J Clin Pathol: first published as 10.1136/jcp.41.7.711 on 1 July 1988. Downloaded from

J Clin Pathol 1988;41:711-715

Review article Haematological abnormalities in human virus (HIV) disease

CHRISTINE COSTELLO From the Department ofHaematology, St Stephen's Hospital, London

Peripheral blood and bone marrow changes are com- patients with AIDS and opportunistic tumours.2 Care monly seen in disease associated with human immun- must be taken when interpreting the ratio of T helper odeficiency virus (HIV). This annotation aims to to T suppressor cells. Only when there is lymphopenia summarise these changes and to suggest possible does a decreased ratio indicate depletion of T helper factors entailed in their occurrence. cells. In patients with a normal lymphocyte count a decreased ratio might result either from T helper cell The wideranging clinical and pathological changes in depletion or from T suppressor cell increase. patients infected with HIV virus are both fascinating Mir found a 79% incidence of lymphopenia in 40 and challenging to physicians and pathologists alike. patients with AIDS and in our series of 925 HIV Haematological abnormalities are well recognised in antibody positive patients studied during 1987, 305 HIV disease and result from diverse influences on the (33%) were lymphopenic; most of these patients had haemopoietic tissue. Changes in the peripheral blood AIDS or ARC.3 and bone marrow may reflect disease elsewhere in the Granulocytopenia is a less well recognised feature of body, may result from treatment for that disease, may HIV disease but was seen in 185 (20%) of 925 HIV reflect an attempt to attack the HIV virus itself, or may antibody positive patients (Haematological features of seem to be isolated haematological disorders. Only by HIV disease, Costello C, unpublished observations). http://jcp.bmj.com/ monitoring blood changes and correlating them with In Treacy's series two thirds ofthe patients with AIDS the clinical state of the patient can we hope to or ARC having bone marrow examinations were understand the mechanisms involved and to suggest granulocytopenic' and this figure was similar in a what their clinical importance might be. larger series of 60 patients at St Stephen's Hospital undergoing bone marrow examinations (Proceedings Peripheral blood changes of meeting on prospective indications for intravenous

immunoglobulin, 1988).3 on October 1, 2021 by guest. Protected copyright. Leucopenia is common in patients with HIV infection A left shift in the granulocytic series is a common and seems to correlate with the severity of the disease. finding'4 and may reflect the clinical condition of the Two hundred and twelve (23%) ofa series of 925 HIV patient. The pathogenesis of is obscure, antibody positive patients at this hospital were though several factors are likely to be important: leucopenic at some stage during their illness, and 88% concurrent infections, drugs which suppress the ofpatients with acquired immune deficiency syndrome marrow, and probably, in some cases, an immune (AIDS) or AIDS-related complex (ARC) were process. Murphy et al studied 105 HIV antibody leucopenic at presentation.' Ofinterest is the contribu- positive patients and found neutropenia in 20% of tion of lymphopenia, neutropenia, and granulo- patients with AIDS, 25% of patients with persistent cytopenia to the reduction of total number of white generalised lymphadenopathy (PGL), but none of 26 cells. asymptomatic HIV antibody positive subjects.5 He Lymphopenia in HIV disease is common, cells of performed immunofluorescence tests the T helper phenotype being specifically depleted. In (GIFT) on 34 HIV antibody positive men, two with patients with AIDS and opportunistic infections AIDS, 24 with PGL, and eight who were asymp- immune function is more severely disturbed than in tomatic. Seven of the 34 were neutropenic and in four the GIFT reaction was positive. Six patients with Accepted for publication 3 March 1988 normal neutrophil counts also showed positive GIFT 711 J Clin Pathol: first published as 10.1136/jcp.41.7.711 on 1 July 1988. Downloaded from

