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Cold agglutinin syndrome associated with a pediatric severe systemic Mycoplasma pneumoniae infection

Sara Geitoeira¹, Inês Paiva Ferreira², Ana Lachado³, Lurdes Morais⁴, Paula Cristina Fernandes⁵, Emília Costa³, Esmeralda Cleto³, Isabel Couto Guerra³
¹Pediatrics, Unidade Local de Saúde de Viseu Dão-Lafões, Viseu, Portugal, ²Pediatrics, Unidade Local de Saúde do Tâmega e Sousa, Penafiel, Portugal, ³Pediatric Hematology, Unidade Local de Saúde de Santo António, Porto, Portugal, ⁴Pediatric Pneumology, Unidade Local de Saúde de Santo António, Porto, Portugal, ⁵Pediatric Intensive Care Unit, Unidade Local de Saúde de Santo António, Porto, Portugal

Address for Correspondence: Sara Geitoeira, Rua Tenente Valadim, 161, 1º posterior, 4400-325 Vila Nova de Gaia, Portugal.
Email: sarageitoeira@hotmail.com

Keywords: autoimmune hemolytic anemia, cold agglutinin syndrome, cold agglutinins, Mycoplasma pneunomiae

Clinical Problem :
A healthy 14-year-old boy presented to the emergency department with a 3-day history of fever, dry cough, sore throat and dizziness. On physical examination, peripheral oxygen saturation was 84% (FiO2 0,21), he had a moderate respiratory effort and breathing sounds were decreased on the left lung’s base. A complete blood count (CBC) revealed a normal hemoglobin (16,1 g/dL), lymphopenia (470/µL) and mild thrombocytopenia (118000/µL), and C-reactive protein (CRP) was 291 mg/L. Chest radiograph showed a hypotransparency in the lower 2/3 of the left hemithorax. After ultrasound confirmation of pleural effusion, thoracocentesis was performed, draining 250 ml of serohematic fluid. Bacteriological study of the pleural effusion was negative and nasopharyngeal aspirate did not reveal any respiratory viruses. The patient was admitted to the pediatric ward (PW) and started treatment with intravenous Ceftriaxone and clindamycin. By day 3, due to persistent fever and increasing oxygen requirements, Vancomycin was added. On the following day, due to the need for noninvasive ventilation, he was transferred to Pediatric Intensive Care Unit (PICU). Previously ordered Mycoplasma pneumonia (MP) PCR test result was positive, so Clindamycin was replaced by azithromycin. Nevertheless, fever persisted after a 5-day course of Azithromycin and it was decided to start Levofloxacin because of possible macrolide resistance. By day 9 in PICU, clinical improvement was observed and he was transferred to the PW. By day 3 in this ward, the patient was afebrile and with no supplemental oxygen need. However, looking at the several CBCs that had been done since admission, a progressive decrease in hemoglobin was noted (16,1 g/dL to 8,2 g/dL) with de novo erythrocyte agglutination in peripheral blood smear (PBS). There was a reticulocyte count of 84000/uL (3,18%) and TGO and DHL were elevated for the first time since hospital admission (131 U/L and 407 U/L, respectively), with normal total bilirubin. The direct antiglobulin test (DAT) was positive (4+), monospecific for the complement component C3d and anti-I IgM autoantibody was identified. Therefore, management started with cold avoidance (room temperature and intravenous solutions at 37ºC and heated food). An improvement was observed, with hemoglobin level of 10,9 g/dL 9 days later, with reticulocytosis. TGO and LDH also returned to normal levels. Globally, he completed an antibiotic regimen of Ceftriaxone (10 days), Clindamycin (3 days), Vancomycin (8 days), Azithromycin (5 days) and Levofloxacin (10 days). The patient was discharged after a 25-day hospital stay, with positive DAT. Cold avoidance measures were kept at home until negative DAT obtained, three months later. He had normal CBC three weeks after CAS diagnosis. Ten months later, chest radiograph was normal and he had occasional dry cough, with no other respiratory complaints.

