American Journal of Hematology 5 : 5 5 - 6 2 (1978)
Adult Severe Combined Immunodeficiency and Sarcoid-Like Granulomas With Hypersplenism Alan D. Edelstein, Aaron Miller, Abraham P. Zimelman, Ross E. Rocklin, and Richard S. Neiman Medical and Pathology Services of the Boston Veterans Administration Hospital (A.D. E., R.S. N.), the Robert B. Brigham Hospital (R. E. R.) Boston University School of Medicine (A. D. E., A.M., A. P.Z., R.S. N.), and Harvard Medical School (R. E. R.)
A patient presented with lymphopenia, anergy, hypogammaglobulinemia and hypersplenism. Histologic examination of the spleen and lymph node revealed noncaseating sarcoid-like granulomas. Despite a significant rise in circulating lymphocytes after splenectomy there was in VIVO and in vitro evidence of B- and T-lymphocyte dysfunction. A histologic picture mimicking sarcoidosis may occur in patients with immune deficiency. ’The granulomatous proliferation may represent an altered host response t o antigen. Key words: anergy, hypogammaglobulinemia, lymphopenia, hypersplenisrn, sarcoid-like granuloma
INTRODUCTION
A patient with combined immunodeficiency and hypersplenism underwent splenectomy. A histopathologic diagnosis of “early sarcoidosis” was made. In view of the unusual association of this immune defect with sarcoid-like lesions and hypersplenism, the case will be presented in detail and the literature relative to these findings reviewed and discussed. Data on lymphocyte testing and function will also b e presented. CASE PRESENTATION
K.E., a 43-year-old male, had a history of multiple staphylococcal skin and pneumococcal respiratory infections over the past six years. In 1973, the patient was admitted t o another hospital with splenornegaly, axillary adenopathy, leukopenia (3,000-4,000/ cu nini) and thronibocytopenia (60,000- lOO,OOO/cu mm). Bone marrow and peripheral
Received for publication February 20, 1978; accepted May 23, 1978 Address reprint requests to Abraham P. Zimelman, MD, Dept of Medicine, Veterans Administration Hospital, 150 S Huntington Ave, Boston, MA 02130.
0361-8609/78/0501-055$01.70 0 1978 Alan R. Liss, Inc.
56
Edelstein et a1
smear were consistent with hypersplenism. A chest x-ray film revealed left apical scarring. A purified protein derivitive (PPD) and multiple sputa for acid-fast bacilli were negative. In April 1976 the patient’s overall clinical status had remained stable despite bacterial pneuinonias diagnosed on at least four occasions in the ensuing three years. The patient was admitted t o the Boston Veterans Administration Hospital for further evaluation. Family history revealed four sisters and two brothers alive and well. The patient was not married and was employed as a bookkeeper. He denied drug or chemical exposures and did not smoke nor drink alcohol. Positive physical findings on admission included wheezing and diffuse rhonchi, bilateral axillary and inguinal adenopathy, and a firm spleen, palpable 8 cm below the left costal margin. Laboratory data revealed: hematocrit 44%, reticulocytes 1.5%, white blood cells 3,400 Diff. 14B, 81P, 2L, 3M, platelets 69,000 cu mm. The prothrombin time, partial thromboplastin time, urinalysis, Australia antigen, antinuclear antibody (ANA), lupus erytheinatosus (LE) prep, latex fixation, VDRL, fungal titers for Aspergillus, blastomycosis, Candida, and histoplasmosis were all negative. A chest x-ray film showed left apical scarring, essentially unchanged from 1973. The peripheral smear continued to show leukopenia, with profound lymphopenia, and moderate thrombocytopenia with large platelets. Pulmonary function tests were normal except for a moderate reduction in the carbon monoxide diffusing capacity (DLCO) of 1 8 (predicted: 33). The patient also had a normal opthalmologic exam and normal 24-hour urinary calcium. Sputa for acid-fast organisms were negative. On May 27, 1976, the patient underwent a splenectomy. A wedge biopsy of the liver and multiple abdominal lymph node biopsies were also obtained. The protein electrophoresis revealed: Total protein 6.5 gm%, albumen 4.2 gm%, alpha-1 0.3 gm%, alpha-2 1 .O gm%, beta 0.7 gm%, gamma 0.2 gm%. Immunoglobulin electrophoresis revealed LgC 140 mg/dl; IgA and IgM were virtually undetectable. Im~nunoglobulin subgroups were as shown: IgG-1 1.35 mg/ml, lgG-2 0.17 mg/ml, IgC-3 0.36 mg/ml, lgC-4 0.009 mg/ml; complement CH-50, C-4, and C-3 were normal. Serum IgE was less than 5 IU/ml. Postsplenectomy white blood cell, platelet, and absolute lymphocyte counts returned to normal levels; lymphocyte typing was as shown in Table I. Repeated skin tests with streptokinase/streptodornase, intermediate and secondstrength PPD, Candida, mumps, and dinitrochlorobenzene were all negative and remained so after splenectomy.
