908

aminoglycan, a semisynthetic heparin analogue,also seems to release endogenous heparin-likematerial with anti-factor- Xa activity.I7 Althoughthis analogue has low anticoagulant activity in

vitro, its antithrombotic properties in vivo are saidto be comparable with those of heparin. 8The work of NEGUS and colleagues raises the in-

triguing prospect of preventing deep-vein throm-bosis by doses of heparin that would at one timehave been judged homoeopathic. Such doses are un-likely to cause haemorrhagic complications, and in-deed may work primarily by stimulating endo-genous defence mechanisms. If ultra-low-dose

heparin does protect against postoperative DVTwithout risk of haemorrhage, it will represent a sub-stantial improvement in the cost/benefit ratio ofprophylaxis against venous thromboembolism.

Chronic NeutropeniaIN chronic neutropenia the blood neutrophil

count is below 2000/[1.1 for long periods. Typically,other blood-cell counts are normal; there is no his-tory of exposure to myelotoxic agents, the spleen isnot enlarged, and there is no evidence of bone-mar-row infiltration or systemic disease to which theneutropenia can be ascribed. Although there are noconstitutional signs of a genetic disorder, and thephasic variations in the granulocyte count found incyclical neutropenia are absent, the isolated caseswhich arise in adult lifel may be hard to distinguishfrom certain hereditary marrow disorders; the label"benign familial neutropenia"2,3 has been attachedto a similar syndrome in which several members ofthe family are affected. Interestingly, the latter ab-normality has sometimes been encountered in fami-lies of which other members have the more seriousFanconi’s anxmia. 4

Another confusing area is classification of the

symptomless neutropenia found quite commonly incertain ethnic groups such as African and Ameri-can Blacks56 and Yemenite Jews.’8 Some authori-ties have broadened the concept of benign familial

17. Thomas DP, Barrowcliffe TW, Johnson EA, Stocks J, Dawes J, Pepper DS.A heparin analogue that releases endogenous heparan sulphate. Throm-bosis Haemostas 1979; 42: 418.

1. Kyle RA, Linman JW. Chronic idiopathic neutropenia: a newly recognisedsyndrome? N Engl J Med 1968; 279: 1015-19.

2. Gansslen M. Konstitutionelle familiare Leukopeme (Neutropenie). Klin

Wschr 1941; 20: 922.3. Cutting HO, Lang JE. Familial benign chronic neutropenia. Ann Intern Med

1964; 61: 876-87.4. Finch SC. Granulocytopenia. In: Williams WJ, Butler EB, Erslev AJ,

Rundles RW, eds. Hematology. London: McGraw Hill, 1977: 726.5. Ezeilo GC. Non-genetic neutropenia in Africans. Lancet. 1972; ii: 1003-04.6. Broun GO, Herbig FK, Hamilton JR. Leucopenia in negroes. N Engl J Med

1966; 275: 1410.7. Djaldetti M, Joshua H, Kalderson M. Familial leukopenia-neutropenia in

Yemenite Jews: observations on eleven families. Bull Res Counc Isr 1961;9E: 24.

8. Mintz J, Sachs L. Normal granulocyte colony-forming cells in the bone mar-row of Yemenite Jews with genetic neutropenia. Blood 1973; 41: 745-51.

neutropenia to include these cases, which may bedue to a defect in release of granulocytes from themarrow. Others seem to be examples of "pseudo-neutropenia" in which there is abnormal vascularmargination of neutrophils, marrow function beingnormal. 4

Most of the published reports of chronic idio-pathic neutropenia describe only one case, or a verysmall number, and it is useful to have a compre-hensive account of the natural history of the dis-order from DALE and his colleagues,9 who identi-fied, investigated, and followed (for up to 22 years)29 patients with this blood disorder: possible casesof "ethnic" neutropenia were excluded. Their

average age was 30; there were 22 females and 7males. 2 of the patients came from a large familywith several neutropenic individuals; 2 more gavea family history of chronic neutropenia. Althoughmost showed some fluctuation in the neutrophilcount, 22 of the 29 had mean values less than

