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HIV-associated cytopenias

HIV-associated cytopenias
Literature review current through: Jan 2024.
This topic last updated: Jan 10, 2024.

INTRODUCTION — Human immunodeficiency virus (HIV) can infect multiple hematopoietic cell types and cause several hematologic abnormalities.

This topic review discusses an approach to evaluating and managing cytopenias (anemia, thrombocytopenia, neutropenia, pancytopenia) in people with HIV. Related aspects of HIV care are discussed in separate topic reviews:

General management – (See "Initial evaluation of adults with HIV" and "Primary care of adults with HIV".)

Choice of antiretroviral therapy (ART) regimen – (See "Selecting antiretroviral regimens for treatment-naïve persons with HIV-1: General approach".)

ART agents overview – (See "Overview of antiretroviral agents used to treat HIV".)

Opportunistic infections overview – (See "Overview of prevention of opportunistic infections in patients with HIV".)

GENERAL CONCEPTS

Definitions

Anemia – Anemia refers to hemoglobin or hematocrit below the age-specific and sex-specific reference range. Anemia is correlated with poor prognosis in people with HIV, although a causal association has not been determined [1].

Thrombocytopenia – Thrombocytopenia is defined as a platelet count <150,000/microL. Bleeding risk is most likely to increase in individuals with severe thrombocytopenia (platelet count <30,000/microL), although the absolute bleeding risk depends on several factors and is difficult to predict.

Neutropenia – The reference range for the absolute neutrophil count (ANC; neutrophils plus bands) depends on the individual's Duffy antigen status. (See "Red blood cell antigens and antibodies", section on 'Duffy antigens'.)

Non-Duffy-null - Neutropenia in non-Duffy-null individuals is generally defined as an absolute neutrophil count (ANC; neutrophils plus bands) <1500/microL (calculator 1). The risk of infection depends on the underlying cause of neutropenia and the ANC, with the greatest risk in individuals with bone marrow suppression and an ANC <500/microL.

Duffy-null - Definitions of neutropenia in Duffy-null individuals have not been well-established. Duffy-null associated neutrophil count (DANC, formerly referred to as constitutional neutropenia, benign ethnic neutropenia [BEN], or benign familial neutropenia) might be related to reduced clearance of cytokines by RBCs. Approximately 10 to 15 percent of Duffy-null individuals have an ANC <1500/microL, which is not associated with an increased risk of infections. (See "Laboratory test reference ranges in adults", section on 'ANC (absolute neutrophil count)' and "Gene test interpretation: ACKR1 (Duffy blood group gene)", section on 'Reference ranges for Duffy-null and non-Duffy-null'.)

Lymphopenia – Lymphopenia (also called lymphocytopenia) is generally defined as an absolute lymphocyte count (ALC) <1000 cells/microL in adults and older children; younger children may have higher lymphocyte counts. (See "Approach to the adult with lymphocytosis or lymphocytopenia", section on 'Definitions and normal values' and "Approach to the child with lymphocytosis or lymphocytopenia", section on 'Lymphocytopenia'.)

Bi-cytopenias and pancytopenia – Bi-cytopenia refers to reduction of two cell lines; pancytopenia refers to reduction of all three cell lines (red blood cells, white blood cells, and platelets).

Prevalence in untreated patients — The prevalence of cytopenias has declined over the course of the HIV epidemic, likely due to earlier diagnosis and use of less-toxic combination antiretroviral therapy (ART). However, cytopenias continue to occur, both as a presenting finding or during the disease or its treatment.

Case series have generally found neutropenia to be most common, followed by anemia and thrombocytopenia:

In a series of 621 people with HIV living in Seoul, South Korea from 2005 to 2010 who had not started ART, after exclusion of 149 individuals with known conditions other than HIV that could cause cytopenias, the following frequencies were noted [2]:

Lymphopenia – 26 percent

Neutropenia – 10 percent

Anemia – 3 percent

Thrombocytopenia – 2.4 percent

The median CD4 count before ART was 300/microL. Treatment with ART reversed the cytopenias in most cases (84 percent of lymphopenias, 91 percent of neutropenias, 85 percent of anemias, and all thrombocytopenias).

A series of 1571 people with HIV living in a number of countries in Africa, Asia, and the Americas with CD4 cell counts <300/microL who were evaluated between 2005 and 2007 and who had not started ART found the following frequencies of cytopenias [3]:

Neutropenia – 14 percent

Anemia – 12 percent

Thrombocytopenia – 7 percent

Approximately 5 percent had more than one cytopenia (mostly bi-cytopenias). Cytopenias were somewhat less common in the Americas compared with Africa and Asia, but there was significant heterogeneity across countries.

Data regarding specific cytopenias include the following:

Anemia – Anemia may be more common in certain populations. In the pre-ART era, anemia was common in individuals with AIDS (as many as 70 percent in one early series) [4]. In a study of 400 people with HIV living in Uganda who were not receiving long-term ART, nearly one-half had anemia [5]. In a series of 905 adults in the Johns Hopkins Clinic Cohort from 2002, 27 percent had a hemoglobin level between 10 and 12 g/dL, and an additional 11 percent had a hemoglobin level <10 g/dL [6]. Institution of ART resulted in a hemoglobin level above 12 g/dL in 83 percent, suggesting that the anemia was due to HIV or an opportunistic infection that resolved with ART. The frequency of anemia has declined, but mild anemia (eg, hemoglobin in the 10 to 12 g/dL range) remains common [7].

Thrombocytopenia – Thrombocytopenia is often seen as a sentinel event in HIV infection:

In one early series of patients with AIDS published in 1982 (the pre-ART era), thrombocytopenia was noted in 40 percent [4].

In a case-control study from the ART era (2009) that included 73 people with HIV who had platelet counts <100,000/microL and 73 people with HIV who had normal platelet counts, risk factors for thrombocytopenia included HIV RNA >400 copies/mL, hepatitis C virus (HCV) infection, and cirrhosis (adjusted odds ratios [ORs] 5.3, 6.1, and 24, respectively) [8]. The individuals with thrombocytopenia were more likely to have major bleeding than controls (18 versus 3 percent; OR 6.5, 95% CI 1.5-29). There were no fatal bleeding events, but thrombocytopenia was correlated with death from other causes.

In a systematic review from 2011 that evaluated participants in the Collaborations in HIV Outcomes Research/US (CHORUS) cohort from 1997 to 2006 and participants in HIV clinical trials from 1996 to 2004, the prevalence of thrombocytopenia was approximately 14 percent in both cohorts [9].

A 2012 publication from the British Columbia Centre for Excellence in HIV/AIDS reported that in the ART era, thrombocytopenia was only diagnosed in 0.6 percent of 5290 people living with HIV [10].

Unexplained thrombocytopenia has been identified as an indicator condition that should trigger testing for HIV [11-13]. Data from a large European cohort obtained between 2009 and 2011 demonstrated a 3.2 percent prevalence of HIV infection among individuals presenting with unexplained thrombocytopenia or leukopenia lasting for more than four weeks [11]. Thrombocytopenia due to direct effects of HIV or immune thrombocytopenia (ITP) typically resolves within one to five months of starting ART. (See 'Mechanisms' below.)

Neutropenia – In a longitudinal study from 2016 in over 370,000 individuals in a primary care practice, HIV was one of the more common causes of neutropenia, accounting for 30 of 188 cases (16 percent) [14]. Unexplained leukopenia (low white blood cell count), which is usually due to neutropenia, has been identified as an indicator condition that should trigger HIV testing [11,12].