PATHOLOGY DATA
The spleen weighed 920 gm and on cut section displayed prominent white pulp nodules. Histologic examination revealed an expansion o f the white pulp with proininent reactive germinal centers and wide marginal zones (Fig 1). The red pulp appeared unreTABLE I. Hematological and Immunological Findings Before and After Splenectomy
Total WBC / cu mm Platelet Lount / cu mm Lymphocyte count / cu m m % sheepLell rosettes % immunoglobulin coating % C-3 reLeptors
Pre-splenectomv
Post-sulcncctomv
Normal range
3,400 70,000 68
10,600 497,000 2,332 58 12 8
4,300-10,000 150,000 -350,000 1,500-4,000 45-80 10-55 10 35
Combined Immunodeficiency With Hypersplenism
57
markable with no evidence of widening of the pulp cords that might suggest splenic pooling or sequestration. Numerous noncaseating sarcoid-like granulomas were noted in relation t o the periarteriolar lymphoid sheath of the white pulp and in juxtaposition t o the central arteriole or its branches (Fig 1). In instances where the granulomas initially appeared t o be located in the red pulp, careful examination proved that they were intimately associated with the penicilliary arterioles, as terminal branches of the center arteriole with an attenuated cuff of the lymphoid sheath entering the red pulp (Fig 2). All lymph nodes examined contained both epitheloid and sarcoid-like granulomas that were located in the region o f the lymphatic sinuses (Fig 3). The cortical and paracortical lymphoid tissue appeared richly cellular but no cortical germinal centers were noted. The liver biopsy appeared histologically normal, with no granulomas noted. The bone marrow biopsy was hypercellular, with normal maturation of all three cell lines. No granulomas were seen. Special stains for fungal and protozoal organisms were negative. IMMUNOLOGY Methods
Production and assay for human macrophage inhibitory factor have been previously reported [ l 11 . The results were expressed as the percentage inhibition o f migration. Migration inhibition of 20% was calculated t o be significant activity. Lymphocyte proliferation data were obtained by culturing 2 X lo5 lymphocytes in TC-199 containing 15% AB serum with penicillin and streptomycin in quadruplicate in microtiter wells in 0.2-ml volumes with or without stimulant for three t o six days at 37°C
Fig 1. Section of spleen showing expanded white pulp with prominent germinal center (left); a large noncaseating granuloma is located adjacent t o it (right). Periodic acid-Schiff, magnification X 250.
58
Edelstein et al
Fig 2. Penicilliary artery in splenic red pulp. A sarcoid-like granuloma encompasses the vessel and replaces the lymphoid sheath. Periodic acid-Schiff, magnification X 400.
Pig 3. Section of lymph node showing lymphatic sinus filled with epithelioid cells (right); a noncaseating granuloma is present in the paracortical lymphoid tissue as well (left). Periodic acid-Schiff, magnification x 400.
in a carbon dioxide (55%) and air mixture. We added 1 iiiCi of H-thymidine (specific activity of 6.7 Ci/mmole, New England Nuclear, Boston) for the last 20 hours of incubation and deterinined incorporation of these precursors into cellular DNA b y liquid scintillation counting. Results were expressed as counts per minute incorporation of H-thytni-
Combined Immunodeficiency With Hypersplenism
59
dine and as a stimulation index (ratio o f antigen-stimulated cpm t o cpm without antigen). The antigen concentrations used were the same as those for the migration-inhibitory factor assay.
