Lupus Nephritis Complicated by Haemophagocytic Lymphohistiocytosis: An Uncommon but Critical Association

INTRODUCTION

Haemophagocytic lymphohistiocytosis (HLH) is an unregulated, excessive systemic inflammatory pathology. It primarily affects infants and young children by causing abnormal activation of natural killer (NK) cells, CD8+ cytotoxic T cells, and macrophages. Cytotoxic lymphocytes abnormally accumulate in the body and propagate the immune response, resulting in extensive tissue damage. It may lead to multi-organ failure and sometimes fatal outcomes.^[1,2] HLH is often associated with elevated tumour necrosis factor-alpha (TNF-α) and TNF-gamma levels due to an accentuated Th1 Helper cell response, resulting in pancytopenia. Common symptoms include fever, malaise, fatigue, cytopenias, anaemia, and hepatosplenomegaly.^[3] HLH is divided into primary (familial) and acquired (secondary). Primary HLH is inherited and characterised by mutations in a gene encoding a signalling protein involved in immune system inactivation. Acquired HLH is the leading cause of adult HLH, and various infections, including viral, bacterial, fungal, parasitic, autoimmune diseases, and malignancies, are the triggers.^[4] Secondary HLH is an uncommon complication of lupus nephritis and is rare in children, primarily seen in females.^[5,6] HLH diagnosis includes the presence of at least five criteria: fever, cytopenias (minimum 2 cell lineages), splenomegaly, hypertriglyceridemia, hypofibrinogenemia, haemophagocytosis on biopsy, raised serum ferritin (>500 mg/L), low or absent natural killer cell activity, and raised IL-2Ra levels ≥2400 U/L.^{[7] 18}F-FDG PET/CT has a complementary role in detecting inflammatory and malignant pathologies in secondary HLH and in guiding biopsies. Parameters, such as the spleen-to-mediastinum maximum standardised uptake value (SUVmax) ratio, can help predict prognosis by assessing the inflammatory load in the patient.^[1] Scan features include hepatosplenomegaly, bone marrow involvement, serous effusion, and increased FDG uptake in affected organs. Lymphoma is the most common cause of secondary HLH. Authors have proposed a supportive role of ¹⁸F-FDG PET/CT in the management of secondary HLH.^[1] The present case represents the rarity of secondary HLH occurring in a paediatric patient with lupus nephritis.

CASE REPORT

A 14-year-old male child presented with symptoms of decreased appetite, swelling over the submandibular region, pedal oedema, facial puffiness, and mild ascites for three months. On biochemical evaluation, proteinuria, hypoalbuminemia, hyponatremia, and severe transaminitis were evident. Aspiration cytology of the submandibular gland was unremarkable. Anti-nuclear and anti-double-strand deoxyribonucleic acid (DNA) antibodies were positive. Renal biopsy showed features of membranous lupus nephritis (class V). The patient subsequently developed a focal seizure; however, the magnetic resonance imaging (MRI) of the brain was unremarkable. After two months, the patient then developed a persistent high-grade fever. Routine blood examination revealed anaemia (8.4 mg/dl), thrombocytopenia (124 x 1000/mm³), leukopenia (3.52 x 1000/µL), hyponatremia (129 mg/dl) and hypoalbuminemia (3.0 mg/dl). ¹⁸F-FDG PET/CT was performed for the evaluation of pyrexia of unknown origin (PUO) in the patient with a three-week history of fever unresponsive to antibiotic therapy. ¹⁸F-FDG PET/CT scan showed diffuse extensive uptake in the bone marrow, hepatosplenomegaly (liver measuring~ 15.9 cms and spleen~ 12.5 cms) along with hepato-splenic reversal (SUVmax of liver- 1.48 & SUVmax of spleen- 2.20) [Fig 1]. The spleen-to-mediastinum (S/M) SUVmax ratio was 1.8 (2.2/1.2), suggesting a substantial inflammatory burden consistent with hyperinflammatory states.^[1] A possible diagnosis of diffuse bone marrow pathology was raised as there was no evidence of other inflammatory foci or malignancy. Blood investigation revealed hyperferritinaemia, hypofibrinogenemia and hypertriglyceridemia. Bone marrow examination revealed increased histiocytes, with a few showing haemophagocytosis [Fig 2]. Based on clinical, biochemical, and histopathological evidence along with supportive ¹⁸F-FDG PET/CT findings, the diagnosis of HLH was established. The patient was then started on immunosuppressive therapy and responded well to treatment. Authors have identified the supporting role of ¹⁸F-FDG PET/CT metabolic parameters in identifying the aetiology and prognosticating secondary HLH in children. Absence of extranodal organs involved and SUVmax less than 4.4 is associated with non-malignant HLH.

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Fig 1: (A) Maximum intensity projection (MIP) view and (B) coronal section view of whole body ¹⁸F-FDG PET/ CT scan showing physiological tracer uptake in the brain, oral mucosa, bilateral renal calyces, urinary bladder (green arrows in A and B) and abnormal diffuse intense uptake in the entire skeleton (red arrows in A and B). Hepato-splenic reversal is noted with SUVmax value of spleen (2.20) more than the liver (1.48). (C and D) Hepatosplenomegaly (Liver~ 15.9 cms; Spleen~ 12.5 cms).

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Fig 2: Giemsa-stained BMA smears showing erythrophagocytosis (indicated by red arrow). Other myeloid series cells are seen in the background (Oil Immersion, 100× magnification). BMA: Bone marrow aspiration

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¹⁸F-FDG PET/CT serves a complementary role in detecting underlying causes and directing targeted biopsies, as the imaging features are non-specific. The differential diagnosis of secondary HLH are paediatric population is diverse and includes lymphomas, leukaemia, Epstein–Barr virus infections, autoinflammatory diseases and other rare diseases.^[8] Typical ¹⁸F-FDG PET/CT findings in secondary HLH include hepatosplenomegaly and increased FDG uptake in the bone marrow and spleen, which reflect increased systemic inflammation and elevated acute-phase reactants.^[1,9]

DISCUSSION

Hemophagocytic lymphohistiocytosis (HLH) represents a hyperinflammatory syndrome characterised by dysregulated immune activation and cytokine storm, often leading to multiorgan dysfunction.^[1,2] Secondary HLH in association with autoimmune disorders, particularly lupus nephritis, is uncommon and poses a significant diagnostic challenge due to overlapping clinical and laboratory features. Early recognition is crucial, as delayed diagnosis can result in poor outcomes. In our case, the patient fulfilled established diagnostic criteria for HLH consistent with the HLH-2004 guidelines.^[7] However, the initial clinical presentation was nonspecific, underscoring the importance of adjunctive diagnostic tools. In this context, ¹⁸F-FDG PET/CT demonstrated diffuse bone marrow uptake, hepatosplenomegaly, and hepatosplenic metabolic reversal, suggestive of HLH in conjunction with other biochemical parameters.

CONCLUSION

This case highlights the rare diagnosis of secondary HLH in a child with lupus nephritis. ¹⁸F-FDG PET/CT serves as a valuable adjunctive imaging modality in the evaluation of suspected HLH. When interpreted in conjunction with biochemical parameters, it provides important supporting evidence that helps establish the diagnosis.