Bi-cytopenias or pancytopenia – Case reports have described presentations in people with HIV, including various combined cytopenias or pancytopenia, which may be due to several conditions including primary HIV infection, opportunistic infections, thrombotic microangiopathies (TMAs), hemophagocytic lymphohistiocytosis (HLH), or a hematologic malignancy. (See 'Clinical case vignettes' below.)

Mechanisms — HIV can infect hematopoietic stem cells and can impair production of any hematopoietic lineage (lymphocytes, granulocytes, red blood cells, or platelets) [15]. HIV can also suppress the bone marrow via production of proinflammatory cytokines that block hematopoiesis [7,14]. Underlying causes are summarized in the table (table 1).

Opportunistic infections due to HIV-induced immunosuppression can also affect developing blood cells, either directly or via cytokine upregulation. In the epidemiologic study involving people with HIV living in Korea who had not yet started treatment (see 'Prevalence in untreated patients' above), over 90 percent of the cytopenias resolved with institution of combination ART [2].

Autoimmune mechanisms (immune thrombocytopenia [ITP], autoimmune hemolytic anemia [AIHA], autoimmune neutropenia) and vitamin deficiencies such as vitamin B12 deficiency are other common causes of cytopenias [15]. In an otherwise well individual with thrombocytopenia as the presenting finding of HIV, thrombocytopenia is often mediated by autoantibodies or direct effects of HIV on the bone marrow, and the institution of ART is likely to resolve the thrombocytopenia or at least raise the platelet count into a safe range to reduce the risk of bleeding. In a systematic review from 2011, the time to improvement in platelet count varied from approximately one month in the clinical trials group to approximately five months in the CHORUS cohort [9].

Occult or overt liver disease, such as from concomitant viral hepatitis or steatohepatitis, may cause mild cytopenias due to hypersplenism; thrombocytopenia may also be due to reduced thrombopoietin levels in severe liver disease. (See 'Thrombocytopenia' below.)

Drug-induced cytopenias can also occur in people with HIV, often due to antibiotics or cancer chemotherapy. There are several potential mechanisms, including immune reactions, bone marrow toxicity, or oxidant injury, especially in individuals with glucose-6-phosphate dehydrogenase (G6PD) deficiency. In contrast to antibiotics and chemotherapy, drug-induced cytopenias due to combination ART are uncommon. This differs from the early HIV/AIDS epidemic, when several cytopenias were commonly caused by early antiretroviral therapies such as zidovudine.

ILL/SYMPTOMATIC PATIENT; CD4 CELL COUNT <200/microL — There are numerous potential causes of cytopenias in individuals with low CD4 counts. Typically, a CD4 count <200 cells/microL is used as a marker to indicate increased risk of opportunistic infections, but there is no absolute cutoff, and different infections become more likely at different CD4 cell counts depending on whether the HIV virus is effectively suppressed by antiretroviral therapy (ART), as discussed separately. (See "Overview of prevention of opportunistic infections in patients with HIV".)

Rapid evaluation for acutely ill/symptomatic patients — The evaluation in an acutely ill or symptomatic patient with a low CD4 cell count (<200/microL) and one or more cytopenias focuses on identifying life-threatening opportunistic infections, malignancies, and other rare disorders.

Individuals with fever and/or severe reductions in cell counts may warrant ferritin testing (for hemophagocytic lymphohistiocytosis [HLH]) as well as urgent hematology evaluation with review of the blood smear and possible bone marrow testing for malignancy, opportunistic infections, and hemophagocytosis. (See 'Other 'can't miss' diagnoses (TMAs, HLH, HHV8 disorders)' below and 'Bone marrow: Indications and specific testing' below.)

Key findings on the blood smear that help narrow the diagnosis and point to a specific therapy include:

Infectious organisms (eg, intracellular red cell parasites such as Babesia) – (See 'Evaluating for OIs and other infections' below.)

Immature white blood cells (blasts) – (See 'Testing for hematologic and other malignancies' below.)

Schistocytes, suggestive of a thrombotic microangiopathy (TMA) – (See 'Other 'can't miss' diagnoses (TMAs, HLH, HHV8 disorders)' below.)

Macrocytosis of red blood cells, suggestive of thyroid dysfunction, vitamin B12 or folate deficiency, alcohol use, or liver disease – (See "Macrocytosis/Macrocytic anemia".)

Microcytic red blood cells, suggestive of iron deficiency or thalassemia – (See "Microcytosis/Microcytic anemia".)

Findings suggestive of drug-induced hemolytic anemia (bite cells, spherocytes, polychromatophilic cells [reticulocytes]) – (See 'Non-HIV causes of anemia' below.)

ART is initiated concurrently in almost all cases. (See 'Role of ART' below.)

Evaluating for OIs and other infections — Testing for opportunistic infections (OIs) is appropriate in people with HIV who have a low CD4 cell count along with fevers, other systemic symptoms (weight loss, sweats, chills), and/or localizing findings such as respiratory or neurologic symptoms. The incidence of most OIs is greatest in individuals with CD4 cell counts <200/microL (<100/microL for certain fungal and mycobacterial infections) [16,17]. However, the risk of developing an OI is markedly reduced if the patient's viral load is suppressed by ART, even if the CD4 cell count is <200 cells/microL.

Testing for localized or disseminated bacterial and other infections is appropriate for most patients who present with a fever and cytopenias. The initial evaluation typically includes standard blood cultures, urine culture, and chest radiography.

Additional evaluation depends upon the patient's presentation and type of cytopenia. As examples:

Testing for Mycobacterium avium complex (MAC) with mycobacterial blood cultures and for Cryptococcus by checking a serum cryptococcal antigen is typically done if the CD4 cell count is <100/microL. The risk for MAC is even greater if the CD4 cell count is <50/microL. (See "Mycobacterium avium complex (MAC) infections in persons with HIV" and "Epidemiology, clinical manifestations, and diagnosis of Cryptococcus neoformans meningoencephalitis in patients with HIV" and "Cryptococcus neoformans infection outside the central nervous system".)

Testing for parvovirus, using polymerase chain reaction (PCR), is warranted in a patient with fevers, severe isolated anemia (particularly if the reticulocyte count is very low), and a CD4 cell count of <100 cells/microL. (See "Clinical manifestations and diagnosis of parvovirus B19 infection".)

Testing for cytomegalovirus (CMV) using PCR is appropriate if there is evidence of organ involvement, such as gastrointestinal disease, hepatitis, or retinitis, or a mononucleosis-like syndrome or a hemophagocytic lymphohistiocytosis (HLH)-like syndrome. (See 'Other 'can't miss' diagnoses (TMAs, HLH, HHV8 disorders)' below and "Overview of diagnostic tests for cytomegalovirus infection".)

Testing for Epstein-Barr virus (EBV) using PCR is appropriate if there is a mononucleosis-like syndrome or an HLH-like syndrome. (See 'Other 'can't miss' diagnoses (TMAs, HLH, HHV8 disorders)' below and "Clinical manifestations and treatment of Epstein-Barr virus infection".)

Testing for tuberculosis is appropriate in individuals exposed via travel to an endemic area or close contact with an infected individual. (See "Tuberculosis transmission and control in health care settings".)

