Referral
Subject: Urgent Referral for Pediatric Assessment of Systemic Juvenile Idiopathic Arthritis Complicated by Pancytopenia and Splenomegaly
Dear Colleague,
I am referring a 2-year-old female patient for urgent evaluation and management following a recent diagnosis of Systemic Juvenile Idiopathic Arthritis (SJIA). Her clinical presentation has rapidly evolved, and she has developed significant new complications that necessitate specialist intervention.
Patient Background:
- Age: 2 years old
- Initial Symptoms: The patient initially presented with a two-week history of persistent fever, accompanied by a nonspecific rash, decreased activity, bony aches, joint pain, and decreased feeding.
- Recent Developments: Following the initiation of treatment with indomethacin for SJIA, her condition deteriorated within a day. She developed high-grade fever, pancytopenia, and was found to have splenomegaly during clinical assessment.
Current Medication:
- Indomethacin: Recently started for SJIA but coincided with an acute deterioration in her clinical status.
Clinical Concerns: The development of pancytopenia and splenomegaly in the context of SJIA treatment raises concerns about possible drug-induced side effects, complications of SJIA itself, or an alternative or concurrent underlying pathology that needs to be addressed urgently.
This case requires a detailed and swift evaluation due to the complexity and rapid progression of symptoms. A multidisciplinary approach involving pediatric rheumatology and hematology may be necessary to fully address her clinical needs and adjust her treatment plan accordingly.
Thank you.
Reply
Dear Colleague,
Thank you for referring the 2-year-old female patient diagnosed with Juvenile Idiopathic Arthritis (JIA) and presenting with complex symptoms suggestive of a severe systemic complication. Following a comprehensive evaluation and based on the clinical and laboratory findings, we have a significant update regarding her diagnosis and management.
Patient Overview: Upon initial assessment, the patient appeared underweight, febrile, and tachycardic, with generalized lymphadenopathy. The largest lymph node measured 1.5 x 1.3 cm in the right axilla. Additionally, joint tenderness without obvious swelling, palpable liver, and notable splenomegaly (7 cm below the costal margin) were observed. These findings prompted an urgent and detailed evaluation.
Diagnostic Workup and Findings:
- Laboratory Investigations: Included Complete Blood Count (CBC), peripheral blood film, liver and renal function tests, coagulation profile, Erythrocyte Sedimentation Rate (ESR), C-Reactive Protein (CRP), triglycerides, and serum ferritin.
- Outcomes: Revealed very high serum ferritin levels, hypertriglyceridemia, hypo-fibrinogenemia, prolonged Prothrombin Time (PT) and Partial Thromboplastin Time (PTT), elevated d-Dimer, and low ESR.
| WBCs | 1.2 | d-Dimer | 11 |
| Hb | 6.6 g/dl | PT | 17 sec |
| Platelets | 15,000 | PTT | 55 sec |
| ESR | 3 mm | TGL | 550 mg/dl |
| Fibrinogen | 120 | Ferritin | 13600 ng/ml |
Initial Impression:
These findings are highly suggestive of Macrophage Activation Syndrome (MAS), a form of secondary Hemophagocytic Lymphohistiocytosis (HLH), associated with her underlying JIA.
Specialized Procedures
Bone Marrow Aspirate: Demonstrated mild hemophagocytosis.
Lymph Node Biopsy: Excision biopsy of the right axillary lymph node indicated reactive hemophagocytosis without signs of malignancy.
Management Plan
- Immediate Interventions: Initiation of Dexamethasone and Etoposide to manage MAS. Supportive treatments included transfusions of blood, platelets, and fresh frozen plasma to address the hematological abnormalities and coagulation disturbances.
- Ongoing Care: Continuation of Dexamethasone along with full-spectrum IV antibiotics to manage underlying septicemia and disseminated intravascular coagulation (DIC).
Current Status and Follow-Up
The patient’s condition has markedly improved following the initiation of targeted therapy. She is currently afebrile, with resolution of hepatosplenomegaly, normalization of blood counts, triglycerides, fibrinogen, and ferritin levels. We will continue to closely monitor her condition with regular follow-ups and necessary adjustments to her treatment regimen based on her clinical response.
Discussion
Introduction: Hemophagocytic lymphohistiocytosis (HLH) is a severe and life-threatening syndrome characterized by excessive immune activation and systemic inflammation. This condition requires prompt recognition and treatment to improve survival outcomes. HLH can be categorized into two main forms: primary (familial) HLH, which is often linked to genetic abnormalities and increased prevalence in populations with higher rates of consanguinity; and secondary HLH, which arises from intense immunological activation due to infections, malignancies, or immune dysfunctions.
Macrophage Activation Syndrome (MAS): MAS is a specific manifestation of HLH associated with rheumatologic conditions, particularly juvenile idiopathic arthritis (JIA). It shares many pathophysiological features with other forms of HLH, including the dysfunctional activity of NK and T cells. Genetic studies in patients with MAS have revealed abnormalities such as decreased expression of perforin or mutations in the SAP gene, which are also observed in familial HLH and X-linked lymphoproliferative disease (XLP), respectively.
