European Journal of

Europ. J. Pediat. 124, 207 216 (1977)

Pediatrics 9 by Springer-Verlag 1977

Immunodeficiency with Lymphoid Hyperplasia I. Mutz and W. St6gmann The Department of Pediatrics of the University of Graz (Director: Univ.-Prof. Dr~ E. Zweymuller), Auenbruggerplatz, A-8036 Graz, Austria

Abstract. A 2Y2-year-old boy presented with recurrent respiratory tract infections, generalized lymphadenopathy and hepatosplenomegaly. Immunologic evaluation revealed a deficiency of humoral immunity. Repeated lymph node biopsies during a 10-year follow-up constantly showed excessive follicular hyperplasia with huge germinal centers consisting of germinoblasts, but lacking plasma cells. The disease can be interpreted as a subtype of the common variable immunodeficiency in which the commutation of germinoblasts to plasma cells in the evolution of B cells is blocked.

Key words: Lymphadenopathy - Immunodeficiency - Common Variable immunodeficiency. Zusammenfassung. Es wird tiber einen zu Erkrankungsbeginn 21/2Jahre alten Knaben berichtet, der klinisch neben rezidivierenden Infekten eine generalisierte Lymphknotenschwellung und Hepatosplenomegalie aufweist. Immunologisch l~tl]t sich ein humoraler Immundefekt mit starker Verminderung der B-Zellen bei normaler Anzahl von T-Zellen nachweisen. Bei der Lymphknotenbiopsie findet sich eine exzessive follikulgre lymphatische Hyperplasie mit grogen floriden Keimzentren, in denen viele Germinoblasten und das Fehlen von Plasmazellen auffallen. Dieses Krankheitsbild wird als eine Form der common variable immunodeficiency diagnostiziert, der pathogenetisch ein Defekt der B-Lymphocytengerminoblasten (mit gest6rter Umschaltung in eine Plasmazellbildung bzw. in die Bildung von immunglobulinproduzierenden Zellen) zugrunde liegen dtirfte.

The immunologic deficiency disorders include congenital and acquired disorders of humoral immunity (B-cell function) or cell-mediated immunity (T-cell function). The most recent classification of immunodeficiencydisorders recommended by WHO still contains a largely unclassified group, the so-called common or

208

I. Mutz and W. St6gmann

variable immunodeficiency (= vlD) [2]. The heterogeneity of this group has been analyzed and at least four different types have been shown [7]. We describe here a patient whose disorder may represent a fifth type of vID. Case R e p o r t Herbert H. (hospital chart 60 674/67, 77 069/72, 82 009/73), born 10/31 / 64 the second child of healthy parents by uneventful delivery. Birth weight: 4150g. Length: 56em. Inconspicuous family history, two healthy siblings. Normal physical and mental development during infancy and early childhood. Immunization against diphtheria, pertussis and tetanus during 1st year of life, against smallpox in 2nd year without unusual reported reaction. Table 1. Patient H. H. Clinical findings July 1967 age 2 9/12 Otitis media Sinusitis Tonsillitis Bronchitis Pneumonitis Skin infection Diarrhea Lymph node hyperplasia Splenomegaly Hepatomegaly

February 1972 age 7 3/12

April 1973 age 8 6/12 yrs.

q-

+ + +

+

+ +

(+) (+)

++ + +

++

+(+)

++

-H-

+

+

+

+

(Removed)

+

+ +

Table 2. Patient H. H. Laboratory findings 07-i967 2 9/12

02-1972 7 3/I 2

04-1973 8 6 / 1 2 yrs.