Bone marrow aspirate and biopsy is appropriate if other testing is negative and the findings might change clinical decision making. (See 'Bone marrow: Indications and specific testing' below.)

Additional evaluation also depends upon risk factors and may include evaluation for tuberculosis, malaria, histoplasmosis, leishmania, coccidioidomycosis, and/or talaromycosis (previously called penicilliosis). (See "Treatment of histoplasmosis in patients with HIV" and "Visceral leishmaniasis: Clinical manifestations and diagnosis" and "Primary pulmonary coccidioidal infection" and "Diagnosis and treatment of Talaromyces (Penicillium) marneffei infection" and "Malaria: Clinical manifestations and diagnosis in nonpregnant adults and children", section on 'HIV infection'.)

The use of empiric antibiotics pending evaluation depends upon the presence of neutropenia and the severity of disease. (See 'Fever and neutropenia' below.)

Additional details about these infections are presented separately:

Coccidioidomycosis – (See "Primary pulmonary coccidioidal infection".)

Cryptococcus – (See "Epidemiology, clinical manifestations, and diagnosis of Cryptococcus neoformans meningoencephalitis in patients with HIV" and "Cryptococcus neoformans infection outside the central nervous system".)

Histoplasmosis – (See "Treatment of histoplasmosis in patients with HIV".)

Leishmaniasis [18] – (See "Visceral leishmaniasis: Clinical manifestations and diagnosis".)

MAC organisms – (See "Mycobacterium avium complex (MAC) infections in persons with HIV".)

Toxoplasmosis – (See "Toxoplasmosis in patients with HIV".)

Tuberculosis – (See "Treatment of drug-susceptible pulmonary tuberculosis in nonpregnant adults with HIV infection: Initiation of therapy".)

Testing for hematologic and other malignancies — HIV/AIDS confers an increased risk of certain hematologic malignancies, especially Hodgkin and non-Hodgkin lymphomas. Lymphoma may cause cytopenias by several mechanisms including bone marrow involvement, splenic involvement, and immune cytopenias such as immune thrombocytopenia (ITP) and autoimmune hemolytic anemia (AIHA).

Evaluating for opportunistic malignancies is appropriate in people with HIV regardless of CD4 cell count particularly if they have fevers, other systemic symptoms (weight loss, sweats, chills), and/or physical findings to suggest a malignancy such as lymphadenopathy, splenomegaly, skin lesions suggestive of Kaposi sarcoma or cutaneous lymphoma, or abnormal-appearing white blood cells on the blood smear. Patients with Burkitt lymphoma may have normal or near normal CD4 cell counts.

The evaluation of lymphoma or unexplained and clinically significant cytopenias typically involves bone marrow aspirate and biopsy with specialized testing. (See 'Bone marrow: Indications and specific testing' below.)

For individuals with lymphadenopathy, lymph node biopsy may also be helpful, especially if the bone marrow is unrevealing. Positron emission tomography with computed tomography (PET-CT) may be used to identify a fluorodeoxyglucose (FDG)-avid mass or bone lesion in an individual who requires biopsy for suspected cancer.

Additional details of the diagnostic testing and management of specific disorders are discussed in separate topic reviews:

Primary effusion lymphoma (PEL) – (See "Primary effusion lymphoma".)

Central nervous system (CNS) lymphomas – (See "HIV-related lymphomas: Primary central nervous system lymphoma".)

Burkitt leukemia/lymphoma – (See "Treatment of Burkitt leukemia/lymphoma in adults", section on 'AIDS-related lymphoma'.)

Hodgkin and non-Hodgkin lymphomas – (See "HIV-related lymphomas: Clinical manifestations and diagnosis" and "HIV-related lymphomas: Treatment of systemic lymphoma".)

Leukemia and plasma cell disorders – (See "HIV infection and malignancy: Management considerations", section on 'Lymphoproliferative and hematologic malignancies'.)

If the patient has a hematologic malignancy for which immediate chemotherapy is warranted, ART is usually started concurrently (or staggered by a few days). Individuals with advanced HIV infection and lymphoma may be more sensitive to the bone marrow-suppressive effects of chemotherapy.

There are complex drug-drug interactions between some cancer drugs and various ART regimens. It is important for a pharmacist and/or an infectious disease physician to review and advise medical teams on these interactions. Additional details regarding overlapping toxicities of systemic chemotherapy and ART, as well as strategies to minimize these toxicities, are presented in detail separately. (See "Systemic therapy for malignancy in patients on antiretroviral medications".)

Other 'can't miss' diagnoses (TMAs, HLH, HHV8 disorders) — Several other conditions should be considered, with the threshold for testing determined by additional findings in the initial evaluation.

HHV8-associated disorders – Human herpes virus 8 (HHV8) is the cause of Kaposi sarcoma (KS) and a form of multicentric Castleman disease (MCD). HHV8-associated disorders may be suspected in an individual with HIV and a low CD4 cell count who presents with fever, systemic symptoms, lymphadenopathy (especially in multiple lymph nodes), hepatosplenomegaly, and cytopenias. KS and MCD can coexist in the same patient. Further details of the evaluation are discussed separately. (See "HHV-8/KSHV-associated multicentric Castleman disease".)

HLH – Hemophagocytic lymphohistiocytosis (HLH) is a syndrome of immune dysregulation in which there is excessive activation of immune cells (macrophages, natural killer cells, and cytotoxic lymphocytes) that results in inflammation and tissue damage, including involvement of bone marrow and cytokine storm. The cause may involve a heritable genetic variant, underlying malignancy (most commonly hematologic), and/or connective tissue disorder. Immunodeficiency states including HIV/AIDS are also implicated in some cases [19,20]. (See 'Clinical case vignettes' below and "Clinical features and diagnosis of hemophagocytic lymphohistiocytosis".)

HLH may be suspected in a child or adult who presents with cytopenias, fever, neurologic findings, and/or coagulopathy. The evaluation includes several laboratory tests, genetic testing, and bone marrow evaluation, as discussed in detail separately. Extreme elevations in triglyceride levels, IL-2 receptor, and serum ferritin are among the laboratory hallmarks of HLH. Several commercially available gene panels may be used to test for familial HLH. (See "Clinical features and diagnosis of hemophagocytic lymphohistiocytosis", section on 'Evaluation and diagnostic testing'.)

HLH is treatable, with some individuals responding to treatment of the underlying (causative) disorder and others requiring systemic chemotherapy (and in some cases hematopoietic cell transplantation), as discussed in detail separately. Early involvement of the consulting hematologist is advised. (See "Treatment and prognosis of hemophagocytic lymphohistiocytosis".)

TMAs – Thrombotic microangiopathies (TMAs) involve microvascular thrombosis associated with thrombocytopenia and microangiopathic hemolytic anemia (MAHA), inferred from finding schistocytes on the peripheral blood smear (picture 1). The index of suspicion is raised if there is thrombocytopenia and evidence of end-organ ischemia (eg, neurologic symptoms, reduced kidney function). Coagulation studies are typically normal (ie, prothrombin time [PT] and activated partial thromboplastin time [aPTT] are not prolonged). An approach to distinguishing among TMAs and immediate initial management decisions are discussed separately. (See "Diagnostic approach to suspected TTP, HUS, or other thrombotic microangiopathy (TMA)", section on 'Initial evaluation (all patients)'.)

