Haematological problems and HIV infection

Sam Milliken : Immunology/HIV/Infectious Diseases Clinical Services Unit, St Vincent’s Hospital, Sydney, NSW

Despite significant reductions in all complications of human immunodeficiency virus (HIV) infection since the introduction of antiretroviral therapy (ART), haematological problems remain common.[1]

Anaemia

Anaemia is a common problem and increases in frequency with stage of HIV infection, ranging from 3% of asymptomatic patients to 12% in people with CD4 lymphopenia (CD4 T-lymphocyte [CD4] cell count < 200 cells/μL or percentage < 14%) and 37% of patients with acquired immune deficiency syndrome (AIDS) in one large surveillance study.[2] Anaemia has been associated with reduced survival in a number of studies independent of other risk factors such as CD4 cell count and HIV viral load.[3][4] This relationship is more pronounced in patients who remain anaemic after commencing ART.[5] Causes of anaemia are often multifactorial. Common causes include inflammatory disease (previously termed anaemia of chronic disease), drugs such as zidovudine, cotrimoxazole, amphotericin B, ganciclovir, ribavirin and dapsone, and both opportunistic and non-opportunistic infections. Other causes are malignancy (lymphoma and Kaposi sarcoma involving the gastrointestinal tract) and hypersplenism (often associated with liver disease such as cirrhosis-caused chronic viral hepatitis). Rarer important causes include Castleman disease, human parvovirus B19 infection, thrombotic thrombocytopenic purpura and haemophagocytic syndrome. Anaemia of inflammatory disease may be due to HIV infection, other infections or cancer. Zidovudine and lamivudine may cause a macrocytosis.[6][7] Low B12 levels are not uncommon but true B12 deficiency is rare.[8] Similarly, while direct antiglobulin tests are often positive, ranging from 18 to 43% of people with HIV infection,[9] autoimmune haemolytic anaemia is rare.[10]

The ideal treatment for anaemia is to identify and manage the underlying cause (e.g. treat HIV or other infections or remove causative drugs). Human parvovirus B19 infection is a rare but interesting cause of pure red cell aplasia in severely immunosuppressed patients; it responds to ART and intravenous immunoglobulin therapy.[11] If the cause of anaemia cannot be corrected, then exogenous erythropoietin may improve haemoglobin levels and quality of life.[12][13] However it is not effective in patients with high endogenous levels (> 500 IU/L). Treatment with erythropoietin may reduce the risk of mortality while blood transfusion therapy may increase this risk.[14] Consequently, only patients with symptomatic anaemia without a correctable cause should be considered for transfusion.

Thrombocytopenia and immune thrombocytopenic purpura

Thrombocytopenia is commonly observed in association with HIV infection with immune thrombocytopenic purpura (ITP) the most common cause. It may occur in 30% or more of patients with AIDS[15] and can occur at any time during HIV infection. It may be seen before other clinical manifestations.[16] As such, HIV antibody testing is recommended in the assessment of new cases of thrombocytopenia. Platelet depletion in HIV-associated ITP has several causes. Immune complexes of antibodies toHIV glycoprotein (gp) 120, and gp120 may bind the platelet membrane GPIIIa complex[17] and it appears that megakaryocytes may be directly infected by HIV.[18] Platelet survival is decreased, especially in patients with only mild-to-moderate suppression of CD4 cell counts, as is platelet production.[19] Other common causes of thrombocytopenia in HIV patients are drugs, such as ganciclovir, cotrimoxazole and rifabutin, infections such as Mycobacterium avium complex (MAC), lymphoma and hypersplenism (most commonly due to co-morbid liver disease). Rarer causes that appear directly related to HIV infection are thrombotic microangiopathies, thrombotic thrombocytopenic purpura and haemolytic uraemic syndrome. Bleeding is uncommon in ITP unless the platelet count is less < 30 x 109/L. However, patients with co-existing haemophilia or other coagulopathies should be treated if platelet counts fall below 50 x 109/L.[20] The treatment of choice for ITP is ART. Corticosteroids are effective but long-term use is not desirable due to immunosuppression. Other drugs such as dapsone and danazol can be effective. Intravenous immunoglobulin is very effective in increasing platelet counts in the short term but is expensive. Splenectomy may be successful for refractory cases and does not increase risk of progression to AIDS.[21] For other causes of thrombocytopenia, treatment of the underlying cause is usually effective. Support with platelet transfusions should only be considered for patients at immediate risk of bleeding as the effect of transfusion is short lived and platelet allo-antibodies rapidly develop, limiting the effectiveness of future transfusions.