6.03 6.18 6.0 Total protein g/100 ml 10,5 6.5 4,0 Gammaglobulins % 210 134 IgG mg/100 ml 16 0 IgA mg/100 ml IgM rag/100 ml 34 20 Plasma cells 0 0 in peripheral blood % 1 in bone marrow % 0.5 0 0 Lymphocytes 16 41 in peripheral blood % 55 1.5 5 10 in bone marrow % Leukocytes x 109/1 3.2 6.6 6.0 29 84 52 Granuloeytes % Eosinophils % 11 0 5 0 0 2 Monocytes % Erythrocytes ~ 1012/1 3.07 3.91 3.8 9.5 11.1 9.4 Hb g/100 ml 0,6 0.7 0.5 Reticulocytes % Thrombocytes x 109/1 312 134 210 Extreme follicular hyperpiasia Lymph node biopsy

209

Immunodeficiency with Lymphoid Hyperplasia Table 3. Patient H. H. Immunoglobulins 8-25-70 IgG mg/100ml 164 IgA mg/100 ml 0 IgM mg/100ml 20

3-9-71

2-26-72 7-12-73 1-17-74 9-2-74

Normal for age

142 0 18

210 16 34

1187_+289 147_+35 108_+37

142 0 18

164 0 26

139 18 26

Table 4. Patient H. H. Immunologic findings A) Humoral immunity: markedly impaired Recurrent sinusitis, bronchitis, diarrhea, skin infection Immunglobulins markedly diminished Plasma cells lacking B-lymphocytes diminished: (Determination by membrane fluorescence, normal: 20--27%a) Carrier of IgGAM: 11% IgM : 7% (subnormal) IgG : 5% (diminished) IgA : 0--1% (markedly diminished) ~-Isoagglutinins: very weakly positive Antistreptolysin-0 titer: negative C-reactive protein: negative (No heterolysins and -agglutinins) (Negative CBR of toxoplasmosis, cytomegaly, mononucleosis) B) Cellular immunity: normal No fungal infections, no abnormal frequency or severity of viral infections Normal number of lymphocytes in blood and bone marrow T-lymphocytes: 57% (normal) (Determination by E-rosette technique, normal: 50--70%a) DNCB test: positive Mumps skin test: positive (PPD skin test: negative--no BCG immunization) (Skin tests for candida and trichophytin negative) C) Auxiliary immunity: normal Nitrobluetetrazonium test: normal Complement C~ 94 mg/100 ml Stimulation of neutrophils (by etiocholanolon) normal a We are grateful to Dr. J. Fritz (Department of Dermatology of the University of Graz; Director: Prof. Dr. H. Kresbach) for these determinations

Hospitalization: Two weeks prior to first admission (July 1967) generalized lymphadenopathy was noted. Physical findings on admission (see also Table 1): 21/2-year-oldboy, Caucasian, no apparent distress, subfebrile temperature, painless generalized lymphadenopathy with marked enlargement (3--4 cm in diameter) of cervical and axillary nodes. Enlarged tonsils showed hyperemia and scarring. Patient had non-productive cough and rhonchi were heard over both lungs. Liver and spleen were palpable 2 cm below costal margin. X-ray studies revealed marked bilateral hilar lymphadenopathy and bilateral maxillary sinusitis. During hospitalization the boy had repeated episodes of skin infection and diarrhea. Laboratory findings (Table 2): Total white blood cell count between 2 and 4x 109/1, increased percentage of eosinophils (5--25%) thought to be due to nematode infestation because eggs of Trichiuris trichiura, Ascaris lumbricoides, Enterobius vermicularis were found in stool

210

I. Mutz and W. St6gmann

Fig. 1. Patient H. H. Lymph node biopsy: total germinal center (original magnification x 140, Giemsa stain; for description see text)