Which anemia should be suspected of when approaching this Mycoplasma pneumoniae infection and how can it be treated?

Discussion :

Correct Answers :

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Answer 1

MP is a frequent cause of respiratory infections, mainly in children and young adults, and most patients develop mild and self-limited upper respiratory symptoms.^1,2,3 However, some patients may develop community-acquired pneumonia and 20-25% of infected patients can also have extrapulmonary manifestations.^2,4,5,6 These can affect the central nervous system, skin, gastrointestinal, cardiovascular, and hematological systems.^3,7 Autoimmune hemolytic anemia is the most common hematologic complication and it is often asymptomatic.⁵ Severe hemolysis is very rare and usually develops in patients with marked pulmonary involvement.^8,9
Autoimmune hemolytic anemia (AIHA) is an acquired autoimmune disorder characterized by the production of autoantibodies targeted against red blood cell (RBC) membrane antigens, leading to their premature destruction.^10,11,12 AIHA is rare in childhood, with an annual incidence of 0.8/100000 individuals under 18 years old.¹³ AIHA is referred to as primary or idiopathic when there is no recognized underlying condition, with poorly understood pathogenesis.^10,12,14,15 The secondary form occurs in around two thirds of the patients with AIHA¹² and consists of a single manifestation of a systemic illness, such as autoimmune diseases, immunodeficiencies, malignancies or, as in the present case, infections.^10,14
AIHA is also classified according to the autoantibodies’ type and the temperatures at which they present maximal reactivity against RBCs.^10,11,14,16 It is divided into warm antibody AIHA (w-AIHA), cold agglutinin syndrome (CAS), cold agglutinin disease (CAD), paroxysmal cold hemoglobinuria and mixed AIHA.10 W-AIHA is the most frequent, described in 60 to 80% of AIHA cases.^14,16,17,18 Cold agglutinins may be found in CAD and CAS, two entities that should be distinguished. CAD refers to a chronic AIHA due to cold reactive antibodies typically seen in adults with a clonal B-cell lymphoproliferative disorder.^10,19 CAS is an AIHA that occurs mainly in children secondarily to specific infections, such as MP pneumonia and Epstein-Barr virus infection, or malignancies.^19,20 In most CAS cases, IgM autoantibodies coat RBCs and activate the complement system, causing extravascular but also intravascular hemolysis.^10,18,21 These antibodies show maximal reactivity at 4ºC.^16,21 As in our patient, DAT pattern is C3 positive and IgG negative.^10,18 As expected, other laboratory signs of hemolysis were also present, such as low hemoglobin levels, reticulocytosis, increased LDH and RBC agglutination in PBS.
Despite being considered an autoimmune disorder, the underlying mechanism for the MP-associated CAS remains to be fully elucidated.^6,9 Cold agglutinins cross-reactivity has been considered between ciliated cells of the bronchial epithelium and the I antigen on the erythrocyte membrane.^2,3,6
As described in the literature, the course of our CAS case was short and self-limited.¹⁰ Only the most basic measures were needed, such as keeping the patient warm until disease resolution (while IgM antibody is still present).^14,16 When transfusion is indicated, it may be prudent to use pre-warmed RBCs in order to reduce the risk of transfusion-related hemolysis.^5,18 The underlying disease was already being properly addressed, which should always be a priority in CAS approach.¹⁰
This case highlights the importance of investigating possible extrapulmonary manifestations during MP infection approach, including hematologic complications. Despite the marked pulmonary involvement, no severe hemolysis occurred and only supportive care was necessary.
The authors emphasize the need to always carefully value and interpret anemia in patients with underlying infections, because of its multiple possible etiologies. Although it is a rare condition, CAS demands a specific approach that should be promptly initiated.