There are several types of primary TMAs with different underlying causes:

TTP – Autoimmune thrombotic thrombocytopenic purpura (TTP) is an acquired condition in which autoantibodies directed against the protease ADAMTS13 cause severe ADAMTS13 deficiency (typically, activity <10 percent), along with thrombocytopenia and MAHA. Neurologic findings are common; kidney failure is rare. Therapy involves plasma exchange along with immunosuppressive therapy until the results of ADAMTS13 testing. (See "Diagnosis of immune TTP" and "Immune TTP: Initial treatment".)

DITMA – Drug-induced TMA (DITMA) can be caused by several medications (including chemotherapy drugs such as gemcitabine and oxaliplatin), drugs of abuse, and quinine, which is present in over-the-counter tablets for leg cramps and certain beverages. The major therapy involves drug discontinuation and supportive care. (See "Drug-induced thrombotic microangiopathy (DITMA)".)

HUS – Hemolytic uremic syndrome (HUS) is characterized by thrombocytopenia and MAHA occurring in the setting of acute kidney injury. There are infectious causes (eg, Shiga toxin-producing diarrheal organisms) and non-infectious causes (eg, alterations in complement regulation). Treatment is usually supportive, although some individuals may be treated with anti-complement therapies or other interventions. (See "Overview of hemolytic uremic syndrome in children" and "Complement-mediated hemolytic uremic syndrome in children" and "Thrombotic microangiopathies (TMAs) with acute kidney injury (AKI) in adults: CM-TMA and ST-HUS".)

Other causes of MAHA and thrombocytopenia include disseminated intravascular coagulation (DIC), severe hypertension, and pregnancy-associated conditions such as severe preeclampsia/HELLP syndrome. (See "Diagnostic approach to suspected TTP, HUS, or other thrombotic microangiopathy (TMA)".)

People with HIV can develop any of these conditions. In the early years of the HIV epidemic, TMA was more common; the incidence has been declining with the use of combination ART.

In a 2004 report from the Collaborations in HIV Outcomes Research/US (CHORUS) cohort that evaluated the presence of TMA in people with HIV, 17 (0.3 percent) were diagnosed with a TMA [21]. Most had an opportunistic (AIDS-defining) infection and a CD4 cell count <200/microL. The underlying cause of TMA was not well-established, as the distinction between TTP and HUS relied on clinical features and disease severity (there was no ADAMTS13 or complement testing).

In a 2009 report from the Oklahoma TTP registry that included 326 individuals with a TMA, six (1.8 percent) were diagnosed with HIV infection [22]. In most cases, the findings of MAHA and thrombocytopenia were attributed to a cause other than TTP such as severe hypertension or disseminated malignancy. MAHA and thrombocytopenia in a person with HIV is considered a secondary disorder rather than a primary TMA, the implication being that therapy is directed at the infection rather than at the TMA itself in the majority of patients.

Bone marrow: Indications and specific testing — Bone marrow aspirate and biopsy with additional specialized testing can be helpful in making the diagnosis of an infection or malignancy but is not always required.

Depending on the diagnoses under consideration, the following testing on the bone marrow is appropriate:

Staining for acid fast bacilli, fungi, iron, and viral pathogens

Flow cytometry using lymphoid markers

Chromosomal analysis if there are blasts on the peripheral blood smear

Close evaluation for hemophagocytosis if the ferritin is elevated (eg, >500 ng/mL)

Fluorescence in situ hybridization (FISH) and chromosome analysis

The urgency of bone marrow testing depends on the suspected diagnoses, as discussed in the sections above. Coordination with the hematology consultant is important to ensure that appropriate testing for malignancy and infection is performed and that the timing of sample submission is optimized.

Immediate interventions in the acute setting

Fever and neutropenia — Fever and neutropenia in a person with HIV may differ in significance from fever and neutropenia in a person with cancer who has received chemotherapy. This is because chemotherapy-induced neutropenia is also associated with toxicity to gut epithelial cells, which greatly increases the risk of bacterial seeding due to loss of integrity of the bowel wall.

However, fever in a person with HIV-associated neutropenia could be a sign of a life-threatening infection, and empiric antibiotics are given when there is fever and an absolute neutrophil count (ANC) <500/microL (calculator 1) while assessing and treating the causes of fever and neutropenia. Antibiotics may be discontinued following negative culture results, rather than waiting for the neutropenia to resolve as is done with chemotherapy-induced neutropenia; this decision is individualized.

Management of neutropenia may also involve one or more of the following:

Narrowing or altering antibiotic spectrum (eg, switch to anti-fungal therapy).

Discontinuing drugs known to cause neutropenia (with substitution of alternatives of a different class if possible). (See "Drug-induced neutropenia and agranulocytosis".)

Use of growth factors (eg, granulocyte colony-stimulating factor [G-CSF]), especially in those with severe neutropenia (ANC <500 or <750/microL), longer expected duration of neutropenia, or other features that increase infectious risk. Hematologist input is usually sought. (See 'Role of G-CSF' below.)

Acutely ill patient with thrombocytopenia — A finding of schistocytes on the blood smear is highly suggestive of a TMA or other cause of microangiopathic hemolysis such as DIC. In most cases, initial management of suspected TTP or other TMA is based on a presumptive clinical diagnosis until laboratory data become available, and subsequent management is based on laboratory findings. There is no evidence to alter practice in people with HIV. The PLASMIC score is useful for evaluating the likelihood of TTP (calculator 2), although it has not been validated in people with HIV. (See "Diagnosis of immune TTP" and "Diagnostic approach to suspected TTP, HUS, or other thrombotic microangiopathy (TMA)".)

If none of the above diagnoses are present, it may be appropriate to start empiric treatment for immune thrombocytopenia (ITP), which is a diagnosis of exclusion. (See 'Interventions for bleeding or severe thrombocytopenia' below.)

STABLE OR ASYMPTOMATIC PATIENTS

Overview of approach to the evaluation (stable patients) — The main difference in the evaluation of a stable or asymptomatic (or minimally symptomatic) patient is that severe infections are less likely and there is generally more time to perform a more systematic evaluation. Stable patients can be stratified according to whether they are receiving antiretroviral therapy (ART):

Patient on ART – For those on effective ART who have viral suppression and a high CD4 cell count, the approach is like individuals without HIV, and the emphasis should be on non-HIV causes of cytopenias.

Our general approach is to review the medication list, the CD4 cell count, and the findings on complete blood count (CBC), including red blood cell indices, presence of immature cells, and blood cell morphology. For individuals with concerning findings (eg, lymphadenopathy, other cytopenias, abnormal red blood cell indices), we also review the blood smear. For those with anemia, the reticulocyte count is obtained to distinguish impaired red blood cell production from hemolysis.

Patient not on ART – For those not on ART who are relatively well and have one or more cytopenias as the presenting finding of HIV, initiation of ART is generally appropriate. There is usually time to review the medication list and CBC as noted above.

However, unless a non-HIV cause is apparent, we often defer extensive testing for the cause of cytopenias until the individual has been on ART for several months (assuming the cytopenias are not worsening), as HIV is often the cause, and ART is likely to resolve cytopenias in the majority of these individuals.

We generally would not check M. avium complex (MAC) cultures in a patient who is asymptomatic (ie, who does not have fever, weight loss, diarrhea, hepatosplenomegaly, lymphadenopathy, and/or abnormal liver function tests). (See 'Prevalence in untreated patients' above and 'Role of ART' below.)

Additional testing and interventions to raise blood counts in specific cytopenias are discussed below.

