What is the differential diagnosis of a low CD4 (Cluster of Differentiation 4) count?

Differential Diagnosis of Low CD4 Count

The differential diagnosis of low CD4 count must first exclude HIV infection, then systematically consider primary immunodeficiencies, secondary causes including medications and malignancies, acute severe infections, autoimmune conditions, and idiopathic CD4 lymphocytopenia. 1

Primary Approach: HIV Status Determination

• HIV infection is the most common cause of low CD4 counts and must be ruled out first with serologic testing, especially in patients who are asymptomatic or have very low viral loads 1
• Confirm HIV status even in patients with previous negative tests or questionable documentation, as patients may present with misinformation regarding test results 1
• Use CDC's HIV testing algorithms for proper interpretation based on assays employed 1

HIV-Negative Causes of Low CD4 Count

Idiopathic CD4 Lymphocytopenia (ICD4L)

• Suspect ICD4L in patients with opportunistic infections and persistent CD4 counts <300 cells/mL in the absence of HIV or other identifiable causes 1
• Most common presentations include cryptococcal infection, persistent human papillomavirus infection, and non-tuberculous mycobacterial infections 1
• Typically presents in the third and fourth decades of life 1
• Autoimmunity occurs in 23% of patients, most frequently systemic lupus erythematosus 1
• Other lymphocyte subsets may also be reduced, but immunoglobulin levels are typically normal 1
• Spontaneous resolution occurs in some cases, though most remain CD4 lymphopenic 1
• Genetic causes identified include heterozygous missense mutations in UNC119 and dysregulation of CXCR4 expression 1

Primary Immunodeficiencies

DiGeorge Syndrome (DGS):

• Investigate in patients with thymic hypoplasia, cardiovascular structural defects, midline craniofacial defects, and hypoparathyroidism 1
• Characteristic facial features include hypertelorism, saddle nose, shortened philtrum, and low-set abnormally shaped ears 1
• Patients are almost always mildly to severely T-cell lymphopenic with both CD4 and CD8 subsets reduced 1
• In vivo and in vitro T-cell function measures are usually normal despite lymphopenia 1

Immuno-osseous Dysplasias:

• Consider in patients with severe growth retardation, skeletal abnormalities, and T-cell lymphopenia 1
• Schimke syndrome presents with spondyloepiphyseal dysplasia, progressive nephropathy, pigmentary skin changes, and T-cell lymphopenia 1
• Cartilage-hair hypoplasia (CHH) exhibits short-limbed dwarfism, hypoplastic hair, defective immunity with frequent infections, and anemia 1
• Lymphopenia occurs in roughly two-thirds of CHH patients, with decreased CD4 count in more than half 1

Secondary Causes

Acute Severe Infections:

• Severe respiratory tract infections can cause transient CD4 lymphocytopenia even in patients with previously normal lymphocyte counts 2
• Consider pneumocystis jiroveci pneumonia in patients with severe infection and low CD4 counts, even without HIV 2
• Blood cultures and acid-fast bacilli testing should be performed to identify causative organisms 2

Medications and Treatments:

• Drug-induced myelotoxicity accounts for 6% of cases presenting with low CD4 counts in HIV clinics 3
• Impediment in using antiretroviral therapy due to toxicity represents 8% of low CD4 presentations 3
• Chemotherapy and immunosuppressive agents can cause CD4 depletion 1

Malignancies:

• Lymphoma (primary CNS or systemic with CNS involvement) should be considered in severely immunocompromised patients 4
• Hematologic malignancies can directly affect lymphocyte production and distribution 1

Autoimmune Conditions:

• Systemic lupus erythematosus is the most frequent autoimmune disease associated with low CD4 counts 1, 5
• Autoimmune phenomena increase with immune activation and may present at various stages of immune dysfunction 5
• The spectrum of autoimmune diseases includes vasculitis, polymyositis, Graves' disease, and idiopathic thrombocytopenic purpura 5

Other Secondary Causes:

• Chronic kidney disease can affect lymphocyte counts 2
• Malnutrition causes immunosuppression and lymphopenia 2
• Diabetes mellitus may be associated with altered immune function 2

Critical Diagnostic Considerations

Laboratory Variability and Interpretation

• CD4 percentage is more consistent than absolute CD4 count with successive measurements and less variable with delays in specimen processing 1, 6
• Absolute CD4 counts are derived from three separate measurements (WBC count, lymphocyte differential, and CD4+ percentage), introducing multiple sources of variability 6
• Biological variability includes approximately 10% diurnal variation and 13% week-to-week variation 6
• CD4 counts may be affected by various medications and intercurrent illnesses, requiring caution in interpretation during acute illness 1
• Total CD4 counts of 200 and 500 cells/µL generally correspond to CD4 percentages of 14% and 29%, respectively 1

Risk Stratification by CD4 Level

CD4 >200 cells/µL:

• Patients appearing well are very unlikely to have Pneumocystis pneumonia and other opportunistic infections 1
• Chronic symptoms are far more likely caused by the same disorders as in the general population 1
• Suspect opportunistic infections if unexplained fever, weight loss, or thrush present even with CD4 >200 cells/µL 1

CD4 <200 cells/µL:

• Defines severe immunodeficiency and is a CDC criterion for AIDS diagnosis in HIV-positive patients 4
• High risk for Pneumocystis jirovecii pneumonia requiring prophylaxis 4
• Suspect opportunistic infections even when chest radiograph findings are normal 1

CD4 <150 cells/µL:

• Increased risk for toxoplasmosis, histoplasmosis, and cryptococcosis 4

CD4 <100 cells/µL:

• Risk threshold for disseminated fungal infections and cerebral toxoplasmosis 4
• Cryptococcosis typically occurs at this level 4

CD4 <50 cells/µL:

• Risk for disseminated Mycobacterium avium complex 4

Common Pitfalls and Caveats

• Do not assume HIV-negative status without confirmatory testing, as this is the most common and treatable cause 1
• Avoid relying solely on absolute CD4 counts without considering CD4 percentage, as absolute counts have higher variability 6
• Do not dismiss the possibility of opportunistic infections in patients with normal chest radiographs if CD4 <200 cells/µL 1
• Consider geographic factors in the differential diagnosis, as endemic tuberculosis and fungi predispose to invasive infections 1
• Recognize that laboratory markers may not reflect disease severity in severely immunocompromised patients due to blunted inflammatory responses 4
• Maintain a broad differential diagnosis as multiple concurrent conditions are possible 4
• Repeat CD4 measurements to confirm persistent lymphopenia before extensive workup, as transient decreases can occur with acute illness 1, 2
• Evaluate for anergy in patients with suspected tuberculosis, as cutaneous anergy may be present in >10% of asymptomatic persons with CD4 >500 cells/µL and >60% with CD4 <200 cells/µL 1