Document R2BBVYq05rQgmMa67BjbY7RD8

Canad. Med. Ass. .* Aug. 23, 1969, vol. 101 nic reviewed 130 patients over a 16-year period and showed a 48% five-year survival rate for those treated with ACTH or corticosteroid therapy compared with only 13% for untreated patients. These results agree with those reported by the British Medical Research Council12 but differ somewhat from the opinion expressed by Rupe.13 It is also interesting to note that in 4 of the 18 cases of necrotizing vasculitis reviewed by Owano and Sueper3 there was involvement of veins as well as of small arteries and arterioles. The author wishes to thank Drs. F. I. Rounthwaite, R. E. Greenway and M. S. Smout for their 'help in publishing these two oases. CASE REPORTS: HODGKIN'S DISEASE 231 REFERENCES 1. BEESON, P. B. AND MCDERMOTT, W., editors: CecilLoeb textbook of medicine, vol. 1, 12th ed., W. B. Saunders Company, Philadelphia, 1967, pp. 461 and 462. 2. KUssMAuL, A. AND MAIER, R.: Dtsch. Arch. Kim. Med., 1: 484, 1866. 3. OWANO, L. R. AND SUEPER, R. H.: Amer. J. Olin. Path, 40: 527, 1963. 4. KLINGE, F.: Bestr. Path. Anat., 83: 185. 1929. 5. MELLORS, R. C. AND ORTEGA, I,. G.: Amer. J. Path., 32: 455, 1956. 6. METE, W.: Beitr. Path. Anat., 88: 17, 1931. 7. PARONETTO, F. AND STRAuss, L.: Ann. Intern. Med., 56: 289, 1962. 8. ZEEK, P. M.: New Eng. ,T. Med., 248: 764, 1952. 9. Idem: Amer. J. Olin. Path., 22: 777, 1952. 10. BEEsON, P. B. AND MCDERMOTT, W.: CeCil-Loeb text- book of medicine, vol. 1, 12th ed., W. B. Saunders Company, Philadelphia, 1967, p. 460. 11. FRONNERT, P. P. AND SHEPs, S. G.: Amer. J. Med., 43: 8, 1967. 12. Great Britain, Medical Research Council, Collagen Diseases and Hypersensitivity Panel: Brit. Med. J., 1: 1399, 1960. 13. RUPE, C. E.: Mod. Treatm., 3: 1280. 1966. Hodgkin's Disease Complicated by Infection with Mycobacterium kansasu JULES HARRIS, M.D., F.R.C.P.[C], F.A.C.P.,* RAYMOND ALEXANIAN, M.D., EVAN M. HERSH, M.D. and WILLIAM LEARY, M.D., F.A.C.P., Houston, Texas, U.S.A. P ATIENTS with Hodgkin's disease have an increased incidence of tuberculosis. This was recognized by Ewing1 in 1940: ". .. in New York, where the disease is very common, tuberculosis follows Hodgkin's disease like a shadow". In 1947 Jackson and Parker2 cited a 20% incidence of active tuberculosis in patients with Hodgkin's disease. In 1959, Razis, Diamond and Craver2 reported 20 cases of tuberculosis in a series of 1024 patients with Hodgkin's disease seen at The Memorial Hospital in New York, an incidence of 1.8%. Evidence of tuberculosis was found in 12 (5.1%) of 234 autopsies in that senes. The report below describes the first case of Hodgkin's disease complicated by pulmonary infection with Mycobacterium kansa&ii. In November 1959, G.W., a 51-year-old white man, complained to his family physician of fatigue. weight loss and fever. Physical examination revealed enlarged axillary and anterior and posterior cervical From the Departments of Developmental Therapeutics and Medicine, The University of Texas M. D. Anderson Hospital and Tumor *Assistant Professor oIfnsMtietduitcei,neH,ouDsetpoanr.tmTeexnats,ofU.DSe.vAe.lop- mental Therapeutics, The University of Texas M. D. Anderson Hospital and Tumor Institute. Reprint requests to: Dr. J. E. Harris, Faculty of Medicine, University of Ottawa, Ottawa General Hospital, Ottawa 2, Ontario. lymph nodes. A chest radiograph showed hilar lymphadenopathy. In December 1959, Hodgkin's granuloma was diagnosed from a cervical node biopsy. The patient was treated with nitrogen mustard and a complete clinical remission of the disease followed. In July 1960, palpable nodes were found in the left cervical, left axillary and both inguinal regions. After radiotherapy there was an- other complete remission. In November 1960 and again in March 