Neutropenia, pancytopenia and myelodysplasia

Neutropenia may be due to HIV infection itself, autoimmune neutropenia, infections such as MAC and tuberculosis (TB), marrow infiltration by malignancy (commonly lymphoma), hypersplenism and drugs. Treatment is directed at the underlying cause: ART for the HIV infection; antibiotics for opportunistic infections; and withdrawal of potentially causative drugs. Granulocyte colony stimulating factor (G-CSF) will usually correct severe neutropenia in refractory cases and may allow marrow suppressive drugs such as ganciclovir to be continued until infection has resolved. Infection or undiagnosed fever associated with severe neutropenia (neutrophil count < 0.5 x 109/L) should be considered a medical emergency with immediate commencement of broad spectrum antibiotics and supportive therapies such as G-CSF.[22]

All of the causes of individual cytopenias may produce a generalised pancytopenia. Late HIV infection commonly causes a myelodysplasia-type syndrome with impaired bone marrow function. Pancytopenia with severe lymphopenia and eosinophilia are commonly observed in the blood. Examination of the bone marrow commonly demonstrates normal or increased cellularity suggesting the impaired marrow function is due to inhibition of cellular maturation and production. Marrow plasmacytosis, lymphoid aggregates, granulomata and fibrosis are common.[23]

Lymphadenopathy and splenomegaly

Lymphadenopathy and splenomegaly are commonly seen in association with HIV infection, particularly with acute infection. Both tend to regress in late stages of infection. Other causes of lymphadenopathy and splenomegaly include infections (such as cytomegalovirus [CMV], Epstein Barr virus, hepatitis B and C viruses, MAC, TB, syphilis and Cryptococcus), lymphoma, Kaposi sarcoma and rarer causes such as haemophagocytic syndrome and Castleman disease.

Paraproteinaemia

An increase in immunoglobulin production occurs as part of the immune dysfunction caused by HIV infection and monoclonal paraproteins have been reported in as many as 7% of people with HIV infection. They do not appear to be clinically significant and may persist despite ART.[24] Similarly, cryoglobulinaemia has been reported in HIV infection, again without clinical significance. Over 90% of HIV patients with cryoglobulinaemia have hepatitis C virus co-infection and HIV infection does not appear to be a causative factor.[25]

Thromboembolic disease

Thrombosis has been reported in up to 2% of people with HIV infection. Risk factors for this group are age over 45 years, advanced stage of HIV infection, co-existing opportunistic infections, hospitalisation, and therapy with indinavir and megestrol acetate.[26] A number of potentially pro-thrombotic abnormalities have been reported in association with HIV infection including: decreased levels of antithrombin (seen in HIV nephropathy), free protein S, protein C and heparin cofactor II, lupus anticoagulant and anticardiolipin antibodies, co-existent malignant, inflammatory and autoimmune disorders, as well as vascular damage due to injecting drug use, vascular catheters and CMV infection.[27] The presence of lupus anticoagulant or anticardiolipin antibodies are weakly associated with venous thrombosis but cerebrovascular accidents, bone and skin necrosis and brachial artery thrombosis have been reported.[28]

Investigations

Lymph node biopsy should be considered for any symptomatic lymphadenopathy or asymptomatic lymph node enlargement over 2 cm, persisting for more than one month, where an infective cause cannot be determined, or for any persistently enlarging lymph nodes. Fine needle biopsy has a good diagnostic yield but excision biopsy should be considered if fine needle biopsy is non-diagnostic and lymphadenopathy persists or progresses.

Bone marrow examination should be undertaken for any unexplained moderate-to-severe anaemia or isolated cytopenia or pancytopenia and for pyrexia of unknown origin where initial tests are unhelpful.

Specimens should be sent for special microbial cultures, such as MAC, flow cytometry to help exclude lymphoma, as well as for morphological examination.

