Cold agglutinin syndrome in paediatric practice: A case series

Methodology

Data collection

We collected data on demographics, presenting complaints, Hb values at different time points, peripheral smear findings, reticulocyte counts, lactate dehydrogenase (LDH), cold agglutinin titres and treatments.

Of the 10 cases of acute fall in Hb, which presented to us from January 2024 to December 2024, four had post-infectious cold agglutination, one child was diagnosed with hereditary spherocytosis, three with acute leukaemia – acute lymphoblastic leukaemia, one with malaria with haemophagocytic lymphohistiocytosis and one with nutritional anaemia with pneumonia sepsis.

Ethical clearance

Ethical committee clearance was waived off as this was a retrospective case series and on the condition of protection of patient privacy.

All patient consent was taken, and confidentiality was maintained.

Case summaries

Four paediatric patients, aged 9–13 years, were diagnosed with post-infectious CAS following respiratory tract infections. Three cases were associated with confirmed M. pneumoniae infection, while one had a probable viral aetiology. The clinical presentation ranged from mild respiratory symptoms to severe anaemia. One 13-year-old boy presented with Hb of 4.3 g/dL, elevated LDH (3052 IU/L), reticulocytopenia and RBC agglutination [Figure 1]; he improved following warmed packed RBC transfusion and vitamin B12 and folate supplementation. Another 10-year-old male presented with pneumonia and a normal Hb level (13.5 g/dL), with positive Coombs test and high cold agglutinin titres (>1:512) but no haemolysis; he was managed conservatively with azithromycin. A third child, also 10 years old, had moderate anaemia (Hb 5.5 g/dL), RBC agglutination and elevated LDH; he required warmed transfusion and iron supplementation along with antibiotic therapy. The fourth patient, a 9-year-old girl, had mild bronchopneumonia and a modest Hb drop (12.8–11.5 g/dL) with raised LDH; she was treated with ceftriaxone, azithromycin and doxycycline and recovered fully without transfusion. Reticulocyte responses ranged from suppressed to appropriately elevated following treatment. All patients demonstrated complete recovery without the need for immunosuppressive agents, highlighting the typically self-limiting nature of paediatric CAS and the effectiveness of conservative, infection-targeted therapy [Table 1 and Figure 2].

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Figure 1:

×40 magnification view of peripheral smear under microscope, blue arrow showing red blood cell agglutination.

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Figure 2:

Summary of clinical findings in the four cases, 3 (blue bar) of the 4 cases were positive for mycoplasma serology, 2 (red bar) presented with haemolysis, 2 (pink bar) were positive for cold agglutinin titres, 2 (orange bar) required transfusions and 2 (green bar) required haematinic supplements.

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Diversity of clinical presentation

Our findings illustrate the remarkable heterogeneity in clinical manifestations of paediatric CAS, ranging from asymptomatic laboratory abnormalities to severe anaemia requiring transfusion intervention. This variability contrasts with adult CAS, which typically presents as a more homogeneous clinical entity with predictable patterns of chronic haemolysis. The diversity observed in our paediatric cohort likely reflects multiple contributing factors, including the nature of the triggering infection, preexisting haematological status and individual immunological responses.

The association with M. pneumoniae infection, identified in three of our four cases, aligns with previous literature that has consistently identified this organism as the predominant trigger for paediatric CAS. Liang and Liu (2024)^[4] reported a severe case of M. pneumoniae infection in a child, complicated by cold agglutinin disease (CAD) and pulmonary embolism, emphasising the potential severity and systemic impact of cold agglutinin-mediated pathology. While our cases did not progress to such critical complications, two of our four patients (Cases 1 and 3) presented with profound anaemia (Hb <6 g/dL), requiring transfusions. This supports Liang and Liu’s^[4] observation that M. pneumoniae-induced CAS can cause significant haematologic compromise, though severe systemic complications may be uncommon in most paediatric presentations. The mechanisms underlying mycoplasma-induced cold agglutinin production involve molecular mimicry between mycoplasma antigens and the I antigen on erythrocyte surfaces, leading to cross-reactive antibody generation.^[5] The variability in haemolytic severity despite similar infectious triggers suggests that host factors substantially modify the clinical expression of this pathophysiological process.

