CASE OF PRIMARY IDIOPATHIC HYPOGAMMAGLOBULINAEMIA ... · MayI962 THOMPSONand SLEIGHJOHNSON:Primary Idiopathic HFypogammaglobulinaemia 293 EXPECTED NORMAL RED CELL SURVIVAL 90\_____.__PATIENTS

POSTGRAD. MED. J. (I962), 38, 292

Case Reports

A CASE OF PRIMARY IDIOPATHICHYPOGAMMAGLOBULINAEMIA ASSOCIATED WITH

HAEMOLYTIC ANAEMIAEILEEN N. THOMPSON, M.B., B.S. R. SLEIGH JOHNSON, M.D., M.R.C.P.

Medical Registrar Consultant PhysicianChelmnsford Hospital Group

DEFICIENCY in the gamma globulin content of theblood may be a congenital, and usually familial,abnormality, or acquired, and of the latter groupsome cases are primary or idiopathic, withoutdemonstrable cause, while others are secondary toa known disease, especially one affecting the bloodor reticulo-endothelial system. The case nowdescribed shows features of the primary acquiredtype, but with the rare accompaniment of ahemolytic anemia.

Case ReportA woman, aged 5i years, first seen in April 1959,

gave a history of four years' recurrent upper respiratoryinfections and two episodes of erysipelas, all respondingslowly to prolonged antibiotic therapy. Her previoushealth had been good and the family history unrelated.Two months before attending she had developed a severebilateral patchy bronchopneumonia, which respondedonly slightly and temporarily to antibiotics. A mildhypochromic aniemia with 71% hiemoglobin and normalleucocyte count was present at this time, but no bio-chemical investigations of the blood were then made.Despite a gradual lessening of symptoms and consolida-tion, fatigue and malaise persisted, with an early relapseof productive cough.

In September 1959 she was admitted to hospitalextremely ill from an exacerbation of chest infection,preceded for a month by intermittent pyrexia with rigors,cough and abundant creamy,purulent sputum. She wasthin, sallow and dyspnceic, with pale mucous membranesand finger clubbing, and showed clinical signs of ex-tensive pneumonia. X-ray examination confirmed asoft patchy consolidation involving all lobes, with prob-able early cavitation in both lower lobes (Fig. i). Sputumexamination was repeatedly negative for tubercle bacilliand fungus infection and showed a growth of penicillin-resistant H. influenzee and streptococcus pneumoniee.She was further noted on admission to have a firmenlargement of the liver i in. and of the spleen i J in.below the costal margin, with small discrete glands pal-pable in the neck, axillw and groins. Apart from theabove findings, clinical examination was negative.

Despite frequent changes of antibiotics, six in all,clinical improvement was slight and temporary and theradiological changes those of steady deterioration.Bronchiectatic cavitation increased, with secondaryinterstitial changes widely throughout the lung fields.In view of the repeated and resistant respiratory infec-tions, in conjunction with the hepato-splenomegaly, the

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FIG. I.-Postero-anterior X-ray film of chest, 29.9.59,showing widespread patchy broncho-pneumonicconsolidation.

possibility of hypogammaglobulinumia was consideredand appropriate investigations made for this and relatedstates.

InvestigationsInitial blood count: Hb 67%, r.b.c. 3,360,ooo/c.mm.,

normal appearance, with 4% of reticulocytes and normalblood platelets; w.b.c. 9,ooo/c.mm, 86% polymorphs,14% lymphocytes. E.S.R. (Westergren) 100 mm./hour.Blood urea normal; urine, only a trace of albumin;liver function tests normal. Daily faecal fat excretion,an average of 2.2 g. over a five days' observation,excluding a steatorrheea. Needle-biopsy of the liver,no abnormality; that of the sternal marrow showed anover-active erythropoiesis with marked increase ofnormoblast cells and slight iron deficiency; leuco-poiesis appeared normal and no plasma cells were seen.