1962, enlargement of the lymph nodes recurred in the same areas but disappeared after additional treatment with nitrogen mustard. In February 1963, local radiotherapy was successful in the treatment of enlarged nodes in the right cervical and in both axillary areas. In August 1963, the patient was referred to our hospital with symptoms of fever, night sweats, nausea and vomiting. Physical examination showed enlarged left posterior cervical nodes and left axillary nodes. The oral temperature was 1030 F. The hemoglobin was 13.6 g. per 100 ml.; the leukocyte count was 2800 and the platelet count was 106,000 per c.mm. A lymphangiogram was normal. The patient was given cyclophosphamide 100 mg. daily. All symptoms and clinical evidence of disease disappeared. In June 1964 a spontaneous left pneuxnothorax developed; this was successfully managed by closed suction of the pleural cavity. His disease remained in complete remission while he was receiving cyclophosphamide (75 to 150 mg. daily, depending on the leukocyte count) until August 1964. 232 Case Reports: Hodgkin's Disease Canad. Med. Ass. J. Augr. 23, 1969, vol. 101 Then the patient developed fever, nausea and vomiting, and lost 10 lbs. Enlarged nodes were found in the right axilla and in both inguinal areas. Liver function tests were reported as abnormal. A chest radiograph showed right middle-lobe pneu monia. The patient was admitted to hospital and his pneumonia successfully treated with penicillin. A liver biopsy revealed Hodgkin's granuloma. Cyclophosphamide was discontinued and the pa tient was given vinblastine sulfate (Vincaleucoblastine) 10 mg. weekly; once more, all clinical and laboratory evidence of Hodgkin's disease dis appeared. This drug was then given only once a month and the patient continued in remission. In December 1964 he developed herpes zoster in volving the right fifth cranial nerve; this resolved without sequelae. In November 1965 a recurrence of the right middle lobe pneumonia was again successfully treated with penicillin, as was yet another recurrence in March 1966. A routine chest radiograph in January 1968, at a time when the patient was asymptomatic and with no clinical evi dence of disease, showed bilateral apical cavitating and infiltrative lesions. Treatment with para-amino- salicylic acid and isoniazid was begun at once. No acid-fast bacilli were seen in repeated smears of sputum specimens. However, after four weeks, cultures of sputum specimens grew atypical acidfast organisms, identified as Mycobacterium kansasii. In vitro sensitivity tests showed resistance to iso niazid, para-aminosalicylic acid, streptomycin and viomycin, but sensitivity to ethionamide and cyclo- serine. The medications were changed to ethiona mide 250 mg. three times daily and cycloserine 250 mg. twice a day. There has been progressive resolution of the pulmonary lesions. Complete remission of the Hodgkin's disease continues; the patient is still receiving vinblastine sulfate, 10 mg. per month. Immunologic studies were first performed at a time when the Hodgkin's disease was in full clini cal remission and when there was progressive resolution of the patient's pulmonary acid-fast dis ease, i.e. one week after he had received the first monthly maintenance dose of vinblastine sulfate. Serum immunoglobulin levels determined by radial immunodiffusion gave values of IgG, IgA and IgM of 1350 mg. (normal: 650 to 1750), 140 mg. (normal: 75 to 330) and 41 mg. per 100 ml. (normal: 30 to 225), respectively. Electrophoresis of the serum proteins performed by the microcellulose acetate technique showed normal values for all fractions. The patient was immunized with 5 mg. of Key- hole limpet hemocyanin (KLH) given sub cutaneously one week after treatment with vin blastine sulfate. In man