and on skin of perianal area. Number of platelets was slightly diminished; bone marrow did not contain pathologic cells. Total serum protein varied between 5.78 and 6.29 g/100 ml with normal electrophoresis and 7.6--14.5% gamma globulins (immun0globulins were not determined at this time), serum iron 71 ~zg/100 ml. Sabin~Feldman test for toxoplasmosis, Hanganutziu-Deicher reaction for infectious mononucleosis, complement fixation for tularemia, Wassermann reaction for syphilis, PPD skin test and antistreptolysin-0-titer were negative. 9Lymph node biopsy (left axilla) (examined by Prof. Dr. K. Lennert, Kiel): Extreme nodular lymphoid hyperplasia, no evidence for giant follicular (nodular) type of malignant lymphoma. Course of disease: No satisfactory diagnosis could be made. A trial of 16-methylprednisolone (2 mg/kg) was given for 9 weeks concomitantly with depot benzathin penicillin (1 200 000 U) every Other week and at random gamma globulin (5 ml, 16%) was administered i.m. twice. The lymphadenopathy vanished and the patient was discharged without further therapy. Regular follow-up (Table 1, also containing data from two later hospital admissions) showed normal mental and physical development, but slightly varying generalized lymphadenopathy and hepatosplenomegaly persisted. The patient encountered repeated episodes of tonsillitis, otitis media, maxillary sinusitis, bronchitis and bronchopneumonia. Chest x-ray showed 'marked bilateral hilar adenopathy as well as strikingly increased pulmonary markings at the lung bases. To rule out bronchiectasis, bronchography was performed in April 1973 and May 1974: both were normal. The inclination to diarrhea disappeared and a duodenal mueosal biopsy was normal in 1973. The patient went through mumps and chickenpox without complications and he was immunized against poliomyelitis in 1969/1970. The blood count (Table 2) constantly showed a moderate (slightly hypochromic) anemia, but normal white blood cell and platelet counts. Plasma cells were seen in t h e first bone marrow, but not thereafter; the number of lymphocytes in peripheral blood was always within normal limits. Six consecutive lymph node biopsies and examination of the removed tonsils revealed always exactly the same morphology of extreme nodular lymphoid hyperplasia without evidence of malignancy.

Immunodeficiency with Lymphoid Hyperplasia

211

Fig. 2. Patient H. H. Lymph node biopsy: upper and lower half of germinal center (original magnification x 350, Giemsa stain; for description see t e x t ) The clinical course aroused suspicion of an antibody deficiency syndrome which was confirmed by quantitation of the immunoglobulins in 1970 and thereafter. IgM, IgA and IgG were markedly below normal (Tables 2 and 3). Additional immunologic findings are shown in Table 4. These results demonstrate an isolated defect of humoral immunity. Normal cellmediated immunity was expected by the history of an uneventful course of measles, chickenpox,

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I. Mutz and W. St6gmann

and mumps as well as smallpox vaccination and life virus poliomyelitis immunization and the lack of a history of moniliasis. Another lymph node biopsy was sent to Prof. Dr. K. Lennert (Kiel) for immunologic evaluation: Morphology again showed extreme nodular lymphoid hyperplasia (Fig. 1). Within the germinal centers (Fig. 2) numerous germinoblasts (centroblasts), but few germinocytes (centrocytes) and only single PAS-negative plasmacytoid forms (with abnormally small cytoplasmatic rims) were seen. The medullary portions contained mostly lymphocytes, some basophilic stem cells, occasionally mast ceils, but no plasma cells. Touch preparations of the lymph node showed mainly medium size and large germinoblasts: typical plasma cells, especially reticular plasma cells, were not seen; however, single lymphoid plasma cells (proplasma cells) were found. Moreover typical macrophages, mast cells, and increased numbers of neutrophil and eosinophil granulocytes were seen. Electron microscopy confirmed the findings above mentioned: Germinoblasts preponderated in the germinal centers. Large germinoblastlike cells with rough endoplasmic reticulum (transition stage to plasmoblasts?) are very rare. Moreover a wretched form of plasma ceils with little endoplasmic reticulum could be found. Prof. Lennert also confirmed the decreased level of serum immunoglobulins: IgM 1/10th, IgA 1/5th, IgG 1/12th of normal values. Urine showed weak positive reaction for kappa and lambda chains (Behring antisera). Interpretation: immunodeficiency syndrome with maximum hyperplasia of lymph node germinal centers and impaired transition to plasma cells, which are almost lacking or hypoplastic. Since a diagnosis of immunodeficiency was made, treatment with gamma globulin was initiated (0.1 g/kg administered i.m. monthly). This treatment markedly reduced the lymphadenopathy as well as the hepatosplenomegaly and very few episodes of upper respiratory tract infections have since been encountered.