1000/pd, and in 17 it was less than 300/jjd for longperiods. Nevertheless, the pattern of infectionsencountered contrasts strikingly with that seen inneutropenic patients with acute leukxmia, aplasticanaemia, and drug-induced agranulocytosis. Mostsuffered, at worst, recurrent upper respiratory in-fections, occasional pneumonia, furunculosis, andotitis media; in none could death be ascribed tooverwhelming infection. In patients with neutro-phil counts over 500/,1, no increased incidence ofinfection was found. Oral ulceration was frequentbut bore little relation to the neutrophil count. Ofcourse, in this "numbers game" 10 in neutropenia itis important to take into account the monocyteswhich, although not as phagocytic as granulocytes,also contribute to the body’s defences: most of thepatients in the DALE study had chronic monocy-tosis. By contrast, many patients with aplasticanaemia have monocytopenia.Bone-marrow cellularity was usually normal,

only a few patients showing a reduced myeloid:erythroid ratio. A few showed apparent maturationarrest of the developing granulocyte series; how-ever, as DALE and co-workers point out, this maybe a morphological misinterpretation. Kinetic stu-dies show that the mitotic activity of neutrophilprecursor cells is certainly not "arrested". "More-over, the colony-forming ability of the marrow-reduced in aplastic anaemia and in preleukx-mialz-was often within normal limits, as were

levels of circulating colony-stimulating activity. Aform of ineffective granulopoiesis, analogous to the

9. Dale DC, Guerry D, Wewerka JR, Bull JM, Chusid MJ. Chronic neutro-penia. Medicine 1979; 58: 128-44.

10. Evslev AJ, Gabuzda GD. In: Pathophysiology of blood. London: Saunders,1979:107.

11. Greenberg PL, Zanger B, Wong H. Studies in granulocytopenic subjectsBlood 1967; 30: 891-92.

12. Milner GR, Geary CG. The aplasia-leukæmia syndrome. In: Geary CG, edAplastic anaemia. London: Baillière Tindall, 1979: 230-43.

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dyserythropoiesis seen in some refractory ansemias,might account for some cases, but this remains aspeculation, as is the notion that an excess of

monocytes is produced at the expense of granulo-cytes.Various laboratory tests have suggested that

some cases of chronic neutropenia are examples ofautoimmune disease in which antibodies are dir-ected against neutrophil-specific antigens.13 DALEet al. emphasise that chronic neutropenia isencountered most frequently in women, reflectingthe age and sex pattern of other well-definedautoimmune disorders. Only 1 patient, of the 16tested, showed circulating anti-neutrophil anti-bodies but, since neutrophil antigens change as thecell matures and such tests are customarily donewith antisera to mature neutrophils, it remains pos-sible that some cases of chronic neutropenia are,like pure red-cell aplasia, the result of immunologi-cal damage to precursor cells which possessantigens restricted to these progenitors. On theother hand, in red-cell aplasia, the morphologicallyidentifiable precursor cells disappear from the mar-row,14 whereas they usually persist in chronic neu-tropenia. CLINE and GOLDE 15 have described neu-tropenic individuals with a variable marrow

hypoplasia in whom antibodies to granulocyte col-ony-forming cells were present; these patients oftenhad other evidence of autoimmune disease but theclinical effect of the neutropenia tended to be moresevere than in the present group. Another possibi-lity is that some cases represent a form of immune-complex disease, in which granulocytes are des-troyed as "innocent bystanders". 16Whatever the pathogenesis of chronic idiopathic

neutropenia, its natural history is often benign;none of the patients in the DALE’S study went onto leukxmia or aplastic anaemia, though both

monocytosis and neutropenia are recognised as

manifestations of the preleukaemic syndrome, es-

pecially in the elderly. Antibiotics may be requiredfor the more severe infective episodes, but DALE etal. conclude that most patients should not be sub-jected to the potential hazards of corticosteroids,androgens, cytotoxic therapy, or splenectomy. Theonly exception is the occasional patient with recur-rent severe infections. After careful investigation todefine the pathophysiology of the neutropenia-including marrow culture studies if possible-atrial of corticosteroids, at doses of 40-80 mg onalternate days, may be justifiable. When circulatinghumoral inhibitors can be demonstrated, intensiveplasmapheresis is also worth a thought.’s

13 Lalezari P, Jiang AF, Yegen L, Santorineou M. Chronic autoimmune neu-tropenia due to anti-NA2 antibody. N Eugl J Med 1975; 293: 744-47.

