Abstract
INTRODUCTION: Macrophage activation syndrome (MAS) is one of the most severe complications of pediatric systemic lupus erythematosus (SLE). Despite numerous case descriptions and established criteria, the underlying causes and optimal treatment strategies remain challenging. MAS typically presents with multiorgan failure, involving the liver, gastrointestinal tract, kidneys, heart, and lungs - often leading to respiratory failure (RF). Morphological changes in the liver associated with MAS are not well characterised. Current treatment approaches for MAS include high-dose corticosteroids (CS), intravenous immunoglobulins (IVIG), and immunosuppressive agents, primarily cyclosporine. Biologics, most commonly interleukin 1 inhibitors (iIL1), iIL6, iIL-18, anti-interferon-ɣ, anti-B-cell-agents have been used in some cases. CASE DESCRIPTION: 16-year-old girl developed back and joint pain following exercise on 20.11.24, accompanied by weakness in the right foot; spinal MRI was unremarkable. She was admitted to regional Hospital (Kharkiv) on 12.12.24 with marked hypertransaminasemia. Electromyography suggested myelopathy and multiplex axonopathy. Poliomyelitis, yersiniosis, viral hepatitis, herpes virus infections were excluded. Oedema and severe stomatitis subsequently appeared. Initial investigations: cytopenia (Hb 98g/l, WBC 2.72x10(9)/l, platelets 54x10(9)/l), ESR 57mm/h, hypocomplementemia, ANA1:3200, dsDNA=22.4IU/l. SLE was diagnosed, and high-dose CS-pulses were started. Myelogram showed macrophages with haemophagocytosis, blasts 0.6%. A second CS-pulse was given, with a short course of azathioprine and hydroxychloroquine. On the 07.01.25 the patient developed gastrointestinal bleeding with thrombocytopenia (48x10(9)/l). Laboratory tests showed ALT 413U/l, AST 564U/l, ferritin 600ng/dl. Patient was transferred to the SI«UCMC.OF.NAMS.OF.UKRAINE»(Kyiv) (08.01.25), she fulfilled SLICC=6 and SELENA/SLEDAI=23. Portal hypertension was evident. SMA-IgG+, LCM1+ antibodies were positive, suggesting the overlap syndrome. Brain MRI showed subcortical-nuclear lesions; serum copper, caeruloplasmin, genetic testing were undertaken to exclude hereditary pathology. CT of the chest and abdomen revealed cirrhotic liver changes, splenomegaly; lungs and heart were otherwise normal. CS (2 mg/kg/day), mycophenolate mofetil 2g/day, hydroxychloroquine 400 mg/day, β-blockers were initiated. Within a month, neurological symptoms improved; platelets rose to 96x10(9)/l, and ESR normalised (4 mm/h). On 30.01.25 hyperglycemia developed leaded to CS tapering. On 03.02.25 (CS = 1.2 mg/kg/d) patient developed a dry cough without catarrhal and auscultatory phenomena. Echocardiography showed tricuspid regurgitation, without signs of PE. On 06.02.25 patient presented with crepitations, new pulmonary opacities, lymphopenia, and hypofibrinogenemia. Procalcitonin was normal, however antibiotic therapy commenced. 10.02.25 worsening of RF (SpO(2)80%) with raising of ESR 37mm/g, CRP 174 mg/l, and thrombocytopenia 35x10(9)/l. IVIG infusion was administered. On 11.02.25 oxygen through a mask was given, escalation of CS dosage, and antibiotic therapy modification were initiated. Infectious screening was negative. Patient developed proteinuria, hypoalbuminemia, chest X-ray showed diffuse bilateral infiltrates (RF gradeIII). On 14.02.25 the pulse of CS was given, and tocilizumab was started. 15.02.25 hypotension developed with oliguria, platelets 22x10(9)/l, INR 1.8, hypoglycemia, metabolic acidosis, and due to SpO2 – 76-62% mechanical ventilation was started. 16.02.25 hemorrhagic endotracheal secretions discharge from the endotracheal tube, cardiac arrest, resuscitation unsuccessful. DISCUSSION: An uncharacteristic symptom complex at disease onset delayed the diagnosis of SLE in this patient. Features of MAS were already evident at the time SLE was established. Underestimating the risk of MAS progression, combined with concerns about bleeding due to thrombocytopenia, resulted in delayed initiation of immunosuppressive therapy. Cirrhotic changes in the liver were confirmed histologically post-mortem; however, the precise timing of disease onset and the interval before the emergence of neurological symptoms could not be determined. It also remained unclear whether the child had a combination of two autoimmune diseases - SLE and autoimmune hepatitis, as antibodies pathognomonic for that condition were detected. Due to limitations in normalizing the platelet level (insufficient supply of platelet concentrate), liver biopsy was deferred, and presumed cirrhosis contributed to the limited choice of immunosuppressive agents. The development of steroid-induced diabetes led to a reduction in oral CS dose, which may have contributed to disease exacerbation; relapse occurred while the daily dose was still relatively high. The epidemiologically unfavorable context necessitated a thorough exclusion of the infectious cause for the lung lesions. This contributed to delays in treatment escalation, including CS pulses and initiation of biologics. Tocilizumab was selected based on its anticipated effectiveness in managing MAS and associated pulmonary involvement. Post-mortem examination, including histological analysis, revealed exudative polyserositis, multiple hemorrhages in the lungs and major bronchi, intestines, brain, and myocardium, along with features of lupus nephritis. The primary cause of death was determined to be pulmonary hemorrhage. KEY LEARNING POINTS: It is known that hypertransaminasemia and hepatosplenomegaly are common in childhood infections; however, clearer guidance is needed on when such findings should prompt investigation for MAS. In pediatric MAS unresponsive to high-dose CS, cyclosporine is usually recommended. It remains debatable whether cyclosporine is appropriate when ferritin levels are stable or whether alternative immunosuppressive agents should be considered in such circumstances. It remains unclear whether the long-term course or recurrent MAS is possible, and whether repeated CS pulses are feasible, particularly when anakinra is unavailable. Consensus on alternative treatment regimens in settings where biologic agents are not accessible would be highly valuable. Post-mortem sequencing analysis (Invitae, USA) of 2085 genes identified three pathogenic heterozygous mutations, ten Uncertain Significance (heterozygous), and three Uncertain Significance (homozygous) mutations. Most could not be linked definitely to known hereditary disorders. The identified homozygous mutation in CHIT1 - a biomarker associated with inflammation and macrophage activation, including sarcoidosis, interstitial lung disease, and neuroinflammatory or neurodegenerative conditions - may have contributed to the severe MAS phenotype and pulmonary complications. This variant, in combination with a heterozygous pathogenic mutation in NOD2, requires further discussion. How should such genetic findings inform therapeutic decision-making in MAS?