Pathophysiology: The underlying mechanism of HLH and MAS involves unchecked activation of T lymphocytes and macrophages, leading to excessive cytokine release (hypercytokinemia) and widespread organ infiltration, which can result in multi-organ failure if untreated. The clinical presentation typically includes persistent fever, splenomegaly, cytopenias, and hyperferritinemia.
Diagnostic Criteria: HLH diagnosis can be established through one of the following:
- A molecular diagnosis confirming genetic mutations associated with HLH (e.g., PRF1, UNC13D, STX11).
- Meeting five out of the following eight criteria:
- Fever (>100.4°F)
- Splenomegaly
- Cytopenias affecting two or more lineages in the peripheral blood:
- Hemoglobin <9 g/dL (infants <4 weeks: <10 g/dL)
- Platelets <100×10^9/L
- Neutrophils <1×10^9/L
- Hypertriglyceridemia (≥265 mg/dL) and/or hypofibrinogenemia (≤150 mg/dL)
- Ferritin ≥500 ng/mL
- Hemophagocytosis in bone marrow, spleen, or lymph nodes
- Low or absent NK cell activity
- Elevated soluble CD25 (soluble IL-2 receptor >2400 U/mL)
Treatment Strategies: The primary goal of HLH treatment is to suppress the immune overactivation. The 2004 protocol from the second international meeting of the Histiocyte Society recommends an 8-week induction regimen consisting of:
- Corticosteroids: To reduce inflammation and suppress cytokine storm.
- Etoposide (VP-16): To inhibit T-cell activation and induce apoptosis in activated immune cells.
- Cyclosporine A: To further suppress T-cell activation and proliferation.
Advanced Therapies:
- Stem Cell Transplant (SCT): Considered for patients with familial HLH, offering a potential cure with a significant improvement in survival rates, especially with reduced-intensity conditioning regimens.
- Supportive Care: In cases of secondary HLH associated with infections or malignancy, immediate management of the underlying condition is critical alongside standard HLH treatment.
Conclusion: Early and aggressive treatment is essential for managing HLH and MAS to prevent rapid progression and fatal outcomes. Ongoing research into the pathophysiology and genetics of HLH will continue to refine diagnostic criteria and treatment protocols, aiming to improve prognosis and patient quality of life.
Read More Articles About MAS
Macrophage activation syndrome: A diagnostic challenge (Review)
The Immunology of Macrophage Activation Syndrome
Diagnostic Guidelines for Familial Hemophagocytic Lymphohistiocytosis Revisited
Check the correct answers.
Question-1:
Correct Answer: C) PRF1 gene mutation, which encodes for perforin, a protein essential for the cytolytic activity of NK and T cells.
Explanation: The PRF1 gene encodes perforin, a protein that plays a critical role in the ability of cytotoxic T cells and NK cells to kill target cells, such as infected or malignantly transformed cells. Mutations in this gene disrupt the cytolytic pathway, leading to the accumulation of activated lymphocytes and macrophages, which is a hallmark of HLH. This is distinct from mutations involved in other immunodeficiencies or hematological disorders, making it a key point in the diagnosis and understanding of HLH pathogenesis.
Question-2:
Correct Answer: B) Elevated sCD25 levels reflect activation of T lymphocytes and are used as a marker of immune activation in HLH.
Explanation: Soluble CD25 (sCD25) is the soluble form of the IL-2 receptor alpha chain and is shed by activated lymphocytes. In HLH, the immune system is excessively activated, and elevated levels of sCD25 serve as a biomarker for this heightened immune response. High sCD25 levels are indicative of significant T cell activation, a core aspect of HLH pathophysiology, and are included in the diagnostic criteria for HLH to reflect the systemic immune activation that characterizes the disease. This marker helps differentiate HLH from other conditions where such immune activation is not a primary feature.
References
- Ehab H. Tumor Lysis Syndrome Occurring During Treatment of Macrophage Activation Syndrome. J J Hemato. 2015, 1(2): 013.
- Schleinitz N, Bernit E, Harle JR. Severe hemophagocytic syndrome after intravesical BCG instillation. Am J Med. 2002;112:593–594
- Henter JI, Tondini C, Pritchard J. Histiocyte disorders. Crit Rev Oncol Hematol. 2004; 50:157–174.
- Janka GE. Familial and acquired hemophagocytic lymphohistiocytosis. Annu Rev Med. 2012; 63:233–246.
- Henter JI, Horne A, Arico M, et al.HLH-2004: diagnostic and therapeutic guidelines for hemophagocytic lymphohistiocytosis. Pediatr Blood Cancer.2007; 48:124–131.
- Horne A, Janka G, Maarten Egeler R, et al.Haematopoietic stem cell transplantation in haemophagocytic lymphohistiocytosis. Br J Haematol.2005; 129:622–630.
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