R es u Its Lymphocyte function in vitro was evaluated by lymphocyte proliferation and migration inhibitory factor (MIF) production in response t o mitogens and/or antigens. When tested on December 12, 1976, the patient’s lymphocytes proliferated in the low normal range (compared t o control) when exposed t o mitogens and gave comparable results four months later (Tables I1 and 111). However, the patient’s cells did not proliferate or produce MIF in response to streptokinase/streptodornase (SK-SD) or Candida on either occasion. The control subject responded t o at least one antigen at each testing. DISCUSSION
Noncaseating sarcoid-like granuloinata o f spleen and lymph nodes, identical to those originally noted in Hodgkiii disease [18] , were found in the present case. However, clinical and laboratory features of both sarcoidosis and Hodgkin disease were absent. On examination of the literature, it is apparent that lyniphoreticular hyperplasia and splenic granulomata indistinguishable from sarcoid can be found in idiopathic acquired hypogainrnaglobulinernia (IAH) [ 1, 21 . The pathogenesis o f this lesion is unclear but it can be presumed t o represent a response of the deficiently immune host t o continual antigenic stimulation. In a recent study of the incidence of sarcoid-like granulomas in a large nuinber of surgically removed spleens, one of us reported that these lesions occurred in some cases of sarcoidosis, Hodgkin disease, non-Hodgkin lymphoma, and chronic uremia, and in a single case of selective IgA deficiency with associated T-lymphocyte deficiency [ 161 . It is o f interest that these conditions are associated with either postulated or proven immunodeficiency [ 2 , 6 , 12, 15, 171. A number of interesting features pertaining t o our patient’s immunodeficiency were found. First, he was severely lymphopenic prior to splenectomy. Most cases of IAH are not lyniphopenic or are only moderately so [ 7 ] . With splenectomy, the lymphocyte count rose t o low normal levels with a normal distribution of B and T cells. This rise in lymphocyte count may represent a shift in distribution of circulating lymphocytes from spleen t o intravascular space [8]. A similar response in lytnpliocyte count has been noted in hereditary spherocytosis in patients subjected to splenectomy [ 9 ] . There is no mention of pre- and postsplenectomy lymphocyte counts in other reported cases of IAH with hyperspenism. Secondly, despite approximately normal numbers of B lymphocytes after splenectomy, the cells were severely deficient in their ability t o produce immunoglobulins, as seen in other cases of IAH [ 101 . In addition, despite normal numbers of T lyinphocytes, a severe defect in their function was also observed. Mild deficiency o f this immune parameter has been reported in some cases o f IAH, but usually in association with a debilitated clinical state. The latter was not true of our patient. We could only find two similar cases of total anergy in patients with IAH and granuloinata 14, l o ] . Studies o f lymphocyte typing or function were not available in both reports. Our patient had a normal proliferative response t o mitogens but abnormal proliferative and MIF responses t o antigens. These findings are consistent with an intrinsic cell defect and may be responsible for his cutaneous anergy. Such findings have been reported previously in patients with
12 669 (64)* 734 (79) 312 (58)
160 f 15 226 f 104 ( I ) 276 * 42 (1)
125 t 8,048 t 9,868 t 7,218 *
t
205 * 65 107 * 10 (1) 1,068 * 4 (5)
80 2,662 (985) 2,537 (237) 1,979 (253)
Control (DL)
134 k 131,980 t 31,749 f 33,872 k
12112176
SEM)
382 * 119 287 t 78 (1) 221 ? 87 (1)
130 i 10 59,101 f 699 (455) 27,634 f 1,120 (213) 12,664 ? 337 (97)
Patient
4% 2% 8%
4/18/77 Tuberculin PPD SK-SD Candida
*20% or greater indicates significant MIF activity
8% 3v>
12/12/76 SK-SD Candida
Patient
10% 22% 9%
4% 28%
Control (DL)
TABLE 111. Mieration Inhibitorv Factor (MIFI Production (% mieration inhibition)*
*Stimulation index : Mean cpm stimulated/Mean cpm unstimulated.