712 Costello tests but in none of these patients with positive immune in aetiology, related to drugs, or part of the reactions was there any correlation with concentra- pancytopenia often seen in ill patients with opportun- tions of circulating immune complexes. Thus in at istic infections. least some patients with neutropenia an autoimmune The incidence ofthrombocytopenia has perhaps not mechanism might be implicated. been fully appreciated. The initial reluctance to put Van der Lehe also found granulocyte bound samples through a whole blood counter led to an immunoglobulin in patients with HIV disease and to a evaluation ofplatelet numbers often being made on a lesser extent in high risk patients without evidence of blood film. Mild degrees of thrombocytopenia were HIV disease.6 In some cases acid eluates from the quite likely overlooked. At this hospital we found a contained immunoglobulins reacting 13% incidence of thrombocytopenia (121 of 925 with normal granulocytes, thus indicating that they patients studied over 12 months) in patients who were were autoantibodies rather than non-specifically at risk for HIV disease. Although most ofthe patients bound immune complexes. Presumably the immune had either AIDS or ARC, 12% of the patients with imbalance in HIV infected patients may result in the thrombocytopenia were HIV antibody positive, and production of autoantibodies to blood cells. asymptomatic. An alternative cause for the neutropenia seen in The diagnosis of immune thrombocytopenia is patients with HIV disease might be decreased bone often made on clinical and bone marrow findings as marrow production of granulocytes consequent on platelet-associated immunoglobulin testing has not inhibition ofgranulocyte progenitors. Leiderman et al been widely used in high risk patients for reasons of described deficiency of growth of the granulocyte- safety. In patients with reduced platelet numbers and macrophage progenitor cell (CFU-GM) from bone no splenomegaly, no drug treatment, and a marrow marrows of patients with HIV disease and postulated showing plentiful megakaryocytes, a presumptive that a glycoprotein present in the marrow of infected diagnosis ofimmune thrombocytopenia may be made. patients might be the inhibitory agent.' The condition varies in HIV antibody positive Monocytopenia was apparent in 79 (8 6%) of the patients, as in other patients with immune throm- 925 HIV antibody positive patients studied by Cos- bocytopenia, from a well compensated state with only tello and in a higher percentage ofpatients from whom a mild reduction in platelet numbers to a severe marrow aspirates were taken (35% of Treacy's series, condition with very low platelet counts. 43% of Mir's patients). Morphological abnormalities The mechanism for immune thrombocytopenia has of monocytes were observed by Treacy and also by been studied by several workers in the United States. the monocytes vacuol- Walsh et al showed high concentrations of platelet- Spivak,4 showing cytoplasmic http://jcp.bmj.com/ isation and abnormal nuclear features. associated IgG and complement in homosexual Anaemia is commonly seen in patients with patients with idiopathic thrombocytopenia (ITP).'2 AIDS,' 48 often reflecting reticuloendothelial iron These values were around four times higher than those block and effects of treatment with drugs such as seen in classic ITP and it is likely that they reflect co-trimoxazole, pentamidine, foscarnet and more deposition ofimmune complexes on the surface of the recently zidovudine (AZT). Blood transfusion is often platelet. Raised concentrations of immune complexes necessary in patients with AIDS, especially in those are commonly found in patients with HIV disease, and receiving AZT, a drug which produces severe anaemia interestingly, the homosexual control patients with on October 1, 2021 by guest. Protected copyright. in a proportion ofrecipients.9 Forty nine (36%) of 138 normal platelet counts had concentrations ofplatelet- patients treated with AZT at this hospital required associated IgG and complement which were sig- blood transfusion at least once.'" nificantly higher than those of non-homosexual con- Erythroid hypoplasia with severe anaemia has trols, suggesting that immune complex deposition on recently been described in patients with disseminated platelets may occur without large scale platelet des- Mycobacterium avium-intracellulae (MAI) infection." truction. Whether bone marrow stem cells are infected with A true antiplatelet autoantibody, however, may the HIV virus is as yet unknown but Zon suggested coexist with immune complexes on the surface of the that erythropoiesis could be suppressed by the action platelet. Strickler et al reported platelet membrane of the retrovirus on progenitor cell proliferation or antibody in homosexual patients with ITP with reac- maturation.8 Spivak raised the possibility of the tivity against a 25000 molecular weight platelet mem- anaemia in HIV disease being at least partly the result brane antigen, suggesting the presence of a 7S platelet of suppression oferythropoiesis by cell to cell interac- antibody.'3 tion.4 The imbalance ofT helper and T suppressor cell Furthermore, Van der Lelie eluted platelet bound populations in AIDS lends credence to this theory. immunoglobulin from his patients with HIV related Thrombocytopenia is a well recognised occurrence disease that was shown to bind to normal platelets, in patients infected with the HIV virus. It may be indicating the presence of a specific platelet autoan- J Clin Pathol: first published as 10.1136/jcp.41.7.711 on 1 July 1988. Downloaded from