Comment. Initially we considered this case of immunodeficiency to be secondary to a hematologic or reticuloendothelial malignancy because of the generalized lymphadenopathy, hepatosplenomegaly and pancytopenia.The suspected diagnosis was n o d u l a r type of malignant l y m p h o m a . The course of the disease and repeated blood and bone m a r r o w examinations without signs of malignancy as well as seven consecutive l y m p h node biopsies over the years eliminated this possibility. Therefore the diagnosis of a primary immunodeficiency was made. A n a t t e m p t to classify this 'humoral immunodeficiency leads to the exclusion of selective i m m u n o g l o b u l i n deficiency, immunopathies with h y p e r g a m m a g l o b u linemia and transient h y p o g a m m a g l o b u ! i n e m i a . The diagnosis of X-linked a g a m m a g l o b u l i n e m i a (Bruton type) is Very unlikely because of the lack Of family history, late onset and hyperplastic 4 y m p h nodes with p r e d o m i n a n t germinal centers. O u r patient has most of the features of the so-called c o m m o n variable i m m u n o deficiency. This group contains various types which cannot be classified otherwise and show I g M , IgA, I g G h y p o g a m m a g l o b u l i n e m i a , onset of the disease after the 2nd year o f life, and no underlying disease. These disorders were also called "acquired" or "adult" or (best) "late onset" a g a m m a g l o b u l i n e m i a [7, 1 I, 13]. The immunodeficiency is not an entity in itself, but rather represents a heterogeneous g r o u p of immunodeficiency [4, 5, 7, 11]. A l t h o u g h in most cases no fixed hereditary pattern can be demonstrated, familiar oceurrence [3, 5] and X-linked transmission [10] have been reported. Similar to our patient, other case reports have shown increased susceptibility to bacterial infections, especially recurrent sinusitis and pneumonitis, occasion-

Immunodeficiency with Lymphoid Hyperplasia

213

Table 5. Immunodeficiency disorders L Primary immunopathies

A) Defects of humoral immunity 1. Transitory hypoimmunoglobulinemia of infancy 2. Infantile agammaglobulinemia (Bruton type) 3. Immunopathy with normo- or hyperimmunoglobulinemia 4. Immunopathy with hyper-IgM-emia 5. Selective IgM defect 6. Selective IgA defect 7. Common variable immunodeficiency (cvI) B) Defects of cellular immunity 1. Thymic hypoplasia (DiGeorge's syndrome) 2. Louis Bar syndrome 3. Wiskott-Aldrich syndrome 4. Nezelof's syndrome C) Combined defects i. Reticular dysgenesis 2. Swiss-type agammaglobulinemia D) Phagocytic defects Granulomatous disease, etc. E) Complement disorders Hereditary angioneurotic edema II. Secondary immunopathies

In leukemias, malignant lymphomas, nephrotic syndrome, etc.

ally diarrhea and steatorrhea, hepatosplenomegaly, and generalized lymphadenopathy [11]. Similar to the X-linked agammaglobulinemia no plasma ceils are found in the hyperplastie lymph nodes [11]. Lymph node hyperplasia in most cases is associated with an increased number of B cells [7]. Seligmann [12] was the first t o emphasize the important role of T and B cells in immunodeficiency disorders. The vID most frequently has normal or only slightly diminished numbers of T cells [7, 15, 16]. However, in vitro studies suggest that in some patients the vID may be caused or perpetuated by an abnormality of regulatory T cells which act to suppress B-cell maturation and antibody production [14]. The number of B cells in patients with vID may vary widely: they may be normal, greatly increased or markedly decreased [4, 6, 7, 9]. Our patient had a normal number of T cells (57%) and a diminished number of B cells (11%; 1). The heterogeneity of vID was investigated in 19 patients by Geha et al. [7] :4 patients had no demonstrable B cells, l0 had a normal number and 5 had increased numbers of B cells. The latter 5 patients suffered from generalized lymphadenopathy. Lymphocyte mitogenic factor stimulation of demonstrable B ceils in 15 patients resulted in production of immunoglobulins in 5 patients,