Candida
SK-SD
Antigens Unstimulated
Mitogens Unstimulated PHA Con A Pokeweed
Patient
TABLE 11. Lymphocyte Proliferation (mean cpm
180 t 40 576 t 314 (3) 197 t 49 (1)
36 16,571 (650) 1,822 (161) 1,716 (125)
Control (Hd)
209 t 135,771 t 33,694 i 26,201 i
4118177
Combined Immunodeficiency With Hyperspleiiism
61
sarcoidosis and Hodgkin disease [12, 131. It is also possible that increased suppressor cell activity could account for diminished cell-mediated immunity and/or antibody production [ 14, 151 . In any event, it would appear that our patient and the two other cases of adult combined imniunodeficiency [4, 91 niay represent a subgroup of IAH patients. Splenomegaly with hyperplenisin was also seen in this patient. Splenomegaly has been reported in 28% o f SO patients with IAH [ 3 ] . No mention o f hypersplenism was made in this group of patients, yet prior literature supports its occurrence in IAH. The original description of this association was that of Prasad and Koza [4] , who reported a case of an adult fernale with aganimaglobulinemia, hepatosplenoniegaly, hypersplenism, and anergy. However, there was no mention of the lymphocyte count prior to splenectomy and lymphocyte function data were not available at that time. As in our patient this individual remained anergic many months after splenectomy. In a subsequent paper, Prasad, Reiner, and Watson [S] presented another such case and reviewed approximately 20 other cases scattered throughout the literature. From these data, it appears that the lyinphoreticular hyperplasia seen in IAH may result in hypersplenism and indeed may be considered a potential complication of this disorder. Patients with IAH and combined immunodeficiency develop a wide range of neoplastic diseases [22] . The possibility o f a lyinphoproliferative disorder in our patient was initially entertained in view of the adenopathy, splenomegaly, and hypersplenism. Although defects in immunity have been observed in patients with lymphoma, profound hypogainmaglobulineniia is rarely seen in malignant lymphoma [ 6 ] . On the other hand, among patients with immunodeficiency, including IAH, malignant lymphoma is a common neoplasm [22] . In addition, a clinical spectrum of histocytic hyperplasia including granulomatous disease, as seen in our patient, Letterer-Siwe syndrome, and fatal histiocytosis niay also be seen [2, 19 --2 I ] . Thus, although no evidence of malignancy was found at laparotomy, our patient is still at great risk of developing neoplasia.
REFERENCES 1. Clinical Pathological Conference: N Engl J Med 268:204 (Case 6:204-213), 1963. 2. Rronsky D, Dunn YL: Sarcoidosis with hypogaininaglobulinemia. Am J Med Sci 250:45-52, 1965. 3. Ilermans PE, Diaz-Ruxo JA, Stobo JD: Idiopathic late-onset immunoglobulin deficiency. Am J Med 61:221-237, 1976. 4. Pasad AS, Koza DW: Aganimaglobulincmia Ann Int Med 41:629--638, 1954. 5. Prasad AS, Reiner E, Watson CJ : Syndrome of hypogammaglobulineniia, splenomcgaly and hypersplenism. Blood 12:926-937, 1957. 6. Jones SE, Griffith K , Dombrowski P, Gaincs JA: Immunodeficiency in patients with nonHodgkin’s lymphomas. Blood 49 :335 --344, 1977. 7. Geha R , Schneeberger E, Merler 17, Kosen 1:: Heterogeneity of “acquired” or common variable agammaglobulinemia. N Engl J Med 291:l-6, 1974. 8. Bullock WE, Evans PE, Wyatt C, Vergamini S : Disturbances of lymphocyte circulation and mobilization in granulomatous disorders of the lymphoid system. Ann N Y Acad Sci 278: 19-28, 1976. 9. Schilling R F : Hereditary spherocytosis: A study of splenectomized persons. Sem Heniatol 13(3): 169-176, 1976. 10. Sharma OP, James DG : Hypogammaglobulinemia, depression of delayed type hypersensitivity and granuloma formation. Am Rev Rcsp Dis 104:228-231, 1971. 1 1. Sheffer AL, Rocklin RE, Goetzel EJ: lmmunologic components of hypersensitivity reactions to cromolyn sodium. N Engl J Med 293:1220-1224, 1975.
62
Edelstein e t a1
12. Rocklin PI’:, Shcffer AD Jr: Sarcoidosis: A clinical and in vitro immunologic study. In Schwnrz MR (ed) : “Proceeding of the Sixth Leucocyte Culture Conference.” New York: Academic, 1972, p 743. 13. Churchill WII, Rocklin RE, Moloney WC, David JR: In vitro evidence of normal lymphocyte function in some patients with Hodgkin’s disease and negative delayed cutaneous hypersensitivity. In “International Symposium on Hodgkin’s Disease.” National Cancer Institute Monograph, No. 36, 1973, p 99. 14. Ashcrson GL, Zembala M : Supressor T cells in cell-mediated immunity. Rr Med Bull 32:158164. 1976. 15. Sicgal FP, Siegal M, Good RA: Suppression of B-cell differentiation b y leukocytes from hypogarn~naglobulinemicpatients. J Clin Invest 58: 109-122, 1976. 16. Nieman RS: The incidence and importance of splenic sarcoid-like granulomas. Arch Pathol 101 : 518--521, 1977. 17. Neinian RS, Bischel M, Lukcs RJ: IIypersplenism in t h e uremic Iiemodialyzed patient: Pathology and proposed pathophysiologic rneclianisrns. Am J Clin Path 6 0 : 5 0 2 - 5 I I , 1973. 18. Kadin ME. Donaldson SS, Dorfman K : Isolated granulomas in Hodgkin’s disease. N Engl J Med 283:859-861, 1970. 19. Barth RF, Kliurana SK, Vergara GG, Lowinan JT : Rapidly fatal familial histiocytosis associated with cosinophilia and primary immunological deficiency. Lancet 2:503-506, 1972. 20. (Iederbaum SD. Niwnyama G , Stiehm I:R: Combined immunodeficiency presenting as the Letterer-Siwc Syndrome. J Pediatr 85:466-47 1, 1974. 2 1 . Hathaway WE, Githcns JH, Blackburn WR: Aplastic anemia, histiocytosis and erythrodernia in iinniunologically deficient children: Probable human runt discase. N Eng1 J Med 273:953-958, 1965. Waldmunn TA, Strobcr W,Blaesc RM: Immunodeficiency disease and malignancy. Ann Intern Mcd 77:605-628, 1972.