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May I962 THOMPSON and SLEIGH JOHNSON: Primary Idiopathic HFypogammaglobulinaemia 293

'........... EXPECTED NORMAL RED CELL SURVIVAL

90\_____.__PATIENTS RED CELL SURVIVAL

80

70

< 60

a 50 FIG. 2.-Red-cell survival timeestimation, 1.3.60, showing in-

I \ .creased rate of destruction of- 40 transfused red blood cells.z) 30

a:CL 20

10

10 20 30 40 50 60 70 80 90 100 110 120D AYS

RED CELL SURVIVAL STUDY 13 60

The total serum protein content was low, 4.5 g./I00ml., with 2.8 g./ioo ml. albumin and 1.7 g./I00 ml.globulin. Paper electrophoresis showed a markeddeficiency of gammaglobulin, quantitative estimatessuggesting that this was less than 0.4 g./ioo ml. Thiswas confirmed by a salt-precipitation method (Wolfson,Cohn, Calvary and Thomas, 1948), which gave a resultof 0.2 g. gammaglobulin per ioo ml. (normal 0.7 to I.2g./ioo ml.). Neither of these methods gives an accuratequantitative result at low levels, but Dr. J. F. Soothill,using a specific immunochemical method, found in thispatient a gammaglobulin level of only 6o mg./ioo ml.,so proving the diagnosis of hypogammaglobulinemia.Biopsy of an enlarged axillary gland showed a markedfollicular hyperplasia, but no evidence of reticulosis.Mature plasma cells, thought to be responsible for theproduction of gammaglobulin, were not seen (Dr.K. A. D. Turk).Other tests were made to determine any related

deficiency of circulatory antibodies and impairedimmunological response. The patient's blood group wasA II Rhesus-negative, but no iso-agglutinins werepresent in undiluted serum. The Mantoux reaction(i in i,ooo dilution) had been positive in 1954, but wasnow negative at i in ioo dilution. The Widal reactionwas negative. After injection of I.25 ml. of T.A.B.vaccine there was a transient rise in the Salmonella typhiH. titre of i in i6o, but two weeks later all titres of thetest were less than i in io. The Schick test was positivebefore and after the giving of i ml. of T.A.F.During these investigations a persistent rise of the

reticulocyte count to between 4% and 6% was observed,and from the lack of evident blood loss and the splenicenlargement present this was suspected to be due tointravascular hxmolysis, with resultant anuemia. Thedirect Coombs' test, however, was negative and theosmotic fragility of the red blood cells was normal,while no rise was found in the serum-bilirubin content(less than o.s mg./ioo ml.), nor any excess of urobilin or

heemosiderin in the urine. As a more exact index ofhlemolysis, an estimation of the red cell survival timewas therefore made, using cells of a different, but com-patible, blood group. This test showed definite evidenceof an increased rate of destruction of the transfused cells(Fig. 2). The continuance of this hemolysis was con-firmed six months later, using a radioactive chromium-labelled red cell technique, by means of which themean red-cell life in this patient was then shown to beapproximately half of the normal red-cell span. Con-firmatory results were given also by an estimation of thefecal stercobilin excretion, which showed an increase to26 mg./24 hours/ioo g. of circulating heemoglobin(normal maximum stated to be 22 mg./24 hours/ioo g.),and of the serum haptoglobin, which was reduced to30 mg./Ioo ml. (normal 50 to 140 mg./ioo ml.); eachof these findings by the methods used being held toindicate the presence of intravascular heemolysis.The diagnosis of hypogammaglobulin-emia, indicated

by the extremely low content of this fraction in theplasma proteins, was thus supported by an absence ofiso-agglutinins and a typical lack of immunologicalresponse to the standard dose of T.A.B. and of diph-theria toxin. In this patient's case a congenital form of thedisease seemed excluded by the absence of illness inchildhood. Other conditions known to be associatedwith a secondary hypogammaglobulinemia, includingmyelomatosis, chronic lymphatic leukemia, nephrosis,amyloidosis, rheumatoid arthritis and reticulosis, wereexcluded, and the condition in this patient thereforeregarded as a primary acquired form of the disease. Thefour remaining siblings in the family were also investi-gated; in none was any abnormality detected on clinicalexamination or on plasma protein analysis and electro-phoresis.