14 Krantz SB. Pure red-cell aplasia. N Engl J Med 1974; 291: 345-50.15 Cline MJ, Golde DW. Immune suppression of hematopoiesis. Am J Med

1978, 64: 301-10.16. Caligaris-Cappio F, Camussi G, Gavosto F. Idiopathic neutropenia: an im-

mune complex disease. Br J Hœmat 1979; 43: 595-605.

TUBERCULOSIS IN CHRONIC RENAL FAILURE

TRADITIONALLY tuberculosis has been a disease of the

weak, attacking preferentially those whose resistance issapped by poor nutrition or incidental disease. Patientswith renal failure, including those treated by main-tenance hxmodialysis, are deficient in both cell-mediated and humoral immunity,l-3 so, a priori, theyare likely to be particularly vulnerable. This matter hasbeen examined in one Japanese4 and two American5,6 6

papers which conclude that patients with renal failurehave an incidence of tuberculosis about ten times that ofthe surrounding population. Several patients had typicalpulmonary illnesses, but roughly half presented withpredominantly extrapulmonary disease and non-specificsymptoms such as malaise, weight-loss, fever, and dis-proportionate ansemia. Initially these symptoms wereapt to be blamed on renal failure or complications of di-alysis, and often the diagnoses were further delayed bynegative tuberculin tests. Sputum smears were usuallynegative and biopsy of tissues such as pleura, lymphglands, or liver was often necessary to establish the diag-nosis. In one of the American series 2 of the 17 cases,including 1 with infection due to Mycobacterium aviumintracellulare, were diagnosed only at necropsy and athird was diagnosed too late to prevent death from mili-ary disease. 9 out of the 12 Japanese patients died,mostly from miliary tuberculosis. Non-White peopleseem more vulnerable than Whites: in one of the Ameri-can reports5 only 1 of the 10 patients was White, whilst4 were Chinese (out of a total of 15 Chinese patients ondialysis), 2 were Negro, and the others were Mexican,Filippino, and American Indian.

Treatment is complicated by interference with theexcretion of the drugs that are normally used, and aneffort should be made to employ drugs that are eitherexcreted via alternative pathways or can be easily mea-sured in plasma. Rifampicin is excreted predominantlyby the liver and can be given in normal doses; and so,probably, can isoniazid, whose disappearance is deter-mined more by the patient’s acetylator status than by hisrenal function. It is wise, however, to check the plasmalevel occasionally and to give prophylactic pyridoxine(and perhaps also nicotinamide) because of the risk ofperipheral neuropathy, to which the patients are alreadyprone. Ideally nerve conduction should be measuredbefore treatment and regularly during treatment. Deter-ioration of renal function during treatment with rifam-picin may, of course, be due either to progression of theunderlying renal disease or to drug toxicity. The choiceof the third drug is rather more difficult but both theAmerican groups employed ethambutol in reduced

dosage of 5-10 mg/kg body weight daily. However, thisdrug is potentially toxic, is excreted predominantly inthe urine, and most physicians do not have access to

1. Wilson WEC, Kirkpatrick CH, Talmage DW. Suppression of immunologicresponsiveness in uremia Ann Intern Med 1965; 62: 1-14.

2. Boulton-Jones JM, Vick R, Cameron JS, Black PJ. Immune responses inuraemia. Clin Nephrol 1973; 1: 351-60.

3. Watson MA, Briggs JD, Diamandopoulos AA, Hamilton DNH, Dick HM.Endogenous cell-mediated immunity, blood transfusion, and outcome ofrenal transplantation. Lancet 1979; ii: 1323-26.

4. Sasaki S, Akiba T, Suenaga M, et al. Ten years’ survey of dialysis associatedtuberculosis. Nephron 1979; 24: 141-45.

5. Andrew OT, Schoenfeld PY, Hopewell PC, Humphreys MH. Tuberculosison patients with end-stage renal disease. Am J Med 1980; 68: 59-65.

6. Rutsky EA, Rostand SG. Mycobacteriosis in patients with chronic renal fail-ure. Arch Intern Med 1980; 140: 57-61.