Role of ART — Antiretroviral therapy (ART) is indicated in all people with HIV. Thus, if an individual with HIV develops cytopenias and is not receiving ART, therapy should be initiated, except in select settings (eg, cryptococcal meningitis, where initiation of ART may be delayed temporarily). (See "Cryptococcus neoformans meningoencephalitis in persons with HIV: Treatment and prevention".)

Any barriers to treatment should be addressed. In some cases, this will be enough to treat the cytopenia(s); in other cases, additional interventions may be required, as discussed in the following sections and the case vignettes below. (See 'Clinical case vignettes' below.)

The presence of specific cytopenias is not a factor in the choice of current ART regimens. For people who have not started ART, any of the preferred ART regimens can be used, unless there are associated comorbid conditions (eg, reduced kidney function). (See "Selecting antiretroviral regimens for treatment-naïve persons with HIV-1: General approach" and "Selecting antiretroviral regimens for treatment-naive persons with HIV-1: Patients with comorbid conditions".)

For patients who have been treated and have drug-resistant virus, there may be fewer options. Zidovudine should be avoided in people with cytopenias if possible (eg, if other treatment options are available).

Detailed discussions about selecting an ART regimen are presented separately. (See "Selecting antiretroviral regimens for treatment-naïve persons with HIV-1: General approach" and "Selecting an antiretroviral regimen for treatment-experienced patients with HIV who are failing therapy".)

Anemia

HIV-associated causes of anemia — HIV-associated causes of anemia are listed above. (See 'Ill/symptomatic patient; CD4 cell count <200/microL' above.)

Non-HIV causes of anemia — For all patients, the possibility of anemia due to causes other than HIV should also be considered. A discussion of the approach to evaluating anemia is presented separately, with selected causes and testing described briefly below. (See "Diagnostic approach to anemia in adults".)

Iron or vitamin deficiencies – Iron deficiency anemia is suspected when there is red blood cell microcytosis and hypochromia on the blood smear, especially in an individual with a history of malnutrition, bleeding, gastric bypass surgery, heavy menses, or prior pregnancies. In a retrospective study of 248 children with HIV living in India, 66 percent had a hemoglobin level <11 g/dL and 8 percent had a hemoglobin level <7 g/dL [23]. The use of iron supplementation or multivitamins correlated with a reduced likelihood of anemia (odds ratio [OR] 0.44, 95% CI 0.22-0.90), suggesting that iron deficiency and other deficiencies played a significant role. However, the use of ART in this study was even more strongly correlated with the absence of anemia (OR 0.29, 95% CI 0.16-0.53).

Standard testing for iron deficiency is appropriate, with iron studies including ferritin level and transferrin saturation (TSAT); in many cases, the interpretation is affected by concurrent inflammation, and additional testing may be warranted, as discussed separately. Individuals diagnosed with iron deficiency should be evaluated for the underlying cause, which may include insufficient dietary iron, impaired iron absorption, and/or bleeding. (See "Iron deficiency in infants and children <12 years: Screening, prevention, clinical manifestations, and diagnosis", section on 'Evaluation for suspected iron deficiency anemia' and "Iron requirements and iron deficiency in adolescents", section on 'Evaluation and presumptive diagnosis' and "Causes and diagnosis of iron deficiency and iron deficiency anemia in adults", section on 'Diagnostic evaluation'.)

Vitamin B12 or folate deficiency may be suspected in an individual with red blood cell macrocytosis or megaloblastic changes on the blood smear (hypersegmented neutrophils), especially if there is malnutrition or neurologic findings. A normal mean corpuscular volume (MCV) but wide red cell distribution width (RDW) may be an additional clue to a mixed picture anemia such as seen with vitamin B12 or folate deficiency superimposed on concomitant iron deficiency. Testing with vitamin B12 and folate levels is discussed separately. (See "Clinical manifestations and diagnosis of vitamin B12 and folate deficiency".)

Parvovirus – The likelihood of parvovirus-associated anemia is low in individuals on effective ART who have viral suppression and a high CD4 cell count [24]. However, case reports continue to describe individuals with severe anemia due to parvovirus. (See 'Clinical case vignettes' below.)

Parvovirus B19 has tropism for erythroid progenitor cells in the bone marrow, and infection can cause erythroid production to cease. This is generally clinically silent in individuals with normal hematopoietic function, but severe anemia can be seen in certain cases (eg, prolonged parvovirus infection due to impaired immune function; chronic hemolysis).

Parvovirus B19 infection is suspected when there is severe anemia and a markedly blunted reticulocyte response. Testing may include bone marrow examination and nucleic acid testing, such as polymerase chain reaction (PCR) for viral nucleic acid amplification. Transfusions may be required if there is severe anemia (especially with absent or low reticulocyte counts), until the parvovirus infection resolves and red blood cell production resumes. Details of testing and management are discussed separately. (See "Clinical manifestations and diagnosis of parvovirus B19 infection", section on 'Diagnosis' and "Treatment and prevention of parvovirus B19 infection".)

Hemolytic anemias – Autoimmune hemolytic anemia, glucose-6-phosphate dehydrogenase (G6PD) deficiency, and hemoglobinopathies are also important considerations. These conditions are most obvious on review of the peripheral blood smear, which should be a component of the evaluation in all individuals with unexplained anemia.

The reticulocyte count is used as a screening test for hemolysis, along with the lactate dehydrogenase (LDH), bilirubin, and haptoglobin. Hemolysis is associated with increased reticulocytes, increased LDH and bilirubin, and in the case of intravascular hemolysis, a decreased or absent haptoglobin. However, the reticulocyte response may be blunted with severe inflammation. Subsequent testing depends on the history and usually starts with a review of the red blood cell indices and a Coombs (direct antiglobulin) test. (See "Overview of hemolytic anemias in children" and "Diagnosis of hemolytic anemia in adults".)

Drug-induced hemolytic anemia may be immune or non-immune. Commonly implicated drugs are listed in the tables for immune hemolysis (table 2) and drug-induced thrombotic microangiopathy (TMA) (table 3) and discussed separately. (See "Drug-induced hemolytic anemia".)

Testing for G6PD deficiency is appropriate in all people living with HIV who have ancestry from regions of the world with a high prevalence (eg, the tropical and subtropical zones of Africa, Europe, and Asia) [25]. This is reasonable regardless of whether they are currently receiving an oxidant medication because some individuals with G6PD deficiency may have chronic hemolysis or may have been exposed to an oxidant substance or food that they are not aware of, as discussed separately. (See "Diagnosis and management of glucose-6-phosphate dehydrogenase (G6PD) deficiency", section on 'Epidemiology'.)

Testing for G6PD deficiency is also reasonable in people who are beginning therapy with a strongly oxidant drug (eg, dapsone or primaquine), as discussed separately. (See "Treatment and prevention of Pneumocystis infection in patients with HIV", section on 'Antimicrobial regimens'.)

Comorbidities and hypersplenism – Several chronic conditions can be associated with an inflammatory block in red blood cell production and anemia of chronic disease. Chronic kidney disease can cause anemia due to reduced erythropoietin levels. Hypersplenism resulting from chronic liver disease can cause cytopenias as blood becomes pooled in the spleen. (See "Anemia of chronic disease/anemia of inflammation" and "Overview of the management of chronic kidney disease in adults", section on 'Anemia'.)