Adult Severe Combined Immunodeficiency and Sarcoid-Like Granulomas With Hypersplenism Alan D. Edelstein, Aaron Miller, Abraham P. Zimelman, Ross E. Rocklin, and Richard S. Neiman Medical and Pathology Services of the Boston Veterans Administration Hospital (A.D. E., R.S. N.), the Robert B. Brigham Hospital (R. E. R.) Boston University School of Medicine (A. D. E., A.M., A. P.Z., R.S. N.), and Harvard Medical School (R. E. R.)
A patient presented with lymphopenia, anergy, hypogammaglobulinemia and hypersplenism. Histologic examination of the spleen and lymph node revealed noncaseating sarcoid-like granulomas. Despite a significant rise in circulating lymphocytes after splenectomy there was in VIVO and in vitro evidence of B- and T-lymphocyte dysfunction. A histologic picture mimicking sarcoidosis may occur in patients with immune deficiency. ’The granulomatous proliferation may represent an altered host response t o antigen. Key words: anergy, hypogammaglobulinemia, lymphopenia, hypersplenisrn, sarcoid-like granuloma
INTRODUCTION
A patient with combined immunodeficiency and hypersplenism underwent splenectomy. A histopathologic diagnosis of “early sarcoidosis” was made. In view of the unusual association of this immune defect with sarcoid-like lesions and hypersplenism, the case will be presented in detail and the literature relative to these findings reviewed and discussed. Data on lymphocyte testing and function will also b e presented. CASE PRESENTATION
K.E., a 43-year-old male, had a history of multiple staphylococcal skin and pneumococcal respiratory infections over the past six years. In 1973, the patient was admitted t o another hospital with splenornegaly, axillary adenopathy, leukopenia (3,000-4,000/ cu nini) and thronibocytopenia (60,000- lOO,OOO/cu mm). Bone marrow and peripheral
Received for publication February 20, 1978; accepted May 23, 1978 Address reprint requests to Abraham P. Zimelman, MD, Dept of Medicine, Veterans Administration Hospital, 150 S Huntington Ave, Boston, MA 02130.
0361-8609/78/0501-055$01.70 0 1978 Alan R. Liss, Inc.
56
Edelstein et a1
smear were consistent with hypersplenism. A chest x-ray film revealed left apical scarring. A purified protein derivitive (PPD) and multiple sputa for acid-fast bacilli were negative. In April 1976 the patient’s overall clinical status had remained stable despite bacterial pneuinonias diagnosed on at least four occasions in the ensuing three years. The patient was admitted t o the Boston Veterans Administration Hospital for further evaluation. Family history revealed four sisters and two brothers alive and well. The patient was not married and was employed as a bookkeeper. He denied drug or chemical exposures and did not smoke nor drink alcohol. Positive physical findings on admission included wheezing and diffuse rhonchi, bilateral axillary and inguinal adenopathy, and a firm spleen, palpable 8 cm below the left costal margin. Laboratory data revealed: hematocrit 44%, reticulocytes 1.5%, white blood cells 3,400 Diff. 14B, 81P, 2L, 3M, platelets 69,000 cu mm. The prothrombin time, partial thromboplastin time, urinalysis, Australia antigen, antinuclear antibody (ANA), lupus erytheinatosus (LE) prep, latex fixation, VDRL, fungal titers for Aspergillus, blastomycosis, Candida, and histoplasmosis were all negative. A chest x-ray film showed left apical scarring, essentially unchanged from 1973. The peripheral smear continued to show leukopenia, with profound lymphopenia, and moderate thrombocytopenia with large platelets. Pulmonary function tests were normal except for a moderate reduction in the carbon monoxide diffusing capacity (DLCO) of 1 8 (predicted: 33). The patient also had a normal opthalmologic exam and normal 24-hour urinary calcium. Sputa for acid-fast organisms were negative. On May 27, 1976, the patient underwent a splenectomy. A wedge biopsy of the liver and multiple abdominal lymph node biopsies were also obtained. The protein electrophoresis revealed: Total protein 6.5 gm%, albumen 4.2 gm%, alpha-1 0.3 gm%, alpha-2 1 .O gm%, beta 0.7 gm%, gamma 0.2 gm%. Immunoglobulin electrophoresis revealed LgC 140 mg/dl; IgA and IgM were virtually undetectable. Im~nunoglobulin subgroups were as shown: IgG-1 1.35 mg/ml, lgG-2 0.17 mg/ml, IgC-3 0.36 mg/ml, lgC-4 0.009 mg/ml; complement CH-50, C-4, and C-3 were normal. Serum IgE was less than 5 IU/ml. Postsplenectomy white blood cell, platelet, and absolute lymphocyte counts returned to normal levels; lymphocyte typing was as shown in Table I. Repeated skin tests with streptokinase/streptodornase, intermediate and secondstrength PPD, Candida, mumps, and dinitrochlorobenzene were all negative and remained so after splenectomy.
