Anemia in HIV
Rajiv Gandhi University of Health Sciences,
Bangalore, Karnataka.
Proforma For Registration Of Subjects For Dissertation
1. Name of the candidate and address:
Dr.Arun Varghese T
Postgraduate,
Department of General Medicine,
St. John’s Medical College Hospital,
Sarjapur road, Bangalore -560034.
2. Name of the Institution:
St. John’s Medical College Hospital
3. Course of Study and Subject:
MD – Medicine
4. Date of Admission to Course:
19.03.2009
5. Title of the Topic:
A study of factors associated with anemia in HIV infected individuals in a tertiary care hospital
6. Brief resume of the intended work:
Introduction:
Human immunodeficiency virus (HIV) causes a broad spectrum of immunologic, infectious and neoplastic complications . Although these diseases are a major concern during the disease course, anemia has been observed as another complicating condition in HIV patients.. Anaemia is rarely a fatal complication ,however it does significantly increase the morbidity as well as precepitates preexisting illnesses. Hence these patients are at a higher risk for reduced survival.
6.1 Need for the study
The overall incidence of anemia among HIV positive patients ranges from 10% in asymptomatic patients up to 92% in individuals with full blown AIDS1. In HIV positive patient’s anemia is a prognostic marker of future disease progression or death, independent of CD4 and viral load2. Anemia impacts a range of dimensions of quality of life3. The common causes of anemia in HIV and non HIV patients are varied so treatment will differ .It may require the modification of antiretroviral drugs and the drugs used for the treatment of opportunistic infections. Hence knowledge of the pathophysiological mechanisms and the prevalence of various causes of anemia will help us in treatment of anemia in HIV positive patients. Very few studies have examined factors associated with anemia in the setting of a developing country.
6.2 Review of literature
According to kreuzer et al1, Potential pathogenetic causes for HIV-associated anemia
· HIV infection of hematopoietic stem cells/erythroid progenitor
· Bone marrow infections (Mycobacterium tuberculosis, atypical Mycobacterium)
· Myelosuppressive drugs (e.g., ZDV >750 mg/day, Ganciclovir)
· Vitamin B12, folate, iron deficiency (malnutrition, malabsorption, disturbed utilization)
· Aplastic anemia (Parvovirus B19, drug-induced)
· Bone marrow malignancies (non-Hodgkin’s lymphoma, Hodgkin’s disease, Kaposi’s sarcoma)
· Autoimmune hemolysis (red cell autoantibodies, circulating immune complexes)
· Blood loss (Intestinal bleeding)
Anemia of chronic diseases:
Anemia of chronic disease is the most frequent cause of anemia in HIV-infected patients. Red cells are mostly normocytic and normochromic; there may be mild anisocytosis with a few microcytes.
Some of the postulated mechanisms are:
· Direct toxic effect of HIV on hematopoietic stem cells and bone marrow microenvironment
· Abnormal expression of inhibitory cytokines.
· Relative deficiency of erythropoietin
· Defective iron metabolism and reutilization.
There is direct cytotoxic effect of HIV on hematopoietic stem cells as well as on stromal microenvironments of the bone marrow. This leads to decreased production of G-CSF and IL-3 resulting in defective erythropoiesis. Inhibitory effect of increased activity of IL-1,TNF-alpha and IFN-gamma on bone marrow erythropoiesis has also been postulated as a contributory factor towards marrow hypoplasia4. Other important mechanisms of anemia in AIDS are decreased erythropoietin production as well as decreased responsiveness of stem cells to erythropoietin5. A low CD4 cell count has a strong independent association with anemia even after controlling for opportunistic infections and malnutrition. This association may represent anemia caused by the HIV virus itself, which may inhibit haematopoiesis directly through infection of progenitor cells or up regulation of cytokines.6
HIV-related infections
A number of opportunistic infections can lead to defective hematopoiesis in HIV-infected patients; the commonest being Parvovirus B19 and Mycobacterium avium complex (MAC). Other less common infectious causes of anemia in HIV-infected patients include tuberculosis, histoplasmosis, cryptococcosis, and pneumocystis jirovecii . As TB is the second most common opportunistic infection in India (after oral candidiasis), it may greatly exacerbate the burden of anemia in this population. The aetiology of anemia in TB is multifactorial, resulting from a combination of anemia of chronic disease and deficiencies of nutrients such as iron, vitamin A and selenium7
Drug-induced anemia:
More than 20% of cases of anemia associated with HIV are drug induced8. The commonest agents are Zidovudine (AZT), and trimethoprim sulphamethoxazole. AZT causes significant macrocytosis (MCV > 100 fl), which is now being used by many as a screen for patient’s compliance with therapy. Treatment of anemia associated with trimethoprim-sulphamethoxazole which is used for the pneumocystis carinii infection in AIDS is due to folate deficiency and is more prevalent in patients with poor nutritional status. Dapsone on the other hand leads to generalized myelosuppression besides causing hemolytic anemia. Use of HAART was associated with an increase in hemoglobin levels during 1 year of follow-up. When used as part of a HAART regimen, patients who received zidovudine had a hemoglobin response that was not significantly different from patients who had alternate HAART regimens.
Hemolytic anemia
Direct antiglobulin (Coomb’s) test is positive in 37% of HIV-infected persons9 but clinically significant hemolysis is rare. This indicates that positive Coomb’s test in HIV-infection may simply be a reflection of polyclonal hypergammaglobulinemia which is common in HIV infection.