this antigen elicits delayed hypersensitivity and humoral antibody formation.6 It also stimulates in vitro lymphocyte blastogenesis in the cultured lymphocytes of immunized individuals.7 Antibody was measured by the tanned-cell hemag glutination method and the difference between 19S and 7S antibody distinguished by sensitivity to 2mercaptoethanol.6 The patient developed 19S anti- TABLE I..Humoral Antibody Formation* in Response to Keyhole Limpet Hemocyanin (KLH) Days after immunization 0 U 21 19S antibody 0 1 22 l (0) (4-4.5-5) (5-6-7) (-)t (0-2-7) 7S antibody 0 0 00 2 (0) (0-0-1) (0-0-1) (-)t (0-3-6) *Range for control population given in parentheses.8 Middle figure represents median. Titres are reported as log2 highest serial dilution showing macroscopic hemag glutination. tValues not obtained. body at seven days and switched over to 7S anti body formation at 28 days after immunization (Table I). This qualitative sequence followed a normal pattern.6* 8 However, the quantity of anti body produced was less than that in a control population. TABLE II..Skin Tests for Delayed Hypersensitivity to Purified Protein Derivatives of Mycobacterial Antigens Reaction at 48 hrs. (mm.) PPD-B* (non-chromogen "Battey" type). PPD-S* (mammalian tubercle bacilli).... PPPPDD--GYft (photochromogen). (scotochromogen). 8x 15 9 0x0 7x8 x 19 *Obtained from U.S. Public Health Service National Communicable Disease Center, Atlanta, Georgia. fObtained from U.S. Public Health Service Tubercu losis Research Department, Bethesda, Maryland. The result of testing with mycobacterial tuberculins is given in Table II. Each skin-test injection of 0.1 ml. contained 0.0001 mg. of tuberculin (puri fied protein derivative). The pattern of skin reactions is compatible with infection by photochromogens. Intradermal injections of 0.1 ml. of streptokinasestreptodornase (Varidase, Lederle, 100 units), Candida dilution 1:10 (Monilia Mix, Hollister-Stier Laboratories) and Dermatophytin "0" dilution 1:10 (Hollister-Stier Laboratories) at 48 hours showed redness and induration of 20 x 25 mm., 5x6 mm. and 5x5 mm., respectively. In response to intra dermal challenge with 100 /xg. KLH seven days after immunization the patient gave a normal re action of 8 x 6 mm.8 The in vitro lymphocyte blastogenesis response was measured by the method of Hersh and Harris.9 There was little response to phytohemagglutinin at 7 or 14 days after treatment with vinblastine sulfate (Table III). The response was also below the normal range when assessed at 21, 28 and 35 days after therapy. The patient's lymphocytes first responded in vitro to KLH seven days after im munization. There was a progressive rise in the re sponse during the 28-day period of evaluation which followed immunization. The responses were below the lower value of the ranges in normal controls. Canad. Med. Ass. J. Aug. 23, 1969, vol. 101 Case Reports: Hodgkin's Disease 233 TABLE III..In vitro Lymphocyte Blastogenesis* in Response to PHYTOHEMAGGLUTiNiNf and Keyhole Limpet Hemocyanin % Days after immunization 0 U 21 Phytohemag glutinin. ... 161.4 Kevhole Limpet Hemocyanin 78.9 (260-660-1400) 85.0 1097.2 (1400-1700-8200) 9994.6 643.4 (2000-5450-15,000) 29,277.4 8608.5 14,226.0 2869.2 (4400-9000-19,000) *Results of thymidine incorporation are expressed as counts per minute (cpm) per 106 lymphocytes. Values are those obtained after subtraction of thymidine incorporation in unstimulated control cultures. tMedian response of 106 lymphocytes to 0.05 ml. PHA is 3.5 x 105 cpm. Lower limit of response is 3 x 104 cpm.25 JMaximal response to antigen dose varying from 1 to 200 micrograms. Normal range of response given in parentheses.8 Middle figure represents median. The absolute peripheral lymphocyte count averaged 1388 per c.mm. over the period