PATHOLOGY DATA
The spleen weighed 920 gm and on cut section displayed prominent white pulp nodules. Histologic examination revealed an expansion o f the white pulp with proininent reactive germinal centers and wide marginal zones (Fig 1). The red pulp appeared unreTABLE I. Hematological and Immunological Findings Before and After Splenectomy
Total WBC / cu mm Platelet Lount / cu mm Lymphocyte count / cu m m % sheepLell rosettes % immunoglobulin coating % C-3 reLeptors
Pre-splenectomv
Post-sulcncctomv
Normal range
3,400 70,000 68
10,600 497,000 2,332 58 12 8
4,300-10,000 150,000 -350,000 1,500-4,000 45-80 10-55 10 35
Combined Immunodeficiency With Hypersplenism
57
markable with no evidence of widening of the pulp cords that might suggest splenic pooling or sequestration. Numerous noncaseating sarcoid-like granulomas were noted in relation t o the periarteriolar lymphoid sheath of the white pulp and in juxtaposition t o the central arteriole or its branches (Fig 1). In instances where the granulomas initially appeared t o be located in the red pulp, careful examination proved that they were intimately associated with the penicilliary arterioles, as terminal branches of the center arteriole with an attenuated cuff of the lymphoid sheath entering the red pulp (Fig 2). All lymph nodes examined contained both epitheloid and sarcoid-like granulomas that were located in the region o f the lymphatic sinuses (Fig 3). The cortical and paracortical lymphoid tissue appeared richly cellular but no cortical germinal centers were noted. The liver biopsy appeared histologically normal, with no granulomas noted. The bone marrow biopsy was hypercellular, with normal maturation of all three cell lines. No granulomas were seen. Special stains for fungal and protozoal organisms were negative. IMMUNOLOGY Methods
Production and assay for human macrophage inhibitory factor have been previously reported [ l 11 . The results were expressed as the percentage inhibition o f migration. Migration inhibition of 20% was calculated t o be significant activity. Lymphocyte proliferation data were obtained by culturing 2 X lo5 lymphocytes in TC-199 containing 15% AB serum with penicillin and streptomycin in quadruplicate in microtiter wells in 0.2-ml volumes with or without stimulant for three t o six days at 37°C
Fig 1. Section of spleen showing expanded white pulp with prominent germinal center (left); a large noncaseating granuloma is located adjacent t o it (right). Periodic acid-Schiff, magnification X 250.
58
Edelstein et al
Fig 2. Penicilliary artery in splenic red pulp. A sarcoid-like granuloma encompasses the vessel and replaces the lymphoid sheath. Periodic acid-Schiff, magnification X 400.
Pig 3. Section of lymph node showing lymphatic sinus filled with epithelioid cells (right); a noncaseating granuloma is present in the paracortical lymphoid tissue as well (left). Periodic acid-Schiff, magnification x 400.
in a carbon dioxide (55%) and air mixture. We added 1 iiiCi of H-thymidine (specific activity of 6.7 Ci/mmole, New England Nuclear, Boston) for the last 20 hours of incubation and deterinined incorporation of these precursors into cellular DNA b y liquid scintillation counting. Results were expressed as counts per minute incorporation of H-thytni-
Combined Immunodeficiency With Hypersplenism
59
dine and as a stimulation index (ratio o f antigen-stimulated cpm t o cpm without antigen). The antigen concentrations used were the same as those for the migration-inhibitory factor assay.
