Table 1). A later report2 indicated that 81 cases of interstitial pneumonia occurred among 712 live births during 1955–1958 in 1 hospital in Heerlen, Netherlands. The overall mortality was 30%.2 To stem what was thought to be a hospital-acquired infection, some hospital nurseries closed.2,9 However, that did not seem to reduce the rates of infection, except possibly in the Heerlen outbreak.2 The abrupt cessation of the epidemic in the early 1960s was never explained. AUTHOR’S OBSERVATIONS 1955–1957 During 1955–1957, one of the authors (A.S.G.) was Chief of Pediatrics at the US Army Hospital in Würzburg, Germany. At that time, he visited the department of pediatrics at the University of Würzburg, where there were many cases of interstitial pneumonia in premature infants.17 His observations of the care of normal premature infants and clinical features of the affected infants and in that hospital are as follows. Two aspects of clinical care of normal premature infants in the Würzburg University hospital were different from US Army hospitals in Europe and hospitals in the United States. The first was that donor human milk was the mainstay for newborn premature infants at Würzburg University and at many other European premature nurseries. Milk collected from lactating women in the surrounding countryside was brought to the hospital each day by a special train. The unprocessed milk was pooled and fed within 24 hours. After 4 weeks, feedings were switched to a mixture of donor human milk and acidified cow’s milk and then, shortly before discharge, just to acidified cow’s milk.17 In contrast, premature infants in the United States and in US Army hospitals in Europe at that time were principally fed cow’s-milk preparations.18 The contrast between the frequency of blood transfusions for premature infants in German civilian hospital nurseries and US Army hospital nurseries in Germany was also striking. At the University of Würzburg, otherwise healthy premature infants often received blood transfusions to prevent infections, whereas blood transfusions to premature infants in US Army hospitals in Germany were limited to the treatment of hemolytic disease of the newborn, blood loss, severe anemia, or shock. A total of 417 cases of interstitial pneumonia in premature infants was treated at the University of Würzburg from 1953 to 1963 (Table 2).17 Males and females were affected equally.17 The number of cases in Würzburg peaked between 1958 and 1961, sharply decreased in 1962, and almost disappeared in 1963 (Table 2).17 Although interstitial pneumonia in premature infants was rampant in Europe during the 1950s,1–3,9,10 it was rare in infants born in the United States and at US Army hospitals in Germany, including those who received blood transfusions. FurtherTABLE 1. Numbers of Publications of Plasma Cell Interstitial Pneumonia and Pneumocystis Pneumonia in Premature Infants in European Countries During the Mid-20th Century Countries 1920–1929 1930–1939 1940–1949 1950–1954 1955–1959 1960–1966 Germany 4 5 8 36 79 2 Switzerland 0 0 3 4 2 1 Netherlands 0 0 1 0 1 0 Belgium 0 0 1 0 0 0 Sweden 0 0 1 2 3 0 Finland 0 0 0 8 5 0 Czechoslovakia 0 0 0 25 8 0 France 0 0 0 5 5 0 Austria 0 0 0 3 6 0 Hungary 0 0 0 5 1 2 Spain 0 0 0 1 2 0 Italy 0 0 0 3 18 0 Poland 0 0 0 0 5 0 Total reports 4 5 14 92 135 5 Data are from reports of Gadjusek,1 Koop,2 and Goudsmit.3 Many affected premature infants were noted in each report. TABLE 2. Numbers of Infants Who Survived or Died From Interstitial Pneumonia at the University of Würzburg From 1953 Through 1963 Year of Occurrence Survivals Deaths Total Cases 1953 8 1 9 1954 13 7 2