Endocrinopathies – Endocrine disorders are a common cause of normocytic and hypoproliferative anemia and should prompt testing for thyroid dysfunction, diabetes mellitus, and/or hypogonadism. Testing for adrenal insufficiency is appropriate for patients with orthostatic hypotension and electrolyte abnormalities.

Indications for transfusion and erythropoietin — Transfusion is indicated for severe anemia (symptomatic or hemoglobin level below a defined threshold) or severe bleeding with expected life-threatening anemia. (See "Red blood cell transfusion in infants and children: Indications" and "Indications and hemoglobin thresholds for RBC transfusion in adults".)

The role of erythropoietin has declined from the early years of the HIV epidemic. Previously, erythropoietin was strongly advocated based on evidence from randomized trials showing a reduction in transfusions for individuals with persistent anemia while receiving zidovudine; this indication (treating anemia due to therapy with zidovudine) was approved by the US Food and Drug Administration (FDA) [26,27]. However, this indication no longer applies to most people living with HIV. In addition, erythropoietin carries a Boxed Warning from the FDA due to the heightened risk of thrombotic complications [28,29].

We do not routinely check erythropoietin levels or give erythropoietin to treat anemia outside of excepted indications such as kidney failure or myelodysplasia. In those contexts, a serum erythropoietin value of <500 milliunits/mL predicts a favorable response to erythropoietin supplementation.

Thrombocytopenia

Thrombocytopenia due to HIV or ITP — As noted above, immune thrombocytopenia (ITP) is common as an initial presenting finding in people with HIV but is rare during stable ART. (See 'Prevalence in untreated patients' above.)

ITP is considered a diagnosis of exclusion. There are no well-validated tests for ITP, and antiplatelet antibodies are not considered useful in the evaluation because the sensitivity and specificity are both very low. This contrasts with drug-induced immune thrombocytopenia, for which drug-dependent platelet antibody testing is useful. Platelet counts are variable in ITP; concerns about possible bleeding are greatest in those with counts below 20,000 to 30,000/microL. (See "Immune thrombocytopenia (ITP) in adults: Clinical manifestations and diagnosis", section on 'Correlation of bleeding and thrombocytopenia'.)

For those with severe thrombocytopenia (platelet count <20,000 to 30,000/microL), it may be prudent to evaluate for other causes of thrombocytopenia such as those described above (see 'Rapid evaluation for acutely ill/symptomatic patients' above) and/or to initiate an ITP-specific treatment (glucocorticoids or intravenous immune globulin [IVIG]). If clinically significant bleeding is present in an individual with thrombocytopenia, platelet transfusions are used. (See 'Interventions for bleeding or severe thrombocytopenia' below.)

For individuals not receiving ART who are otherwise well except for mild to moderate thrombocytopenia (platelet count >40,000 to 50,000/microL), initiation of ART alone (without additional ITP therapies) is appropriate. This frequently will be sufficient to increase the platelet count [2,30,31]. There are rare cases in which HIV-related ITP temporarily worsens with the initiation of ART (eg, as a feature of immune reconstitution inflammatory syndrome [IRIS]) [32,33]; however, improvement is much more likely. (See "Selecting antiretroviral regimens for treatment-naïve persons with HIV-1: General approach".)

For those receiving trimethoprim-sulfamethoxazole (TMP-SMX; eg, for prophylaxis against pneumocystis infection), it may be appropriate to discontinue the drug if the CD4 cell count is >200 cells/microL (or close to that threshold) for >6 months or to switch to a different agent. (See "Overview of prevention of opportunistic infections in patients with HIV", section on 'Pneumocystis' and 'Non-HIV causes of thrombocytopenia' below.)

As noted above, the typical time to improvement in platelet count due to direct effects of HIV or ITP is approximately one to five months. (See 'Mechanisms' above.)

Non-HIV causes of thrombocytopenia — Thrombocytopenia can develop in individuals who are receiving combination ART, even those with good evidence of viral suppression. (See 'Clinical case vignettes' below.)

For those who are stably receiving ART with viral suppression and a CD4 cell count ≥200/microL, possible causes of thrombocytopenia include the following:

Pseudothrombocytopenia – Pseudothrombocytopenia can result from platelet clumping in the collection tube; clumps of platelets may also be seen at the edge of the blood smear. Retesting in a collection tube containing an alternative anticoagulant can be used to document the true platelet count. (See "Diagnostic approach to thrombocytopenia in adults", section on 'Pseudothrombocytopenia'.)

HCV – Hepatitis C virus (HCV) infection can cause thrombocytopenia, typically mild to moderate (eg, platelet count between 60,000 and 149,000/microL) due to hypersplenism and/or direct effects on platelet production (thrombopoietin is made in the liver). HCV testing is routine in individuals with HIV regardless of their platelet count, and re-testing may be appropriate in those who develop thrombocytopenia (see "Initial evaluation of adults with HIV", section on 'Screening for coinfections'). Treatment of HIV and HCV co-infection is discussed separately. (See "Treatment of chronic hepatitis C virus infection in the patient with HIV".)

Drug-induced thrombocytopenia – Numerous drugs are implicated in drug-induced thrombocytopenia, as mentioned above (eg, TMP-SMX) and discussed in more detail separately. People with HIV who are exposed to heparin may be at a higher risk of developing heparin-induced thrombocytopenia (HIT) [34]. (See "Drug-induced immune thrombocytopenia" and "Clinical presentation and diagnosis of heparin-induced thrombocytopenia".)

Liver disease – Liver disease not associated with HCV, such as might be seen with fatty liver, portal hypertension, or occult cirrhosis may also lower platelet counts.

In general, the approach is like the non-HIV population, with confirmation that thrombocytopenia is real and exclusion of causes such as drug-induced, infectious, and connective tissue disorders, with a presumptive diagnosis of ITP if there is isolated thrombocytopenia not due to one of these other causes.

This evaluation is discussed in greater detail separately:

Children – (See "Approach to the child with unexplained thrombocytopenia".)

Adults – (See "Diagnostic approach to thrombocytopenia in adults".)

The role of bone marrow examination is unclear in people with HIV who have isolated thrombocytopenia despite adequate viral suppression. In people without HIV, bone marrow evaluation is often omitted unless there are other concerning features on the physical examination or blood smear, or if the thrombocytopenia fails to respond to ITP therapy. (See "Diagnostic approach to thrombocytopenia in adults", section on 'Bone marrow evaluation' and "Immune thrombocytopenia (ITP) in adults: Clinical manifestations and diagnosis", section on 'Additional testing in selected patients'.)

The pace of the evaluation and need for immediate treatment depend on the absolute platelet count and whether the patient is bleeding or requires an invasive procedure, as discussed below. (See 'Interventions for bleeding or severe thrombocytopenia' below.)

Interventions for bleeding or severe thrombocytopenia — If thrombocytopenia is severe (eg, <20,000 to 30,000/microL) or there is clinically significant bleeding, evaluation and presumptive treatment may need to occur simultaneously.

Platelet transfusions – Platelet transfusions should be given to any patient with clinically important bleeding and a platelet count <50,000/microL (<100,000/microL for bleeding into a closed space or central nervous system). (See "Platelet transfusion: Indications, ordering, and associated risks", section on 'Indications for platelet transfusion' and "Initial treatment of immune thrombocytopenia (ITP) in adults", section on 'Critical bleeding'.)