R es u Its Lymphocyte function in vitro was evaluated by lymphocyte proliferation and migration inhibitory factor (MIF) production in response t o mitogens and/or antigens. When tested on December 12, 1976, the patient’s lymphocytes proliferated in the low normal range (compared t o control) when exposed t o mitogens and gave comparable results four months later (Tables I1 and 111). However, the patient’s cells did not proliferate or produce MIF in response to streptokinase/streptodornase (SK-SD) or Candida on either occasion. The control subject responded t o at least one antigen at each testing. DISCUSSION
Noncaseating sarcoid-like granuloinata o f spleen and lymph nodes, identical to those originally noted in Hodgkiii disease [18] , were found in the present case. However, clinical and laboratory features of both sarcoidosis and Hodgkin disease were absent. On examination of the literature, it is apparent that lyniphoreticular hyperplasia and splenic granulomata indistinguishable from sarcoid can be found in idiopathic acquired hypogainrnaglobulinernia (IAH) [ 1, 21 . The pathogenesis o f this lesion is unclear but it can be presumed t o represent a response of the deficiently immune host t o continual antigenic stimulation. In a recent study of the incidence of sarcoid-like granulomas in a large nuinber of surgically removed spleens, one of us reported that these lesions occurred in some cases of sarcoidosis, Hodgkin disease, non-Hodgkin lymphoma, and chronic uremia, and in a single case of selective IgA deficiency with associated T-lymphocyte deficiency [ 161 . It is o f interest that these conditions are associated with either postulated or proven immunodeficiency [ 2 , 6 , 12, 15, 171. A number of interesting features pertaining t o our patient’s immunodeficiency were found. First, he was severely lymphopenic prior to splenectomy. Most cases of IAH are not lyniphopenic or are only moderately so [ 7 ] . With splenectomy, the lymphocyte count rose t o low normal levels with a normal distribution of B and T cells. This rise in lymphocyte count may represent a shift in distribution of circulating lymphocytes from spleen t o intravascular space [8]. A similar response in lytnpliocyte count has been noted in hereditary spherocytosis in patients subjected to splenectomy [ 9 ] . There is no mention of pre- and postsplenectomy lymphocyte counts in other reported cases of IAH with hyperspenism. Secondly, despite approximately normal numbers of B lymphocytes after splenectomy, the cells were severely deficient in their ability t o produce immunoglobulins, as seen in other cases of IAH [ 101 . In addition, despite normal numbers of T lyinphocytes, a severe defect in their function was also observed. Mild deficiency o f this immune parameter has been reported in some cases o f IAH, but usually in association with a debilitated clinical state. The latter was not true of our patient. We could only find two similar cases of total anergy in patients with IAH and granuloinata 14, l o ] . Studies o f lymphocyte typing or function were not available in both reports. Our patient had a normal proliferative response t o mitogens but abnormal proliferative and MIF responses t o antigens. These findings are consistent with an intrinsic cell defect and may be responsible for his cutaneous anergy. Such findings have been reported previously in patients with
12 669 (64)* 734 (79) 312 (58)
160 f 15 226 f 104 ( I ) 276 * 42 (1)
125 t 8,048 t 9,868 t 7,218 *
t
205 * 65 107 * 10 (1) 1,068 * 4 (5)
80 2,662 (985) 2,537 (237) 1,979 (253)
Control (DL)
134 k 131,980 t 31,749 f 33,872 k
12112176
SEM)
382 * 119 287 t 78 (1) 221 ? 87 (1)
130 i 10 59,101 f 699 (455) 27,634 f 1,120 (213) 12,664 ? 337 (97)
Patient
4% 2% 8%
4/18/77 Tuberculin PPD SK-SD Candida
*20% or greater indicates significant MIF activity
8% 3v>
12/12/76 SK-SD Candida
Patient
10% 22% 9%
4% 28%
Control (DL)
TABLE 111. Mieration Inhibitorv Factor (MIFI Production (% mieration inhibition)*
*Stimulation index : Mean cpm stimulated/Mean cpm unstimulated.