214

I. Mutz and W. St6gmann

Table 6. Possible localization of defect in patient H. H. and other antibody deficiencies Symptoms Ig

Examples Plasma cells

0 0 0 Swiss-type (With defect of cellular immunity) agammaglobulinemia 0 0 0 Bruton type (Without defect of cellular immunity) 0 0 0 (In serum)

Localization

Lymphocytes Stem-cells

0 n ++

++ n -++

B-lymphocyte germinoblasts Patient H.H. Plasma cells Cases of Geha et al.[7] Ig production

n-++

n-++

Cases of Geha et al. [7]

+

(In plasma cells)

Ig secretion

n=normal, '0=lacking, ++=increased, Ig=immunoglobulins

but without secretion by B cells; and no ,production of immunoglo, bulins in 9 patients; 1 patient'had an inhibitor of B-cell maturation. In summary the humoral immunodeficiency in these 19 patients had at least four different pathways: 1) lack of B cells; 2) non-production of immunoglobulins; 3) non-secretion of immunoglobulins; 4) inhibitory factor. In our patient we did not use B-lymphocyte stimulation by means of lymphocyte mitogenic.factor. In any rate, our patient belongs to the group with lack (or greatly diminished number) of B cells. In contrast tO the other cases with diminished numbers of B cells our patient had striking lymph node hyperplasia. Most likely this unusual finding may be caused by another (additional) disorder of the transition of B-cell precursors to mature (immunoglobulin-secreting) B cells. Of special interest in this context are the findings of the lymph node biopsies: The lymph node showed preservation of structure with extreme hyperplasia of the cortical follicles and their germinal centers. The germinalcenters contained very large numbers of germinoblasts, but few germinocytes and just single plasmacytoid forms, while plasma cells were lacking. These findings were confirmed by electron microscopy. In Table 6 we propose a classification to compare the immunodeficiency of our patient with the other types of B-cell deficiency: I) The Swiss type agammaglobulinemia affects the c o m m o n bone marrow-derived stem cell of T and B cells, and therefore also shows a lack of plasma cells [8]. 2) X-linked agammaglobulinemia has normal T cells. The disturbance does not affect the stem cell, b u t prevents the next step, which is development of B cell germinoblasts. 3) The cases with normal or increased numbers of B cells [7] have a defect of production or secretion of immunoglobulins respectively. Our patient showed a maturation arrest of B-cell germinoblasts preventing transition to germinocytes and immunoglobulin-secreting lymphocytes or plasma

Immunodeficiency with Lymphoid Hyperplasia

215

cells respectively. This m a y e x p l a i n the deficiency of i m m u n o g l o b u l i n s as well as the e x t r e m e increase in the n u m b e r of g e r m i n o b l a s t s which causes l y m p h n o d e h y p e r p l a s i a . A l t h o u g h the increase in the n u m b e r o f g e r m i n o b l a s t s m a y be seen a s an ineffective c o m p e n s a t i n g m e c h a n i s m this e x p l a n a t i o n seems highly speculative a n d a final classification r e m a i n s open. In a d d i t i o n to the f o u r possible v a r i a n t s o f v l D described [7] o u r p a t i e n t m a y have a n o t h e r (fifth) t y p e of v l D . This emphasizes the heterogeneity of B-cell deficiency a n d othe r patients m a y well show a d d i t i o n a l defects of the t r a n s i t i o n a n d m a t u r a t i o n to the i m m u n o g l o b u l i n - s e c r e t i n g m a t u r e B cell.

Acknowledgement. We are very grateful to Prof. Dr. K. Lennert, Director of the lymph node register at the German Society of Pathology, for his reports of the lymph node biopsies and for the permission to publish them, and to his co-worker Dr. T. Radaskiewicz for preparing the micrographs.