References :

Søndergaard MJ, Friis MB, Hansen DS, et al. Clinical manifestations in infants and children with Mycoplasma pneumoniae infection. PLoS ONE 2018;13:e0195288.
Baweja G, Singh R. Mycoplasma pneumoniae Infection in Children. Pediatr Inf Dis 2021;3:95-98.
Krafft C, Christy C. Mycoplasma Pneumonia in Children and Adolescents. Pediatr Rev 2020;41;12-19.
Sauteur PMM, Unger WWJ, Rossum AMC, et al. The Art and Science of Diagnosing Mycoplasma pneumoniae Infection. J. Pediatr. Infect. Dis. 2018;37:1192-1195.
Kurugol Z, Onen SS, Koturoglu G. Severe Hemolytic Anemia Associated with Mild Pneumonia Caused by Mycoplasma pneumonia. Case Rep Med 2012;1-3
Khan FY, Yassin MA. Mycoplasma pneumoniae Associated with Severe Autoimmune Hemolytic Anemia: Case Report and Literature Review. Braz J Infect Dis 2009;13:77-79
Defilippi A, Silvestri M, Tacchella A, et al. Epidemiology and clinical features of Mycoplasma pneumoniae infection in children. Respir. Med. 2008;102:1762-1768.
Nascimento LC, Valize PCB, Cardoso LS, et al. Autoimmune hemolytic anemia and acute kidney injury associated with Mycoplasma pneumoniae infection. Residência Pediátrica 2016;6:87-90.
Mishra M, Jain VK, Jayaswal RM. Mycoplasma pneumoniae-associated Severe Fatal Autoimmune Hemolytic Anemia: A Rare Entity. J Mahatma Gandhi Univ Med Sci Tech 2018;3:113-115.
Voulgaridou A, Kalfa TA. Autoimmune Hemolytic Anemia in the Pediatric Setting. J. Clin. Med. 2021;10:216.
Arora S, Dua S, Radhakrishnan N, et al. D. Autoimmune hemolytic anemia in children: Clinical presentation and treatment outcome. Asian J Transfus Sci 2021;15:160-165.
Aladjidi N, Leverger G, Leblanc T, et al. for the Centre de Référence National des Cytopénies Auto-immunes de l'Enfant (CEREVANCE). New insights into childhood autoimmune hemolytic anemia: a French national observational study of 265 children. Haematologica 2011;96:655-663.
Aladjidi N, Jutand M, Beaubois C, et al. Reliable assessment of the incidence of childhood autoimmune hemolytic anemia. Pediatr Blood Cancer 2017;00:e26683.
Vagace JM, Bajo R, Gervasini G. Diagnostic and therapeutic challenges of primary autoimmune haemolytic anaemia in children. Arch Dis Child 2014;0:1-6
Vaglio S, Arista MC, Perrone MP, et al. Autoimmune hemolytic anemia in childhood: serologic features in 100 cases. Transfusion 2007;47:50-54.
Wołowieca M, Adamowicz-Salacha A, Gołębiowska-Staroszczyka S, et al. Autoimmune hemolytic anemia in children during 2004-2014 in the Department of Pediatrics, Hematology and Oncology, Warsaw Medical University. Pol. Ann. Med. 2015;22:119-123.
Sáncheza MN, Zubicarayb J, Sebastiánb E, et al. Autoimmune hemolytic anemia: Case review. An Pediatr (Barc) 2021;94:206-212.
Michel M. Classification and therapeutic approaches in autoimmune hemolytic anemia: an update. Expert Rev. Hematol 2011;4:607-618.
Berentsen S, Röth A, Randen U, et al. Cold agglutinin disease: current challenges and future prospects. J. Blood Med. 2019;10:93-103.
Berentsen S, D'Sa S, Randen U, et al. Cold Agglutinin Disease: Improved Understanding of Pathogenesis Helps Define Targets for Therapy. Hemato 2022;3:574-594.
Paul V, Ittoop AL, Prakash A. Autoimmune Hemolytic Anemia in Children: Clinical Profile and Outcomes. J Appl Hematol 2021;12:232 235.

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Cold agglutinin syndrome associated with a pediatric severe systemic Mycoplasma pneumoniae infection

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