Therapy to raise the platelet count – Presumptive treatment for ITP is appropriate for individuals with a platelet count <20,000 to 30,000/microL for whom another cause of thrombocytopenia cannot be identified. The goal is to provide a safe platelet count to reduce the risk of bleeding; it is not necessary or appropriate to give additional therapies to normalize the platelet count. There is less experience treating ITP in people with HIV than in the general population; however, available evidence suggests that similar responses to therapy and similar adverse effects of therapy can be expected [35-46].

Most individuals are treated with glucocorticoids (eg, dexamethasone, 40 mg orally per day for four days and repeated monthly for 4 to 6 months; prednisone 1 mg/kg orally per day for one to two weeks followed by a taper); intravenous immune globulin (IVIG) may be used if a more rapid increase in platelet count is needed. Response times to available treatments are summarized in the table (table 4), and a general approach to the initiation of treatment is presented separately. (See "Diagnostic approach to thrombocytopenia in adults", section on 'General management principles' and "Initial treatment of immune thrombocytopenia (ITP) in adults", section on 'Overview of decision-making'.)

For those who have persistent thrombocytopenia despite these first therapies, other options include splenectomy, rituximab, a thrombopoietin receptor agonist (TPO-RA), or other therapies. We are generally more likely to use non-immunosuppressive therapies for individuals with HIV who require ITP treatment and have not had sufficient ART to result in a rise in CD4 cell count. As an example, we would be more likely to use a TPO-RA or to wait for the CD4 cell count to increase, depending on the severity of thrombocytopenia). These options are best discussed with the consulting hematologist; details of efficacy, dosing, and adverse effects are described separately. (See "Immune thrombocytopenia (ITP) in children: Management of chronic disease" and "Second-line and subsequent therapies for immune thrombocytopenia (ITP) in adults".)

Neutropenia

Causes of neutropenia — In otherwise stable patients, HIV-related neutropenia does not carry the same risk of infections as chemotherapy-induced neutropenia. (See 'Fever and neutropenia' above.)

Prior neutrophil counts, and in some cases Duffy antigen status, should be reviewed, so as not to conflate Duffy-null associated neutrophil count (a normal variant) with neutropenia. (See "Red blood cell antigens and antibodies", section on 'Duffy antigens' and "Gene test interpretation: ACKR1 (Duffy blood group gene)", section on 'Neutrophils (effect of Duffy status)'.)

In individuals not receiving ART, there are a variety of potential causes of neutropenia including direct effects of HIV, infection, or malignancy, as well as other potentially serious conditions. (See 'Rapid evaluation for acutely ill/symptomatic patients' above.)

Neutropenia in individuals receiving ART is less common. The approach to the evaluation is like that in people without HIV. (See "Overview of neutropenia in children and adolescents" and "Approach to the adult with unexplained neutropenia".)

Role of G-CSF — Hematopoietic growth factors such as granulocyte colony-stimulating factor (G-CSF) can be used to increase the absolute neutrophil count (ANC) in individuals with severe neutropenia (eg, ANC <500 or <750/microL) in whom there is concern about possible infection based on fever or localizing symptoms, as discussed above. (See 'Fever and neutropenia' above.)

The role of G-CSF in individuals who are otherwise well except for neutropenia is more nuanced and depends on the presumptive cause of neutropenia (eg, bone marrow suppression versus peripheral destruction), the perceived risk of infection, and the expected duration of neutropenia, as discussed in more detail separately. Close discussion with the consulting hematologist may be especially helpful in this setting. (See "Management of the adult with non-chemotherapy-induced neutropenia".)

When G-CSF is determined to be indicated, dosing is generally at an initial dose of 5 mcg/kg/day, continued until the ANC is approximately 10,000/microL (calculator 1), and then titrated to maintain an ANC between 2000 and 10,000/microL until the underlying cause of neutropenia can be addressed and/or the risk of infection is no longer a primary concern.

Evidence for the efficacy of G-CSF in people with HIV and neutropenia comes from studies in the 1990s; use outside of chemotherapy regimens has declined following routine use of effective ART. Examples of available studies include the following:

A trial that randomly assigned individuals initiating ART to receive concomitant G-CSF or placebo was stopped early (after only 11 patients were enrolled) due to development of a case of severe encephalopathy in the G-CSF arm [47]. G-CSF was associated with higher neutrophil counts but less pronounced viral suppression (due to a rebound increase in viral load at the 12-week follow-up in three of six individuals on the G-CSF arm), as well as known adverse events such as bone pain and flu-like symptoms. A trial by the same group that initiated G-CSF or placebo in 27 people with HIV following at least 24 weeks of ART did not show this negative effect on viral load; however, other than an increase in white blood cell count there were no benefits of G-CSF [48].

A trial that randomly assigned 258 people with HIV and neutropenia (ANC 750 to 1000/microL) to receive G-CSF (once per day or one to three times per week) or placebo for 24 weeks found that G-CSF raised the ANC and reduced the number of opportunistic infections (adjusted relative risk [RR] 0.65, 95% CI 0.30-0.97) [49]. There was a trend towards reduced number of days in the hospital in the G-CSF groups that did not reach statistical significance and no statistically significant decrease in mortality.

The guidelines for use of G-CSF in individuals with HIV being treated for a hematologic malignancy are the same as for people without HIV. (See "Use of granulocyte colony stimulating factors in adult patients with chemotherapy-induced neutropenia and conditions other than acute leukemia, myelodysplastic syndrome, and hematopoietic cell transplantation".)

Bi-cytopenias or pancytopenia — Often, individuals with more than one cytopenia are acutely ill due to a serious infection, malignancy, or other systemic condition, and these individuals require a rapid evaluation for one or more of these diagnoses, along with presumptive treatment and supportive care, as discussed above. (See 'Ill/symptomatic patient; CD4 cell count <200/microL' above.)

However, some individuals with these serious conditions may initially appear well, and others with a well-controlled viral load and CD4 cell count above 200/microL may develop pancytopenia due to less serious causes. The evaluation is the same as in individuals without HIV. (See "Approach to the adult with pancytopenia".)

CLINICAL CASE VIGNETTES

HLH presenting as leukopenia, thrombocytopenia, and AKI (new HIV diagnosis) – A case report described a 45-year-old man with an unremarkable history who presented to the hospital with fever, thrombocytopenia (platelet count 50,000/microL), mild leukopenia (white blood cell count 3000/microL), and acute kidney injury (AKI) with a creatinine of 1.8 mg/dL (160 micromol/L); his hemoglobin level was mildly elevated at 15.9 g/dL [19]. His ferritin was markedly elevated (69,717 ng/mL), a finding that is often seen in hemophagocytic lymphohistiocytosis (HLH). (See "Clinical features and diagnosis of hemophagocytic lymphohistiocytosis", section on 'Laboratory and radiographic abnormalities'.)

He was evaluated for several infections and rheumatologic conditions and was found to have a subcutaneous abscess on the thigh and bacteremia with two Gram-positive organisms. Bone marrow examination revealed hemophagocytosis without evidence of malignancy or infection. HIV testing was positive with a plasma viral load of >10,000,000 copies/mL. AKI was attributed to rhabdomyolysis, with a creatine kinase of 25,000 units/L. He was treated with antiretroviral therapy (ART) and vancomycin and recovered without requiring primary therapy for HLH. This case emphasizes the importance of identifying HLH and testing for HIV infection in individuals with HLH, as well as the dramatic response to ART.

