What is the appropriate management for a 13‑year‑old female with known cold‑agglutinin disease presenting with a swollen throat and nausea, with negative COVID‑19, influenza, and streptococcal test results?

Management of 13-Year-Old Female with Cold Agglutinin Disease Presenting with Swollen Throat and Nausea

This patient requires immediate symptomatic management with close monitoring for hemolysis, while avoiding cold exposure and investigating for concurrent viral pharyngitis beyond the negative tests already obtained.

Immediate Clinical Assessment

Evaluate for hemolytic crisis and ensure warm environment:

• Check complete blood count, reticulocyte count, lactate dehydrogenase (LDH), indirect bilirubin, and haptoglobin to assess for active hemolysis 1, 2
• Maintain patient in warm environment (>37°C) and ensure all IV fluids, blood products, and monitoring equipment are warmed, as cold agglutinin disease causes hemolysis at less-than-physiological temperatures through complement fixation 1
• Perform direct antiglobulin test (DAT) and cold agglutinin titers if not recently checked, as these can be elevated during acute illness 2, 3

Pharyngitis Management Without Streptococcal Infection

Since strep, flu, and COVID-19 are negative, consider other viral etiologies:

• The negative streptococcal test is reliable in this age group, as rapid antigen detection tests are highly specific and do not require backup culture when positive, though negative tests in children should typically be backed up by culture 4
• Viral pharyngitis remains the most likely diagnosis, with common causes including adenovirus, rhinovirus, respiratory syncytial virus, coxsackievirus, echoviruses, herpes simplex virus, and Epstein-Barr virus 4
• Epstein-Barr virus should be specifically considered if there is generalized lymphadenopathy or splenomegaly beyond isolated throat swelling 4

Symptomatic treatment approach:

• Provide acetaminophen for fever and throat pain rather than NSAIDs, as there were early concerns about NSAIDs potentially worsening outcomes in viral infections, though this remains controversial 5
• Ensure adequate hydration, particularly important given nausea and the increased risk of hemolysis with dehydration in cold agglutinin disease 1, 2
• Avoid cold foods and beverages, as these can trigger hemolysis in cold agglutinin disease 1, 3

Cold Agglutinin Disease-Specific Considerations

Monitor for infection-triggered hemolytic exacerbation:

• Viral infections, including respiratory viruses, can trigger secondary cold agglutinin syndrome and worsen pre-existing disease 1, 2, 6
• COVID-19 specifically has been associated with cold agglutinin syndrome development and exacerbation, though your patient tested negative 1, 2, 6, 3
• Mycoplasma pneumoniae classically triggers cold agglutinin syndrome and should be considered if symptoms persist or worsen, despite negative initial testing 6

Laboratory monitoring strategy:

• Cold agglutinins can complicate laboratory assessment, causing spurious results in automated cell counters and affecting renal replacement therapy if needed 1
• Serial hemoglobin checks every 12-24 hours initially to detect hemolysis, as even minimal in-vivo hemolysis can be clinically significant 1
• If hemoglobin drops >2 g/dL or patient develops jaundice, dark urine, or increased fatigue, escalate care immediately 2, 3

When to Escalate Care

Specific red flags requiring urgent re-evaluation or hospitalization:

• Development of respiratory rate ≥30/min, oxygen saturation ≤93%, or significant dyspnea 5
• Signs of hemolytic crisis: jaundice, dark urine, severe fatigue, tachycardia, or hemoglobin drop >2 g/dL 2, 3
• Inability to maintain oral hydration due to nausea/vomiting 5
• Fever >38.5°C that persists beyond 48-72 hours or worsens 5
• Development of chest pain, severe headache, or altered mental status 5

Treatment Considerations for Severe Hemolysis

If significant hemolysis develops despite supportive care:

• Corticosteroids (prednisone 1 mg/kg/day) are first-line for acute hemolytic episodes in cold agglutinin disease 2, 3
• Rituximab may be considered for refractory cases, though it carries significant infection risks and requires careful monitoring 7, 3
• Eculizumab (anti-C5 monoclonal antibody) has been used in life-threatening cases of cold agglutinin disease with COVID-19, though data are limited to case reports 3
• Blood transfusions must be warmed to >37°C before administration to prevent triggering further hemolysis 1, 3

Follow-Up Plan

Schedule re-evaluation within 48-72 hours or sooner if symptoms worsen:

• Repeat hemoglobin and markers of hemolysis if initial values showed any abnormality 1, 2
• Consider Epstein-Barr virus serology, Mycoplasma pneumoniae testing, or other viral studies if pharyngitis persists beyond 5-7 days 4, 6
• Educate patient and family about cold avoidance strategies and signs of hemolytic crisis requiring immediate medical attention 1, 3

Common Pitfalls to Avoid

• Do not administer cold IV fluids or allow patient exposure to cold environments, as this will trigger hemolysis 1, 3
• Do not prescribe antibiotics empirically without bacterial confirmation, as this contributes to antimicrobial resistance and is not indicated with negative streptococcal testing 4
• Do not assume the negative COVID-19 test rules out all viral triggers of cold agglutinin exacerbation; other respiratory viruses can cause similar complications 1, 6
• Do not delay evaluation for hemolysis based on patient appearing well, as cold agglutinin disease can have minimal symptoms initially but progress rapidly 1, 2