Infectious pulmonary disease in patients receiving immunosuppressive therapy for organ transplantation.

The article by Hill, Rowlands and Rifkind1 was a by-product of an institutional commitment to transplantation in 1961–63, at the University of Colorado (Denver). The programme was launched after the ostensible fantasy of exploiting transplant procedures clinically had been demonstrated to be occasionally feasible at the Peter Bent Brigham Hospital in Boston (Joseph Murray and John Merrill),2,3 and at the Paris centres directed by Jean Hamburger4,5 and Rene Kuss.6 Between January 1959, and the summer of 1962, seven examples had been produced (two in Boston, five in Paris) of patient survival exceeding 6 months following human kidney transplantation, all but one after recipient cytoablation with total body irradiation (Table 1). Table 1 Kidney transplantation ≥ 6 months survival as of March 1963 The seventh recipient, treated in Boston by Murray, was unique in that the patient was immunosuppressed from the outset with daily doses of the 6-mercaptopurine derivative, azathioprine. 7 This therapeutic option, which evolved from the basic investigations in rodents by Schwartz and Dameshek,8,9 and of Meeker and Good et al.,l0 had been greeted initially with feverish enthusiasm, in part because it had been recognized that the strategy of cytoablation with total body irradiation would permit success in only occasional cases of human renal transplantation. The only evidence that this could be achieved in animals was the survival for 73 days of a beagle dog before dying of pneumonia reported by Mannick et al.11 However, this animal also had been given donor bone marrow and was suspected of having received the allograft from a closely related donor.12 The optimism generated by the new drugs was quickly dampened by the results of their preclinical studies by Caine13,14 and Zukoski15 with the outbred mongrel canine kidney transplant model in which only about 5% of the dogs survived for ≥ 100 days.16 In Murray’s clinical trials,16,17 survival did not appear at first to be substantially better than with irradiation. Patient 7 in Table 1 was the only one of the first ten in Murray’s clinical trial (two using 6-MP, eight with azathioprine) who had ≥ 6 months graft function. An overwhelming rate of patient death usually was caused by, or related to, infection. TABLE 1 Type of Transplant, Therapy and Infectious Pulmonary Disease. The dilemma, as it was perceived at the time, is shown in Figure 1. It was feared that chronic drug immunosuppression powerful enough to prevent organ allograft rejection would render the recipient hopelessly vulnerable to indigenous and environmental pathogens. It also was suspected that immune surveillance to tumours would be eroded, a possibility that ultimately was verified.18 At the nadir of the consequent pessimism in 1962–63, two reproducible observations were made at the University of Colorado (Denver) that shaped future developments in organ transplantation.19 Figure 1 The original caption for this figure: ‘Possible mechanisms of simultaneous loss of host reactivity to specific strains of endogenous bacteria, as well as to the alien renal tissue.’ (By permission of Surgery 56, 296, 1964). First in dogs and then in humans, kidney allograft rejection, which had been considered to be one of nature’s strongest reactions, was shown to be readily reversible by adding high doses of prednisone to baseline azathioprine therapy. More importantly, the allografts appeared to self induce tolerance.19 This was manifested by the ability in the Colorado live donor recipients to subsequently wean maintenance immunosuppression to doses below those which had failed at the outset to prevent rejection. Exploitation of these findings resulted in the first series of successful renal transplantations. Nine of the first ten patients had prolonged survival19 and four lived for > 25 years.20 Two of the four bear the longest surviving organ allografts in the world today (>35 years). These two patients, whose transplant operations were separated by a 9 day interval, have been without immunosuppressive drugs for 4 and 32 years, respectively. The early kidney experience triggered the first attempts in Colorado in 1963 to replace the liver,21 a clinical trial with baboon renal xenografts,22 and transplantation of the spleen for anti-tumour objectives,18 All of these cases were failures, as well as three others in which irreparably damaged cadaver kidneys were transplanted.23 accounting for almost half of the autopsies in the Hill–Rowlands–Rifkind report. In contrast, when the high rate of success of the double drug immune suppression (i.e. azathioprine/prednisone) in the live-donor kidney cases became known, a world wide proliferation of renal transplant centres occurred within the succeeding 12 months. Nevertheless the sober report of Hill, Rowlands and Rifkind gave warning that the concept depicted in Figure 1 was correct, at least in part. In this autopsy collection, infections for which specific antibiotics were available had been largely controlled, while opportunistic microorganisms of normally low pathogenicity were over-represented. Of these, CMV was the most common and lethal, presaging a problem that remains endemic today. Although Pneumocystis carinii was found at only one autopsy, its presence as a co-infection with CMV was soon to be reported separately by one of the authors (Rifkind et al.24), anticipating this combination of infectious agents in the AIDS epidemic that lay ahead.