Haematological abnormalities in HIV infection 713 tibody.6 The autoantibody is probably directed Bone marrow changes against an uncharacterised glycoprotein on the platelet surface. Thus it differs from the autoantibody Although bone marrow changes are often seen in HIV in classic ITP which is commonly directed against the disease, there do not seem to be specific abnor- platelet membrane glycoprotein Ilb/IlIa complex. malities-rather the marrow is a target for the com- Karpatkin discussed the intriguing possibility ofthe bined effects of infection, drugs, and chronic disease. presence of "anti-antibodies" in the serum of Several findings ofinterest, however, have been repor- homosexual patients with ITP.'4 Anti-F(ab')2 anti- ted in HIV patients which may be typical, if not bodies have been shown in the IgG fraction of these specific. One finding is the difficulty sometimes patients' immunoglobulin with activity against experienced in aspirating marrow, and probably autologous, homologous, and normal control F(ab')2 related to this, a discrepancy between the cellularity of fragments. Some of the immune complexes deposited the aspirate and the trephine biopsy specimen. Spivak on the platelets in homosexuals with IT? may be reported increased marrow reticulin in 10 of 12 composed of IgG anti-F(ab')2 complexes. Karpatkin patients studied4 as did Geller in 28 of 36 biopsy suggested that these F(ab')2 antibodies might represent specimens,27 and this may be the reason for difficulty in anti-idiotype antibodies against HIV neutralising marrow aspiration. antibody. The cellularity of the marrow on trephine biopsy is Interestingly, Cohen et al described the presence of usually normal or increased,828 though Treacy' and the lupus anticoagulant and anticardiolipin antibodies Namiki29 report hypocellularity in a proportion of in patients with HIV infection."5 Both are correlated their cases and 12 of 60 bone marrows recently with thrombocytopenia in systemic lupus eryth- reviewed at this hospital were hypocellular. Dysplastic ematosus, and anticardiolipin antibodies have also changes are common in erythroid and granulocytic been found in patients with immune thrombo- lines.829 cytopenia without lupus.'6 The presence of the lupus Megaloblastic changes in the red cell series are seen anticoagulant and anticardiolipin antibodies may play in a few cases and may reflect myelodysplastic changes a part in the thrombocytopenia associated with HIV or concurrent treatment with co-trimoxazole. Red cell disease. hypoplasia is an interesting observation in some cases Treatment of immune thrombocytopenia in HIV and may be related to disseminated MAI infection." disease has been discussed elsewhere.'7 21 Although Several workers have reported increased numbers of treatment with prednisolone is effective in most lymphocytes in the marrows of patients with AIDS, patients, the effect is usually reversed when the drug is sometimes in the form of lymphoid aggregates on http://jcp.bmj.com/ withdrawn and it is potentially hazardous in patients biopsy48'282 and may represent a reaction to viral at risk from infection. Similarly, though removal of insult by herpes simplex, cytomegalovirus (CMV), or the spleen will achieve a lasting remission in a high Epstein-Barr virus (EBV). Granulomas are sometimes percentage ofcases, it is as yet unclear as to whether it observed in the marrow8' ' and may be associated hastens or promotes the development ofAIDS in HIV with histochemical evidence of acid fast bacilli or antibody positive patients. Intravenous immuno- fungal organisms. globulin often produces a good rise in platelet count The increased numbers of plasma cells and his- which, though temporary, might permit an invasive tiocytes often observed42829 is likely to be secondary to on October 1, 2021 by guest. Protected copyright. investigation such as lymph node biopsy to be perfor- repeated infections. Some marrows show striking med or might be of value during a bleeding episode. haemophagocytosis and this has previously been Other treatments, such as danazol, vincristine, and described in CMV and herpes simplex infection43' and anti-D immunoglobulin,'8202223 have not been of great in tuberculosis32 and histoplasmosis.33 value though one or two patients have shown a The reticuloendothelial iron block seen in many response. Interestingly, Gottlieb reported an increase patients with AIDS is a reflection of their clinical in platelet count in a patient on AZT with AIDS- condition, with repeated episodes of infection caused related thrombocytopenia.24 At this hospital we have by opportunistic organisms. seen 10 patients with thrombocytopenia improve their Bone marrow aspirates are often requested clin- platelet count on AZT, though in five this ically to exclude Kaposi's sarcoma or non-Hodgkin's improvement was only temporary. We also noted, lymphoma, or for microbiological staining and cul- however, that in five other HIV antibody positive ture. In disseminated infection MAI may be cultured thrombocytopenic patients the platelet count fell from bone marrow aspirates and is associated with further while on the drug. anaemia and red cell hypoplasia." Cryptococci and Recent reports of the use of a-interferon25 26 suggest histoplasma have also been shown in marrow that this agent might be of value in severe AIDS- aspirates2934 and Hayman reported a patient with related ITP. AIDS in whom Pneumocystis carinii organisms were J Clin Pathol: first published as 10.1136/jcp.41.7.711 on 1 July 1988. Downloaded from