Response to TreatmentAs customarily found, at no time did antibiotic

therapy on orthodox lines produce more than an in-

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294 POSTGRADUATE MEDICAL JOURNAL May I962

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FIG. 3.-Postero-anterior X-ray film of chest, 4.11.59,showing failure of response of broncho-pneumonicinfection to intensive antibiotic therapy.

complete and transient improvement, either clinically orradiologically (Fig. 3). Treatment with gammaglobulinwas therefore considered, and as the criteria of suitabilityunder the Medical Research Council's Trial Schemewere satisfied, including a fractional serum content of0.2 g./I00 ml. or less, she was accepted for treatment.This was begun on 30.11.59, giving after loading dosesan average of 0.025 g./kg. body weight by weekly intra-muscular injection for the first year, to be followed bydouble this amount during the second year. Subsequentperiodic blood sampling during this treatment showed arise of serum gammaglobulin content from the initial6o mg./xoo ml. up to a maximum of 56o mg./ioo ml.(Dr. J. F. Soothill). The clinical response in respect ofthe infections was impressive. Without prophylacticantibiotics the patient remained free from any infectiveincident for a period of 14 months, while the pneumonicprocess resolved (Fig. 4), with gain of weight and appetiteand ability to resume work. There was subsequently amild intercurrent upper respiratory infection during aninfluenzal epidemic with some scattered bronchitic signs,which responded quickly to antibiotics and was notassociated with any clinical or radiological recurrence ofpulmonary consolidation; following this incident shehas remained well to the present date over a further Iomonths, with gain in weight and freedom from coughand sputum. Weekly injections of gammaglobulin,2.56 g., have been maintained throughout, but afterthe occasional use of tetracycline in small dosage noantibiotic drugs have been required during the lastthree months of this period, the chest remaining clear ofabnormal signs.

DiscussionWhile the diagnosis of hypogammaglobulineemia

in this patient appears proven, the unusual featurehas been the presence of hFemolysis. In a review

FIG. 4.-Postero-anterior X-ray film of chest, 23.3.60,showing resolution of pneumonic changes aftertreatment with intramuscular gammaglobulin.

by Citron (I957) of the medical literature, out of 45reported cases of hypogammaglobulinamia sixshowed splenic enlargement (Rohn, Behnke andBond, I954; Grant and Wallace, 1954; Rosecan,Trobaugh and Danforth, 1955; Collins and Dudley,1955; Young, Wolfson and Cohn, 1955; Good andMazzitello, I956). All six were of the acquiredidiopathic type of the condition. Of these six caseswith splenomegaly, three showed a neutropenia,with lack of neutrophil response during the infec-tions, and three had an acquired hiemolytic anaemia;in two of the latter patients splenectomy was per-formed with relief of the aniemia in each case.Further instances of associated hypersplenism andheemolytic aniemia in the acquired type of gamma-globulin deficiency have been published by Prasadand Koza (1954, the first case described), Prasad,Reiner and Watson (1957, one additional case) andby Standaert and De Moor (1955), Martin, Gordonand McCullough (1956), and Briickel, Neuffer andFrankel (1956) (each a single case), this serieslikewise including two patients subjected tosplenectomy, with recovery in one and death frombronchopneumonia in the second. A total of eightcases of hypogammaglobulinaemia with hiemolyticanwmia has thus been traced in the medicalliterature.A reasonable explanation of the development of

haemolytic aniemia and neutropenia in these cases,and of their relief by splenectomy, is the hypothesisof a secondary hypersplenism, with destruction oferythrocytes, leucocytes or both by the enlargedspleen. In none of the cases recorded was anyother specific cause found for the splenomegaly,

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May I962 THOMPSON and SLEIGH JOHNSON: Primary Idiopathic Hypogammaglobulinaemia 295

and it was postulated that a compensatory reactivehyperplasia of the reticulo-endothelial system hadoccurred, with hyperphagocytosis, as a result ofrepeated infections due to the almost complete lackof gamhmaglobulin and deficiency or absence ofcirculating antibodies.

In the patient at present described it seemsprobable that the pathology is of the same nature,with hiemolysis a direct result of hypersplenism,the splenic enlargement having now reached nearlyto the umbilical level. An alternative cause of thehaemolysis as due to a specific antibody formationseems unlikely, in that the patient showed nodemonstrable antibody response in the provocativetests employed. Supporting evidence of hyper-splenism was given by the absence of leucocytosisthroughout the course of illness, the white cellcount never being higher than Io,ooo/c.mm. at theheight of the severe pulmonary infection. Theplatelet count was unaltered. The sedimentationrate was persistently raised, being from ioo toI IO mm. in one hour (Westergren) at the height ofthe pulmonary infection, and between 24 and 40mm. subsequently. This was an unusual finding,although present in some recorded cases, the levelsin this condition being more commonly low duringthe infective episodes, in conformity with theknown association between the sedimentation rateand the plasma globulins.