Candida
SK-SD
Antigens Unstimulated
Mitogens Unstimulated PHA Con A Pokeweed
Patient
TABLE 11. Lymphocyte Proliferation (mean cpm
180 t 40 576 t 314 (3) 197 t 49 (1)
36 16,571 (650) 1,822 (161) 1,716 (125)
Control (Hd)
209 t 135,771 t 33,694 i 26,201 i
4118177
Combined Immunodeficiency With Hyperspleiiism
61
sarcoidosis and Hodgkin disease [12, 131. It is also possible that increased suppressor cell activity could account for diminished cell-mediated immunity and/or antibody production [ 14, 151 . In any event, it would appear that our patient and the two other cases of adult combined imniunodeficiency [4, 91 niay represent a subgroup of IAH patients. Splenomegaly with hyperplenisin was also seen in this patient. Splenomegaly has been reported in 28% o f SO patients with IAH [ 3 ] . No mention o f hypersplenism was made in this group of patients, yet prior literature supports its occurrence in IAH. The original description of this association was that of Prasad and Koza [4] , who reported a case of an adult fernale with aganimaglobulinemia, hepatosplenoniegaly, hypersplenism, and anergy. However, there was no mention of the lymphocyte count prior to splenectomy and lymphocyte function data were not available at that time. As in our patient this individual remained anergic many months after splenectomy. In a subsequent paper, Prasad, Reiner, and Watson [S] presented another such case and reviewed approximately 20 other cases scattered throughout the literature. From these data, it appears that the lyinphoreticular hyperplasia seen in IAH may result in hypersplenism and indeed may be considered a potential complication of this disorder. Patients with IAH and combined immunodeficiency develop a wide range of neoplastic diseases [22] . The possibility o f a lyinphoproliferative disorder in our patient was initially entertained in view of the adenopathy, splenomegaly, and hypersplenism. Although defects in immunity have been observed in patients with lymphoma, profound hypogainmaglobulineniia is rarely seen in malignant lymphoma [ 6 ] . On the other hand, among patients with immunodeficiency, including IAH, malignant lymphoma is a common neoplasm [22] . In addition, a clinical spectrum of histocytic hyperplasia including granulomatous disease, as seen in our patient, Letterer-Siwe syndrome, and fatal histiocytosis niay also be seen [2, 19 --2 I ] . Thus, although no evidence of malignancy was found at laparotomy, our patient is still at great risk of developing neoplasia.
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12. Rocklin PI’:, Shcffer AD Jr: Sarcoidosis: A clinical and in vitro immunologic study. In Schwnrz MR (ed) : “Proceeding of the Sixth Leucocyte Culture Conference.” New York: Academic, 1972, p 743. 13. Churchill WII, Rocklin RE, Moloney WC, David JR: In vitro evidence of normal lymphocyte function in some patients with Hodgkin’s disease and negative delayed cutaneous hypersensitivity. In “International Symposium on Hodgkin’s Disease.” National Cancer Institute Monograph, No. 36, 1973, p 99. 14. Ashcrson GL, Zembala M : Supressor T cells in cell-mediated immunity. Rr Med Bull 32:158164. 1976. 15. Sicgal FP, Siegal M, Good RA: Suppression of B-cell differentiation b y leukocytes from hypogarn~naglobulinemicpatients. J Clin Invest 58: 109-122, 1976. 16. Nieman RS: The incidence and importance of splenic sarcoid-like granulomas. Arch Pathol 101 : 518--521, 1977. 17. Neinian RS, Bischel M, Lukcs RJ: IIypersplenism in t h e uremic Iiemodialyzed patient: Pathology and proposed pathophysiologic rneclianisrns. Am J Clin Path 6 0 : 5 0 2 - 5 I I , 1973. 18. Kadin ME. Donaldson SS, Dorfman K : Isolated granulomas in Hodgkin’s disease. N Engl J Med 283:859-861, 1970. 19. Barth RF, Kliurana SK, Vergara GG, Lowinan JT : Rapidly fatal familial histiocytosis associated with cosinophilia and primary immunological deficiency. Lancet 2:503-506, 1972. 20. (Iederbaum SD. Niwnyama G , Stiehm I:R: Combined immunodeficiency presenting as the Letterer-Siwc Syndrome. J Pediatr 85:466-47 1, 1974. 2 1 . Hathaway WE, Githcns JH, Blackburn WR: Aplastic anemia, histiocytosis and erythrodernia in iinniunologically deficient children: Probable human runt discase. N Eng1 J Med 273:953-958, 1965. Waldmunn TA, Strobcr W,Blaesc RM: Immunodeficiency disease and malignancy. Ann Intern Mcd 77:605-628, 1972.