Gastrointestinal involvement in AIDS may cause blood loss anemia. Infections like cytomegalovirus colitis and malignancies like Kaposi’s sarcoma may also cause significant anemia due to gastrointestinal blood loss. Infiltration of the bone marrow by AIDS-associated lymphoma is less frequent but it can cause severe anemia. Hypogonadism is relatively common in HIV infected men10 In clinical terms, corrected reticulocyte counts may be a more useful parameter than serum erythropoietin levels in order to distinguish between potential Epo responders and non-responders1. Risk factors for anemia in developing countries may vary from those in developed countries due to endemic malnutrition, helminth infections, tuberculosis (TB), malaria and a different spectrum of opportunistic infections. Female gender, extrapulmonary TB and pulmonary TB also had strong independent associations with anemia. Age >31 years, oral and oesophageal candidiasis and generalized lymphadenopathy had milder independent associations with anaemia3
Three of the strongest factors associated with anemia – TB, immunosuppression and malnutrition – exacerbate each other in synergistic manner. The net result is a vicious cycle placing HIV-infected patients in TB-endemic countries at very high risk for developing anemia. Therefore, in addition to roll-out of HAART, nutritional support and aggressive TB control should be the cornerstones of anemia management for HIV-infected individuals in India.
Histologically, bone marrow hypoproliferation and dysplasia are the most commonly seen. Both AZT and d4T induce macrocytosis, however, AZT, has broader myelosuppressive effects both in vitro and in vivo. The management of anemia typically includes correction of the underlying cause(s) and blood transfusion or erythropoietin.1
Objectives of the study
• To study the etiology of of anemia in HIV positive individuals
• To study the relationship between anemia and immunological status as indicated by the CD4 count
Materials and methods .
Type of study- Descriptive/cross sectional study
7.1 Source of Data:
All HIV positive patients(old and newly diagnosed) who are admitted in the study period of one year from January 2010 to December 2010 and having anemia as a clinical feature will be included. It is to be conducted in the medical wards of our hospital.
7.2 Method of Collection of Data:
Obtain consent
Information regarding
Demography,
Clinical symptoms signs,
Treatment (ART and antiopportunistic drugs)
CD4 counts are to be obtained
Then the workup for anemia
Routine hemogram,
Reticulocyte count,
Cell volume
Peripheral smear
Bone marrow and other relevant investigations (DCT/ ferritin/ vitaminB12/ folate etc.)according to these primary investigations will be done.
The various factors influencing the anemia are to be analyzed.
(Anemia is classified by the following World Health Organization (WHO) criteria for both men and women:
Grade one (9.5–10.9 g/dl),
Grade two (8–9.4 g/dl),
Grade three (6.5–7.9 g/dL) and
Grade four (<,6.5 g/dL).
For comparison with other studies, anima is also reclassified as hemoglobin values, 12 g/dL for women and 13 g/dL for men).
Statistical analyses will be performed with SPSS (version 10.0.5; Chicago, IL, USA). Normal data will be summarized using mean and standard deviation (SD) and non-normal data using median and interquartile range. Correlation coefficient will be used to compare hemoglobin values and CD4 counts.
7.3 Does the study require any investigations or interventions to be conducted on patients or other humans or animals if so, please describe briefly- The routine investigations being done for evaluation of anemic patients are needed for the study.
8. List of references:
1 K.-A. Kreuzer, J. K. Rockstroh . Pathogenesis and pathophysiology of anemia in HIV infection. Ann Hematol 1997: 75:179–187.
2 Graeme Moyle. Anaemia in Persons with HIV Infection. Prognostic Marker and Contributor to Morbidity. AIDS Rev 2002:4:13-20.
3 R Subbaraman MD, B Devaleenal MBBS, P Selvamuthu MBBS DGO, T Yepthomi MBBS, S S Solomon MBBS MPH, K H Mayer MD, N Kumarasamy MBBS PhD . Factors associated with anaemia in HIV-infected individuals in southern India. International Journal of STD & AIDS.2008: 20: 7 : 489-492 .
4 Fuchs D, Zangerele R, Astuer-Dworzak E, Weiss G,Fritsh P, Tilz GP, Dierich MP, Wachter H. Association between immune activation, changes of iron metabolism and anemia in patients with HIV infection. Eur J Hematol. 1993:50:90.
5 Costaldo A, Tarallo L, Palomba E. Iron deficiency and intestinal malabsorbtion in HIV disease. J PediatrGastroenterol Nutr .1996:22:359-363.
6 Semba RD, Gray GE. Pathogenesis of anemia during human immunodeficiency virus infection. J Investig Med. 2001:49:225–239.
7 Van Lettow M, West CE, van der Meer JW. Low plasma selenium concentrations, high plasma human immunodeficiency virus load and high interleukin-6 concentrations are risk factors associated with anemia in adults presenting with pulmonary tuberculosis in Zomba district, Malawi. Eur J Clin Nutr: 2005:59:526–532
8 Haseeb-ul Hasan Moinuddin .Hematological manifestations in HIV infected persons. Pak J Med Sci .2003:19 : 4
9 Ellaurie M, Burns ER, Rubinstein A. Hematologic manifestation in pediatric HIV infection; severe anemia as a prognostic factor. Ann J Pediatr Hematol Oncology .1990:12: 449-453.
10 Laudat A, Blum L, Guechot J. Changes in systemic gonadal and adrenal steroids in asymptomatic human immunodeficiency virus infected men. Eur J Endocrinol 1995: 133: 418-422.
9. Signature of the candidate:
11. Name and designation of
11.1 Guide: Dr Sara Chandy (Associate professor)
11.2 Signature
11.5 Head of Department: Dr SD Tarey (Professor)
11.6 Signature
11.7 Dean
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