January 1967 to October 1968. It was never less than 700 c.mm. Discussion The declining incidence of tuberculosis in the general population and more effective manage ment of early Hodgkin's disease have combined to make tuberculosis-complicated Hodgkin's dis ease relatively rare. Casazza, Duvall and Car- bone4 found only one case of tuberculosis in 51 patients with Hodgkin's disease who came to autopsy. In the period 1944-1967, 768 patients with Hodgkin's disease were seen at our insti tution. Four of these patients developed tubercu losis during the course of their illness.an in cidence of 0.5%; only one of these had proved reactivation of old tuberculosis. Ten additional patients had an unquestionable history of pre vious tuberculous infection. Patients with Hodg kin's disease and a positive tuberculin skin test should receive prophylactic isoniazid.5 Clinicians will continue to suspect tuberculosis in patients with Hodgkin's disease where chest radiographs are suggestive, but the possibility always exists of a pulmonary infection due to atypical acidfast mycobacteria; these have been recognized in human disease since 1951.10 When it occurs, such pulmonary infection is indistinguishable clini cally, radiologically and pathologically from that caused by M. tuberculosis.11 The atypical myco bacteria are thought to be the cause in from 1 to 10% of patients considered to have tuberculosis.14 Extrapulmonary manifestations may occur with involvement of the lymph nodes,11 bones or joints.12 Disseminated disease may be associated with pancytopenia.13 The immunologic defect in Hodgkin's disease renders patients prone to infectious granulomatous disease.15 Complicat- ing infections occur late in the course of the disease because prolonged therapy and dis seminated disease have contributed to impair- ment of host defence. The identification of acid-fast bacilli in the sputum or gastric wash- ings of a patient with Hodgkin's disease, while clearly an indication for antituberculous chemo therapy, calls for vigorous attempts to identify the acid-fast organism by culture and to de termine in vitro drug sensitivities. Skin testing16 with tuberculins prepared from atypical myco bacteria may be of value. The atypical acid-fast bacilli are frequently resistant to the common antituberculous drugs, so that specific chemo therapy is important in a patient whose ability to resist infection is already seriously compromised. This patient's disease has remained in com plete remission for more than four years in response to maintenance therapy with vinblastine sulfate. This is longer than the seven-month median duration of objective response recently reported for this agent in Hodgkin's disease by Sohier, Wong and Aisenberg.17 But vinblastine sulfate is an immunosuppressive drug.18 The numerous infectious complications experienced by this patient may have been related to his chemotherapy. Evidence of impaired immune function in the intervals between therapy is provided by the patient's poor response to im munization with KLH. The patient developed normal in vivo delayed hypersensitivity in re sponse to this antigen. Established delayed hypersensitivity, as indicated by normal intracutaneous responses to tuberculin, streptokinasestreptodornase and fungal antigens, seemed also to be intact. Humoral antibody formation was less than in normal controls, and in vitro lympho cyte blastogenesis in response to antigen was abnormally low. Study of immune response to KLH in man has suggested that there is a cor relation between humoral antibody formation and in vitro lymphocyte blastogenesis in this system.8 This relationship does not hold between either of these two parameters of immune re sponse and in vivo delayed hypersensitivity. Another indication of