MAC presenting as thrombocytopenia (new HIV diagnosis) – A case report described a 48-year-old woman who presented with significant epistaxis and was found to have severe thrombocytopenia (platelet count, 3000/microL) with a relatively normal white blood cell count (5200/microL) and hemoglobin (11.6 g/dL), and an unremarkable peripheral blood smear [50]. HIV testing was positive, and her CD4 cell count was low (20 cells/microL; reference range, 800 to 1050 cells/microL). A presumptive diagnosis of HIV-associated immune thrombocytopenia (ITP) was made and treatment with ART and intravenous immune globulin (IVIG) was initiated, followed by glucocorticoids for four weeks.

However, her platelet count did not increase, and a bone marrow examination was performed. The aspirate was a "dry tap"; the biopsy showed abundant mycobacteria, consistent with M. avium complex (MAC). Her platelet count improved to 30,000/microL within two weeks of starting ART and to 150,000/microL within three weeks. This case emphasizes the possibility of an opportunistic infection in an individual with what appeared to be an isolated cytopenia, as well as the value of performing a bone marrow examination in an individual with presumed ITP that did not respond to ITP therapy.

Histoplasmosis presenting as anemia, thrombocytopenia and AKI (patient with known HIV) – A case report described a 35-year-old woman with recently diagnosed HIV infection who had not yet started ART and presented to the emergency department with fever, vomiting, and diarrhea [51]. She resided in a region of the United States where histoplasmosis is endemic. Her initial hemoglobin was low (8 g/dL) with a normal white blood cell count (7000/microL) and platelet count (220,000/microL) and a high creatinine (9 mg/dL). There were no schistocytes on her blood smear. Her creatinine two weeks earlier was 1.2 mg/dL, and she had not been started on any new medications. Her CD4 cell count was low (19 cells/microL) and viral load was high (1 million copies/mL). Urinalysis was positive for white blood cells and leukocyte esterase, and she was started on antibiotic therapy for a presumptive diagnosis of pyelonephritis.

She remained febrile and her platelet count declined to 26,000/microL on hospital day 3. Blood Gram stain showed intracellular yeast forms, and fungal culture and urine histoplasma antigen testing confirmed the diagnosis of disseminated histoplasmosis. She improved with antifungal therapy (amphotericin) and was discharged with a normal creatinine and platelet count. This case emphasizes the broad differential diagnosis in an acutely ill person with HIV who has fever and more than one cytopenia.

ITP (patient with known HIV on ART) – A case report described a 13-year-old female who was diagnosed with HIV infection two years prior, when she presented with mild thrombocytopenia (platelet count 90,000/microL) and failure to thrive [52]. The infection was thought to have been transmitted antenatally, as the mother had received blood transfusions during pregnancy. She was treated with zidovudine-containing ART with an initial normalization of her platelet count followed by more severe thrombocytopenia (platelet count 22,000/microL) with epistaxis. Bone marrow examination revealed large megakaryocytes, consistent with ITP. Her platelet count normalized with a course of glucocorticoids that was eventually tapered (ART was continued) and her platelet count remained in the normal range. This case illustrates the use of ART for HIV-associated ITP, as well as occasional need for ITP-specific medications in selected individuals with severe thrombocytopenia and/or bleeding. IVIG is an option if a more rapid improvement is needed, and platelet transfusions can be given if there is clinically significant bleeding.

Parvovirus (patient with known HIV and intermittent adherence to ART) – A case report described a 15-year-old male diagnosed with HIV eight years prior who had intermittently poor ART adherence and who presented with severe anemia (hemoglobin 4.1 g/dL) [53]. His anemia was normocytic and normochromic; his reticulocyte count was inappropriately low; his CD4 cell count was 98/microL; and his viral load was 5210 copies/mL). Serologies for hepatitis and parvovirus were negative. He was treated with transfusions, and ART was reinitiated, which led to improvement in his hemoglobin level. He subsequently re-presented with severe anemia, and bone marrow showed absence of maturing red blood cells beyond the pronormoblast stage, a classic finding in parvovirus infection. A polymerase chain reaction (PCR) on serum for parvovirus was positive. Reinstitution of ART and treatment with IVIG resulted in normalization of the hemoglobin. This case emphasizes the possibility of parvovirus in an individual with isolated severe anemia with a low reticulocyte count, the use of viral PCR and bone marrow to make the diagnosis, the efficacy of ART, and the use of transfusions and IVIG in a case with severe anemia.

SOCIETY GUIDELINE LINKS — Links to society and government-sponsored guidelines from selected countries and regions around the world are provided separately. (See "Society guideline links: Immune thrombocytopenia (ITP) and other platelet disorders" and "Society guideline links: HIV treatment in nonpregnant adults and adolescents" and "Society guideline links: HIV treatment in pregnant patients" and "Society guideline links: Opportunistic infections in adults with HIV" and "Society guideline links: Primary care of adults with HIV".)

SUMMARY AND RECOMMENDATIONS

Biology and prevalence – The prevalence of cytopenias has declined over the course of the HIV epidemic, likely due to earlier diagnosis and incorporation of less-toxic antiretroviral therapy (ART). However, cytopenias continue to occur, both as a presenting finding or during the disease or its treatment. Mechanisms include direct effects of HIV on hematopoietic stem cells, effects of cytokines, autoimmune destruction, liver disease/hypersplenism, and medications; cytopenias related to combination ART are uncommon (table 1). (See 'General concepts' above.)

Acutely ill/symptomatic patient – The evaluation in an acutely ill or symptomatic patient with a low CD4 count focuses on identifying life-threatening opportunistic infections, malignancies, and other rare disorders such as thrombotic microangiopathies (TMAs), hemophagocytic lymphohistiocytosis (HLH), and human herpes virus 8 (HHV8)-associated disorders. Urgent hematology evaluation with review of the blood smear is usually appropriate. The threshold for bone marrow aspirate and biopsy is low, but this may be omitted in selected circumstances as outlined above. (See 'Rapid evaluation for acutely ill/symptomatic patients' above.)

Antibiotics – Fever and neutropenia is generally treated with antibiotics and granulocyte colony-stimulating factor (G-CSF). In some cases, antibiotics may be started as an outpatient or discontinued following negative culture results. Acutely ill individuals with thrombocytopenia may be treated for infection or a TMA if indicated. (See 'Immediate interventions in the acute setting' above and "Diagnostic approach to suspected TTP, HUS, or other thrombotic microangiopathy (TMA)".)

Medication review – In a stable or asymptomatic individual, potential causes of cytopenias depend on whether the individual is receiving ART; if not, initiation of ART is appropriate and may lead to resolution of the cytopenia(s). Other considerations include causes unrelated to HIV that are seen in the general population. (See 'Stable or asymptomatic patients' above.)

Therapy – The role of specific interventions such as transfusions, erythropoietin, therapies for immune thrombocytopenia (ITP), and G-CSF are discussed above. (See 'Indications for transfusion and erythropoietin' above and 'Interventions for bleeding or severe thrombocytopenia' above and 'Role of G-CSF' above.)

Example cases – Some of the important aspects of diagnosing and treating cytopenias are illustrated in a series case vignettes. (See 'Clinical case vignettes' above.)

ACKNOWLEDGMENT — UpToDate gratefully acknowledges Stanley L Schrier, MD (deceased), who contributed as Section Editor on earlier versions of this topic review and was a founding Editor-in-Chief for UpToDate in Hematology.

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Topic 6679 Version 34.0

References

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