During treatment with gammaglobulin, despite afall in the reticulocyte count to 2%, with rise ofhlmoglobin to 85% and serum haptoglobin togo mg./ioo ml., the fecal stercobilinogen excretionwas still found to be increased, and the survivaltime of transfused red cells became further shor.tened, so that it must therefore be concluded thatabnormal heemolysis is still continuing. It is notyet known whether with more prolonged control ofthe infective episodes by gammaglobulin therapythe hypersplenism will be abated. Should this notfollow and a relapse of anaemia develop, the possibleneed for splenectomy must then be considered.

SummaryA case is described in which idiopathic hypo-

gammaglobulinwmia was associated with hwmo-lytic anemia. The evidence for this combineddiagnosis is presented and its implications discussed.

We wish to express our acknowledgments and thanksto the Medical Research Council for supplies of gamma-globulin for use in treatment of this patient, to Dr. J. F.Soothill for estimations of serum-gammaglobulin, toMr. P. M. G. Broughton for many biochemical investi-gations and to the Radiotherapy Department of theNorth Middlesex Hospital for red-cell survival rateestimations.

REFERENCESBRUCKEL, K. W., NEUFFER, P., and FRANKEL, F. H. (1956): Gammaglobulin Mangel Syndrome und Humorale Abwehr

unter besonderer Beriucksichtigung der Agammaglobulinamnie, Klin. Wschr., 34, 304.CITRON, K. M. (1957): Agammaglobulinmemia with Splenomegaly, Brit. med. 3'., i, 1148.COLLINS, H. D., and DUDLEY, W. R. (1955): Agammaglobulinemia and Bronchiectasis: Two Cases in Adults, New

Engl. Y. Med., 252, 255.GoOD, R. A., and MAZZITELLO, W. F. (I956): Chest Disease in Patients with Agammaglobulinmmia, Dis. Chest, 29, 9.GRANT, G. H., and WALLACE, W. D. (1954): Agammaglobulinemia, Lancet, ii, 671.MARTIN, C. M., GORDON, R. S., and MCCULLOUGH, N. B. (I956): Acquired Hypogammaglobulintemia in an Adult,

New Engl. 3. Med., 254, 449.PRASAD, A. S., and KOZA, D. W. (1954): Agammaglobulinemia, Ann. intern. Med., 41, 629.

, REINER, E., and WATSON, C. J. (1957): Syndrome of Hypogammaglobulinemia, Splenomegaly and Hypersplenism,Blood, X2, 926.

ROHN, R. J., BEHNKE, R. H., and BOND, W. H. (I954): Acquired Agammaglobulinwmia with Hypersplenism,.7. Lab.clin. Med., 44, 9I8.

ROSECAN, M., TROBAUGH, F. E., and DANFORTH, W. H. (1955): Agammaglobulinwemia in the Adult, Amer. Y. Med.,19, 303.

STANDAERT, L., and DE MOOR, P. (1955): L'Agammaglobulinemia chez L'Adulte, Acta clin. belg., O, 477.WOLFSON, W. Q., COHN, C., CALVARY, E., and THOMAS, E. N. (1948): Studies in Serum Proteins, .7. Lab. clin. Med.,

33, 1276.YOUNG, I. I., WOLFSON, W. Q., and COHN, C. (I955): Studies in Serum Proteins, Amer. _7. Med., 19, 222.

A CASE OF ACUTE ILEITIS WITH PERFORATIONJ. B. L. TAYLOR, F.R.C.S.

Surgical Registrar, Stockport Infirmary

ACUTE ILEITIS iS uncommon in surgical practice andsome doubt exists about its pathology and naturalhistory. A case report of acute ileitis with perfora-tion in a child is presented.Case ReportThe patient, a boy aged Io, was admitted to hospital

on 8.9.59 with a diagnosis of acute appendicitis. Hegave a history of colicky lower abdominal pain of 36hours' duration. He had vomited several times and hadsome diarrhcea, the motions being loose, but not con-taining blood. On examination there was tendernessand rigidity in the right iliac fossa. The temperatureand pulse were normal.

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