Hb kinetics

The Hb profiles documented in our series reveal distinct patterns that inform clinical management. In cases with severe anaemia at presentation (Cases 1 and 3), we observed an initial stabilisation following transfusion, followed by a sustained improvement as the underlying infection resolved and nutritional deficiencies were corrected. Notably, post-transfusion haemolysis – a theoretical concern in CAS due to thermal amplitude considerations – was not observed in either transfused patient, suggesting that carefully administered warmed blood products can be safely utilised when clinically indicated.

The paradoxical finding of reticulocytopenia in the setting of active haemolytic anaemia, as observed in Cases 1 and 3, indicates particular attention. In typical haemolytic conditions, a compensatory increase in reticulocyte count is expected as the bone marrow responds to peripheral red cell destruction. However, the suppressed reticulocyte response in these patients may be attributable to transient bone marrow suppression from systemic infection, nutritional deficiencies impairing erythropoiesis, or immunologic targeting of erythroid precursors. Notably, in Case 1, the reticulocyte count increased following vitamin B12 and folate supplementation, suggesting that correction of underlying nutritional deficits can restore erythropoietic function and facilitate recovery. This observation is consistent with findings reported by Liesveld et al. (1987),^[6] who described variability in marrow response among patients with AIHA, including cases with unexpectedly low reticulocyte counts during active disease.

Case 2 represents an important clinical scenario of ‘serological CAS’ without haematological manifestations, characterised by elevated cold agglutinin titres in the absence of significant haemolysis or anaemia. This pattern has been previously documented by Gaur et al. (2023) but remains underappreciated in clinical practice, potentially leading to unnecessary interventions if not recognised.^[7] Our observation reinforces the principle that management decisions should be guided by clinical and haematological parameters rather than serological findings alone.

Comparison with adults

Our paediatric cases exhibited several features that distinguish them from typical adult CAD. First, all cases were secondary to identifiable infections rather than primary (idiopathic) or associated with lymphoproliferative disorders. Second, the clinical course was uniformly self-limiting, with complete resolution following clearance of the triggering infection, in contrast to the chronic, relapsing nature of adult CAD. Third, the transient nature of the condition obviated the need for immunomodulatory interventions such as rituximab or complement inhibitors that are frequently required in adults.^[8]

The thermal amplitude of cold agglutinins – the highest temperature at which they remain active – also appears to differ between paediatric and adult cases. In our paediatric patients, haemolysis primarily occurred at temperatures substantially below core body temperature, explaining why peripheral acrocyanosis and Raynaud’s phenomenon (common in adult CAD) were absent.^[9] This lower thermal amplitude may also account for the generally milder haemolytic manifestations observed in children.

In contrast to adult CAD, our paediatric cases were all secondary to infections, self-limited and required no immunomodulatory therapy. None of our patients developed cold-induced peripheral symptoms such as acrocyanosis or Raynaud’s phenomenon, likely due to lower thermal amplitude antibodies as discussed by Moonla et al. (2020).^[2] The absence of these complications, combined with complete recovery in all four children, supports the assertion that paediatric CAS, although potentially severe in presentation, generally follows a benign course when appropriately managed with supportive care and antimicrobial therapy.

Clinical implications

Distinguishing between infection-associated cytopenias and true immune-mediated haemolysis presented another diagnostic challenge; our management approach prioritised treatment of the underlying infection, nutritional supplementation when indicated, avoidance of cold exposure and judicious use of transfusion for symptomatic anaemia. This conservative strategy proved effective across the spectrum of presentations, supporting its application as the initial approach in paediatric CAS. None of our patients required immunomodulatory therapies, consistent with the generally self-limiting nature of post-infectious CAS in children.