714 Costello shown in the bone marrow biopsy specimen.35 We have disease might enable us to elucidate the cause of the recently seen a patient with AIDS who had extensive haematological changes and to assess their clinical marrow disease with Leishmania. importance. The bone marrow cellularity in the patient infected with HIV does not always correlate with the peripheral blood findings. The commonly seen pancytopenia is References often associated with an active, even hyperactive 1 Treacy M, Lai L, Costello C, Clark A. Peripheral blood and bone marrow, suggesting either dysmyelopoiesis or marrow abnormalities in patients with HIV related disease. Br J increased peripheral utilisation of blood cells. As Haematol 1987;65:289-94. 2 Pinching AJ. The acquired immune deficiency syndrome. Clin Exp previously discussed, immune mechanisms have been Immunol 1984;56:1-13. implicated in many cases of thrombocytopenia and in 3 HIV disease and bone marrow changes: a study of 10 cases. Mir N, some cases of neutropenia. Costello C, Lukit J, Lindley R. Eur J Haematol 1 988;(in press). It seems likely that although the bone marrow is 4 Spivak JL, Bender BS, Quinn TC. Haematologic abnormalities in the acquired immune deficiency syndrome. Am J Med obviously an affected organ in HIV disease, it is the 1984;77:224-8. target of many insults-drugs, opportunistic infec- 5 Murphy MF, Metcalfe P, Waters AH, et al. Incidence and tions, and even the HIV retrovirus itself. mechanism of neutropenia and thrombocytopenia in patients with human immuno deficiency virus infection. Br J Haemaiol Lymphoma in HIV disease 1987;66:337-40. 6 van der Lelie J, Lange JMA, Vos JJE, van Dalen CM, Danner S A, von dem Borne AEG. Autoimmunity against blood cells in Patients with HIV disease have an increased incidence human immunodeficiency virus (HIV) infection. Br J Haenmatol of diffuse non-Hodgkin's lymphoma. This is often 1987;67:109-14. high grade and almost always of B cell origin.3637 A 7 Leiderman IZ, Greenberg ML, Adelsberg BR, Siegal FP. A glycoprotein inhibitor ofin vitro granulopoiesis associated with high incidence of extranodal and primary brain dis- AIDS. Blood 1987;70:1267-72. ease is observed, these features being similar to those 8 Zon LI, Arkin C, Groopman JE. Haematological manifestations seen in lymphomas developing in patients with con- of the human immune deficiency virus (HIV). Br J Haematol genital immunodeficiency such as Wiskott-Aldrich 1987;66:251-6. 9 Richman DD, Fischl M, Grieg MH et al. The toxicity of syndrome or ataxia telangiectasia, or in iatrogenic azidothymidine (AZT) in the treatment of patients with AIDS immunodeficiency states such as post-renal trans- and AIDS-related complex. N Engl J Med 1987;317:192-7. plant. Although patients with non-Hodgkin's lym- 10 Costello C, Mir N, Luckit J. The blood transfusion service and phoma associated with HIV infection may respond zidovudine treatment for AIDS. Br Med J 1987;295:1486. initially to combination chemotherapy, the relapse 1 1 Gardener TD, Flanagan P, Dryden MS, Costello C, Shanson DC, Gazzard BG. Disseminated mycobacterium avium- http://jcp.bmj.com/ rate is high and the overall prognosis poor. Patients intracellulare (MAI) infection and red cell hypoplasia in with other manifestations of AIDS at the time of patients with the acquired immune deficiency syndrome development of non-Hodgkin's lymphoma seem to (AIDS). J Infect (in press). 12 Walsh CM, Nardi MA, Karpatkin S. On the mechanism of fare much worse.36 The malignant lymphoma proba- thrombocytopenic purpura in sexually active homosexual men. bly arises as a monoclonal outgrowth from a pool of N Engl J Med 1984;311:635-9. proliferating B lymphocytes36 which have been 13 Strickler RB, Abrams DI, Corash L, Shuman MA. Target platelet stimulated by the Epstein-Barr virus38 and possibly antigen in homosexual men with immune thrombocytopenia. N