References ,1. Abdou, N. L., Alavi, J. B., Abdou,N. I.: Human bone marrow lymphocytes: B and T cell precursors and subpopulations. Blood 47, 423 430 (1976) 21 Cooper, M. D., Faulk, W. P., Fudenberg~ H. H., Good, R. A., Hitzig, W., Kunkel, H. G., Roitt, I. M., Rosen, F. S., Seligmann, M., Soothill, J. F., Wedgwood, R. J.: Meeting report of the second international workshop on primary immunodeficiency diseases in man. Clin. Immunol. Immunopathol. 2, 416--445 (1974) 3. Cruchard, A.. Robert, M., Girard, J. P.. Laperranza, C., Rivat, C., Ropartz, C.: Primary antibody deficiency syndrome of adult onset. Evidence for genetic transmission. Am. J. Med. 48, 515--523 (1970) 4. Dickler, H.. B., Adkinson, N. F., Fisher, R. I., Terry, W. D.: Lymphocytes in patients with variable immunodeficiency and panhypogarnmaglobulinemia. J. Clin. Invest. 53, 834--840 (1974) 5. Douglas, S. D., Goldberg, L. S., Fudenberg, H. H.: Clinical, serologic and leukocyte function studies on patients with idiopathic acquired agammaglobulinemia and their families. Am. J. Med. 48, 48--53 (1970) 6. Gajl-Peczalska, K. J., Park, B. H., Biggar, W. D., Good, R. A.: B and T lymphocytes in primary immunodeficieney disease in man. J. Clin. Invest. 52, 919--928 (1973) 7. Geha, R. S., Schneeberger, E., Merler, E., Rosen, F. S.: Heterogenity of acquired or common variable aggammaglobulinemia. New Engl. J. Med. 291, 1--6 (1974) 8. Hitzig, W. H.: Congenital thymic and lymphocytic deficiency disorders. In: Immunologic disorders in infants and children, 215--235. Ed. Stiehm E. R., Fulginiti. PhiladelphiaLondon-Toronto: Saunders 1973 9. Preudhomme, J. L., Griseelli, C., Seligmann, M.: Immunoglobulins on the surface of lymphocytes in fifty patients with primary immunodeficiency diseases. Clin. Immunol. Immunopathol. 1, 241--256 (1973) 10. Purtilo, D. T., Yang, J. P. S., Cassel, C. K., Harper, R.: X-linked recessive progressive combined variable immunodeficiency (Duncan's disease). Lancet 1975 I, 935--941 11. Rosen, F: S.: Immunological deficiency disease. In: Clinical immunobiology. Ed.: Bach F. H., Good R. A., Vol. I, 271 289. New York-London: Academic Press 1972 12. Seligmann, M., Preudhomme, J. L., Brouet, J. C., B and T cell markers in human proliferation blood diseases and primary immunodeficiencies. Transplant. Rev. 16, 85--113 (1973) 13. Stiehm, E. R., Fulginiti, V. A.: Immunologic disorders in infants and children. PhiladelphiaLondon-Toronto: Saunders 1973

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14. Waldmann, T. A., Broder, S., Blaese, R. M., Duma, M., Blackman, M., Strober, W.: Role of suppressor T cells in pathogenesis of common variable hypogammaglobulinemia. Lancet 1974 II, 609--613 15. Wybran, J., Levin, A. S., Spitler, L. E., Fudenberg, H. H.: Rosette forming cells, immunological diseases and transfer factor. New Engl. J. Med. 288, 710--713 (1973) 16. Wybran, J., Fudenberg, H. H.: How clinically useful is T and B cell quantitation. Ann. Intern. Med. 80, 765--767 (1974) Received February 25, 1976

Immunodeficiency with lymphoid hyperplasia.

European Journal of Europ. J. Pediat. 124, 207 216 (1977) Pediatrics 9 by Springer-Verlag 1977 Immunodeficiency with Lymphoid Hyperplasia I. Mutz a...
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