impaired immunity was the poor response of the patient's lymphocytes to phytohemagglutinin (PHA). The exact signifi- 234 CASE REPORTS: HODGKIN'S DISEASECanad. Med. Ass. J.101 cance of PHA-induced in vitro lymphocyte blastogenesis is not clear, but the test has come to be accepted as a useful index of normal lymphocyte function.'9 Immediately after chemotherapy there was little detectable response to PHA, and while improved responses were obtained over the ensuing weeks of study, these remained below the normal range. We think that the impaired immune function in this patient is the result of chemotherapy. Additional contributing factors may have been involved. Immune function has been shown to decline with age,20 and when tested the patient was 60. The immune deficiency state characteristically seen in Hodgkin's disease is one of impaired delayed hypersensitivity.2' Some reports suggest that humoral antibody formation is also abnormal, but usually at a more ad- vanced stage of the disease.22 Although patients with Hodgkin's disease in complete remission have been shown to have normal immune function,23' 24 occasionally patients are seen in remission with both impaired delayed hypersensitivity and abnormal humoral antibody responses.24 This may be the result of extensive chemotherapy and radiotherapy. Such a consideration might apply in the case of the patient presented. Also, recurrent activation of Hodgkin's disease in this patient may have led to depletion of lymphocytes and exhaustion of immune capability. We acknowledge with thanks the co-operation of the Tuberculosis Unit of the Jefferson Davis Hospital, Houston, Texas, in providing facilities for tuberculin skin testing. We appreciate the useful advice and criticism of Drs. E. J. Freireich, Emil Frei and Elmer Koneman during the preparation of this paper. We thank Mrs. Lynne Rosson for preparation of the manuscript. REFERENCES 1. EWING, J.: Neoplastic diseases, 4th ed., W. B. Saunders Company, Philadelphia, 1940, p. 416. 2. JACKSON, H., JR. AND PARKER, F., JR.: Hodgkin's disease and allied disorders, Oxford University Press, New York, 1947. 3. R..zIs, D. V., DIAMOND, H. D. AND CRAvER, L. F.: Amer. J. Med. Sci., 238: 327, 1959. 4. CASAzzA, A. R., DUVALL, C. P. AND CARBONE, P. P.: Cancer Res., 26: 1290, 1966. 5. American Thoracic Society, Ad Hoc Committee on Chemoprophylaxis for the Prevention of Tuberculosis: Amer. Rev. Resp. Dis., 95: 558, 1967. 6. SWANSON, M. A. AND SCHWARTZ, R. S.: New Eng. J. Med., 277: 163, 1967. 7. HERSH, B. M., CURTIS, J. E. AND HARRIS, J. E.: Clin. Res., 16: 319, 1968. 8. CURTIS, J. B. et al.: Unpublished observations. 9. HERSH, B. M. AND HARRIS, J. E.: J. Immun., 100: 1184, 1968. 10. POLLAK, A. AND BUHLER, V. B.: Amer. J. Path., 27: 753, 1951 (abstract). 11. CURRY, F. J.: New Eng. .T. Med., 272: 415, 1965. 12. KLINENBERG, J. R., GRIMLEY. P. M. AND SEEGMILLER, J. B.: Ibid., 272: 190, 1965. 13. ZAMORANO. J., JR., AND TOMPSETT, R.: Arch. Intern. Med. (Chicago), 121: 424, 1968. 14. ELSTON, H. R. et al.: Ibid., 113: 365, 1964. 15. AISENBERG, A. C.: Medicine (Bait.), 43: 189, 1964. 16. CORPE, R. F., RUNYON, B. H. AND LESTER, W.: Amer. Rev. Resp. Dis., 87: 459, 1963. 17. SOHIER, W. D., JR.. WONG. H. K. L. AND AISENBERO, A. C.: Cancer, 22: 467. 1968. 18. AISENBERG. A. C. AND WILKES, B.: I. Clin. Invest., 43: 2394, 1964. 19. OPPENHEIM, J. J.: Fed. Proc., 27: 21, 1968. 20. WALDORF, D. S., WILLKENS. R. F. AND DECKER, J. L.: ,T. A. At. A., 203: 831. 1968. 21. SCHIER, W. W.: New Ena. J. Med., 250: 353. 1954. 22. CHASE, M. W.: Cancer Res.. 26: 1097, 1966. 23. HERSH, B. M. AND IRWIN, W. S.: Proc. Amer. Ass. Cancer Res., 7: 30, 1966. 24. HARRIS, J. B. AND HERSH, E. M.: Unpublished ob- servations. 25. HERSH, B. M., HARRIS, J. E. AND ROGERS, E.: J. 1w- mun. In press.