Hemophagocytic syndrome (HPS), also known as hemophagocytic lymphohistiocytosis (HLH), is one of those rare diseases that one sees at the bottom of differential diagnoses in textbooks or UpToDate. Indeed, it does remind one of the adage “the eye doesn’t see what the mind doesn’t know,” and even Osler’s aphorism “to study medicine without books is to sail an uncharted sea.” Thus, it is all the more commendable to read this case report from Santoriello et al, where erythrocytes were observed within the macrophages that had infiltrated the glomeruli, and the workup that followed to confirm the HLH diagnosis.
HPS was first reported in 1952 by Farquhar and Clareaux, who gave it the name “familial hemophagocytic reticulosis“. The clinical presentation is that of a systemic inflammatory response syndrome (SIRS), accompanied by lymphadenopathy, hepato-splenomagaly, and cytopenias, along the classical pathologic findings. The genetic subtype of HPS presents in childhood, and the acquired or sporadic subtype, which occurs more commonly in adults, was not described until 1979 by Risdall et al. There does not appear to be any sex or race predilection, though specific mutations vary by race and geography. Though thought to be rare, one estimate of HPS puts the incidence at 1.2 per million individuals. Another estimate of 1 per 3000 inpatient admissions at a tertiary care pediatric hospital suggests it may not be quite so “rare”. In addition, given that HPS might be under-diagnosed, it is quite possible that the true incidence is much higher. To aid with the correct diagnoses, the histiocyte society came up with diagnostic criteria in 2004 (see Box 1, HLH-2004 diagnostic criteria in Santoriello et al). Some of the interesting biochemical (and major) criteria include elevated ferritin and fasting triglyceride levels. The presence of elevated serum soluble CD25/IL-2R levels underlies the profound cytokine storm that accompanies HPS and results in the SIRS.
Acquired HPS has been reported after infections (Epstein-Barr virus being a prominent one), malignancy, and autoimmune disease (where it is also labeled as Macrophage Activation Syndrome or MAS). Renal manifestation is usually acute kidney injury – acute tubular necrosis – and is a harbinger of poor prognosis. HPS-induced glomerular disease has been reported, usually as nephrotic syndrome from collapsing glomerulopathy, supporting cytokine-induced podocyte injury. The case described by Santoriello et al expands the renal manifestation by demonstrating hemophagocytosis in glomerular capillaries by infiltrating macrophages.
Lastly, this syndrome has a poor prognosis, especially given that the diagnosis is often missed. In children, the survival was close to 0% until a protocol based on steroids, cyclosporine, and etoposide (the HLH-94 regimen) showed dramatic improvement in survival up to 55% at 3 years. Immunosuppression is the cornerstone of treatment, and problematic given that many of these patients may be thought to have sepsis as a cause of the SIRS. In the present case, the astute pathology diagnosis lead to prompt steroid therapy and remission with normalization of kidney function. Apart from keeping your eyes and mind open to rare diseases, the other take-home message is the value of a kidney biopsy in cases of acute kidney injury.
Swapnil Hiremath, MD
AJKD Blog Contributor