What is the workup for a patient with concerns about G6PD (Glucose-6-Phosphate Dehydrogenase) deficiency, particularly with a detected 5 mm nodule on a chest x-ray?

Workup for G6PD Deficiency Concerns

Order a quantitative G6PD enzyme assay as the primary diagnostic test, ensuring the sample is obtained when the patient is not acutely hemolysing and has not been recently transfused. 1

Diagnostic Testing Algorithm

Primary Test Selection

• Quantitative G6PD assay is the gold standard for most patients, measuring enzyme activity as a percentage of normal (patient's G6PD level ÷ laboratory upper limit of normal × 100). 1
• Qualitative fluorescent spot tests are acceptable only for detecting severe deficiency (<10% activity) in males and homozygous females, but miss heterozygous females and milder variants. 1
• Flow cytometry or molecular analysis is required for heterozygous females when enzymatic testing is inconclusive. 1

Critical Timing Considerations to Avoid False Results

• Wait at least 50 days after RBC transfusion before testing, as donor RBC contamination of 6-12% causes false-negative results; ideally wait 120 days though this is often impractical. 1
• Avoid testing during or immediately after acute hemolytic episodes, as reticulocytes and young RBCs contain near-normal enzyme levels that mask deficiency. 1
• Calculate the PK/G6PD ratio or compare to controls with similar reticulocyte counts when interpreting borderline results in patients with elevated reticulocyte counts. 1

Essential Pre-Test Preparation

• Ensure buffy coat removal or filtration before testing, as testing whole blood without removing white cells and platelets prevents detection of deficiency in all cases. 1

Variant Identification and Risk Stratification

Genetic Testing Indications

• Order molecular/genetic testing to identify specific variants (Mediterranean vs. African) when enzymatic testing shows deficiency, as this determines hemolytic risk severity and specific drug contraindications. 1
• Mediterranean variant (Gdmed) causes life-threatening hemolysis requiring strict oxidant drug avoidance. 1, 2
• African variant (GdA-) produces milder, self-limited hemolysis with less stringent restrictions. 1, 2

Activity Level Interpretation

• <30% activity: Severe deficiency—absolutely contraindicate primaquine, rasburicase, methylene blue, and dapsone. 1, 3
• 30-70% activity with non-Mediterranean variants: Modified primaquine regimens (45 mg weekly × 8 weeks) may be considered with close monitoring. 1
• >70% activity: Required threshold for tafenoquine use in P. vivax radical cure. 1

Baseline Hematologic Assessment

Pre-Treatment Laboratory Panel

• Measure baseline hemoglobin and hematocrit before initiating any oxidant drug therapy in G6PD-deficient patients. 1, 3
• Perform close hematological monitoring at days 3 and 8 after starting oxidant drugs to detect early hemolysis. 1, 3
• Check for neutropenia, though it is not a reliable screening marker for G6PD deficiency. 1

Special Population Considerations

Neonatal Testing

• Order quantitative G6PD testing in infants with rapidly rising total serum bilirubin approaching exchange transfusion levels or not responding to phototherapy. 1
• Measure G6PD when jaundice appears in the first 24 hours of life or when TSB rises rapidly and crosses percentiles unexpectedly. 1
• Recognize that G6PD deficiency causes 31.5% of kernicterus cases, making testing critical in severe neonatal hyperbilirubinemia. 1

Pregnancy and Reproductive Considerations

• Perform pregnancy testing in sexually-active females of reproductive potential before starting primaquine or other high-risk oxidant drugs. 3
• Recognize that even if the mother is G6PD normal, the fetus may be deficient, making primaquine and tafenoquine absolutely contraindicated in pregnancy regardless of maternal G6PD status. 3, 2

High-Risk Medication Screening

Absolute Contraindications Requiring Pre-Treatment Testing

• Screen before prescribing dapsone, primaquine, rasburicase, methylene blue, nitrofurantoin, phenazopyridine, or tolonium chloride in patients of Mediterranean, African, Indian, or Southeast Asian descent. 1, 2, 4
• Quantitative testing is mandatory before tafenoquine for P. vivax radical cure—do not use if activity <70%. 1

Medications Generally Safe Without Testing

• Chloroquine/hydroxychloroquine, artemisinin-based combination therapies, benzodiazepines, codeine/derivatives, propofol, fentanyl, and ketamine have not been shown to cause hemolytic crises in G6PD-deficient patients. 2, 5, 6

Common Pitfalls to Avoid

• Do not rely on qualitative tests alone in females, as they miss heterozygous carriers who may still experience hemolysis. 1
• Do not test immediately post-hemolysis or post-transfusion, as these scenarios produce falsely reassuring results. 1
• Do not assume all sulfonamides are contraindicated—real-world data shows sulfamethoxazole/cotrimoxazole, sulfasalazine, and sulfacetamide have been prescribed safely to thousands of G6PD-deficient patients. 6
• Do not forget that infections themselves can trigger hemolysis in G6PD-deficient patients, independent of medication exposure. 7, 6

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Regarding the 5 mm Pulmonary Nodule

For the incidentally detected 5 mm nodule on chest x-ray, obtain a CT chest without IV contrast to better characterize the nodule, as chest radiography has limited sensitivity and specificity for nodules <6 mm. 8

Nodule Workup Algorithm

• Order thin-section CT (1.5 mm slices) with multiplanar reconstructions for optimal nodule characterization and accurate size measurements. 8, 9
• Use low-dose technique to minimize radiation exposure (approximately 2 mSv). 9
• Do not use IV contrast, as it adds no value for detecting, characterizing, or determining stability of pulmonary nodules. 8, 9

Follow-Up Based on CT Findings

• If nodule measures <6 mm on CT with no suspicious features: No routine follow-up is recommended, as malignancy likelihood is <1%. 8, 9
• If nodule has suspicious morphology, upper lobe location, or patient is high-risk: Consider optional follow-up CT at 12 months. 8
• If nodule has been stable for 2 years on prior imaging: No further workup is needed. 8