EnglJ Med 1985;313:1375-80. on October 1, 2021 by guest. Protected copyright. also by other infective agents such as CMV. 14 Karpatkin S. Immunologic thrombocytopenic purpura in patients We recently treated a patient with antibodies to HIV at risk for AIDS. Blood Reviews 1987;1: 1 19-25. who developed acute lymphoblastic leukaemia of B 15 Cohen AJ, Philips TM, Kessler CM. Circulating coagulation a inhibitors in the acquired immune deficiency syndrome. Ann cell origin (B-ALL),39 and Rossi4 has reported Intern Med 1986;104:175-80. similar case. It seems likely that B-ALL in addition to 16 Harris EN, Gharavi AE, Hughes GRV. Antiphospholipid non-Hodgkin's lymphoma of B cell origin is a manifes- antibodies. Clin Rheum Dis 1985; 1:591-609. tation of AIDS in a patient with anti-HIV antibodies. 17 Costello C, Treacy M, Lai L. Treatment of immune throm- bocytopenic purpura in homosexual men. Scand J Haematol Hodgkin's disease has been reported in patients at 1986;36:507-10. risk for AIDS by several workers,4"3 though as yet the 18 Oksenhendler E, Bierling P, Farcet JP, Rabian C, Seligmann M, incidence is unclear. Clauvel JP. Response to therapy in 37 patients with HIV-related Undoubtedly over the next few years we shall see thrombocytopenic purpura. Br J Haematol 1987;66:491-5. 19 Delfraissy JF, Tertian G, Dreyfus M, Tchernia G. Intravenous many more patients with haematological abnor- gammaglobulin, thrombocytopenia and the acquired malities related to HIV disease, either directly by the immunodeficiency syndrome. Ann Intern Med 1985;103:478. retrovirus itself or indirectly as a complication of 20 Mintzer DM, Real FX, Jovino L, Krown SE. Treatment of infection or treatment. The complex multisystem Kaposi's sarcoma and thrombocytopenia with vincristine in patients with acquired immunodeficiency syndrome. Ann Intern pathology in patients with AIDS is reflected in the Med 1985;102:200-2. almost universal finding of changes in the blood 21 Tertian G, Risler N, Le Bras P, et al. Intravenous gammaglobulin picture. The study of patients with less advanced treatment for thrombocytopenic purpura in patients with J Clin Pathol: first published as 10.1136/jcp.41.7.711 on 1 July 1988. Downloaded from

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