1.
Volberding PA, Baker KR, Levine AM. Human immune deficiency virus hematology. Hematology Hematology Am Soc Hematol Educ Program 2003:294-313 
2.
Sullivan PS, Hanson DL, Chu SY, et al, and the Adult/Adolescent Spectrum of Disease Group. Epidemiology of anemia in human immunodeficiency virus (HIV )-infected persons: results from the multistate adult and adolescent spectrum of HIV disease project. Blood 1998;91:301-8 
3.
Sullivan PS, Hanson DL, Chu SY, et al, and the Adult/Adolescent Spectrum of Disease Group. Epidemiology of anemia in human immunodeficiency virus (HIV )-infected persons: results from the multistate adult and adolescent spectrum of HIV disease project. Blood 1998;91:301-8 
4.
Mocroft A, Kirk O, Barton SE, et al. Anaemia is an independent predictive markerfor clinical prognosis in HIV-infected patients from across Europe. AIDS 1999;13:943-50 
5.
Kowalska JD, Mocroft A, Blaxhult A, et al. Current hemoglobin levels are more predictive of disease progression than hemoglobin measured at baseline in patients receiving antiretroviral treatment for HIV type 1 infection. AIDS Res Hum Retroviruses 2007;23:1183-8 
6.
Volberding PA, Baker KR, Levine AM. Human immune deficiency virus hematology. Hematology Hematology Am Soc Hematol Educ Program 2003:294-313 
7.
Kawcharoenporn T, Shikuma CM, Williams AE, et al. Lamivudine-associated macrocytosis in HIV-infected patients. Int J STD AIDS 2007;18:39-40 
8.
Remacha AF, Cadafalch J. Cobalamin deficiency in patients infected with human immunodeficiency virus. Semin Hematol 1999;36:75-87 
9.
De Angelis V, Biasinutto C, Pradella P, et al. Clinical significance of positive direct antiglobulin test in patients with HIV infection. Infection 1994;22:92-5 
10.
Koduri PR, Singa P, Nikolinakos. Autoimmune haemolytic anemia in patients infected with human immunodeficiency virus-1. Am J Hematol 2002;70:174-6 
11.
Volberding PA, Baker KR, Levine AM. Human immune deficiency virus hematology. Hematology Hematology Am Soc Hematol Educ Program 2003:294-313 
12.
Henry DH, Beall GN, Benson CA et al. Recombinant human erythropoietin in the treatment of anemia associated with human immunodeficiency virus (HIV ) infection and zidovudine therapy: overview of four clinical trials. Ann Intern Med 1992;117:739-48 
13.
Abrams DI, Steinhart C, Frascino R. Epoetin alfa therapy for anaemia in HIV-infected patients: impact on quality of life. Int J STD AIDS 2000;11:659-65 
14.
Moore JD, Keruly JC, Chaisson RE. Anemia and survival in HIV infection. J Acquir Immune Defic Syndr Hum Retovirol 1998;19:29-33 
15.
Nardi M, Karpatkin S. Antiidiotype antibody against platelet anti-GPIIIa contributes to the regulation of thrombocytopenia in HIV-1-ITP patients. J Exp Med 2000;191:2093-100 
16.
Coyle TE. Management of the HIV-infected patient. Part II. Med Clin North Am 1997;81:449-70 
17.
Nardi M, Karpatkin S. Antiidiotype antibody against platelet anti-GPIIIa contributes to the regulation of thrombocytopenia in HIV-1-ITP patients. J Exp Med 2000;191:2093-100 
18.
Volberding PA, Baker KR, Levine AM. Human immune deficiency virus hematology. Hematology Hematology Am Soc Hematol Educ Program 2003:294-313 
19.
Volberding PA, Baker KR, Levine AM. Human immune deficiency virus hematology. Hematology Hematology Am Soc Hematol Educ Program 2003:294-313 
20.
Coyle TE. Management of the HIV-infected patient. Part II. Med Clin North Am 1997;81:449-70 
21.
Coyle TE. Management of the HIV-infected patient. Part II. Med Clin North Am 1997;81:449-70 
22.
Volberding PA, Baker KR, Levine AM. Human immune deficiency virus hematology. Hematology Hematology Am Soc Hematol Educ Program 2003:294-313 
23.
Bain BJ. The haematological features of HIV infection. Br J Haematol 1997;99:1-8 
24.
Jacobsen MA, Khayam-Bashi H, Martin JN, et al. Effect of long-term highly active antiretroviral therapy in restoring HIV-induced abnormal B-lymphocyte function. JAcquir Immune Defic Syndr 2002;31:472-7 
25.
Fabris P, Tositti G, Giordani MT, et al. Prevalence and clinical significance of circulating cryoglobulins in HIV-positive patients with and without co-infection with hepatitis C virus. J Med Virol 2003;69:339-43 
26.
Sullivan PS, Dworkin MS, Jones JL, Hooper WC. Epidemiology of thrombosis in HIV-infected individuals. AIDS 2000;14:321-4 
27.
Saif MW, Bona R, Greenberg B. AIDS and thrombosis: retrospective study of 131 HIV-infected patients. AIDS Patient Care STDS 2001;15:311-20 
28.
Volberding PA, Baker KR, Levine AM. Human immune deficiency virus hematology. Hematology Hematology Am Soc Hematol Educ Program 2003:294-313