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Year : 2013  |  Volume : 14  |  Issue : 3  |  Page : 83-87

Coexistence of Stevens-Johnson syndrome and hemophagocytic syndrome

1 Department of Dermatology, MIMS Hospital, Calicut, Kerala, India; Department of Dermatology, Hatta Hoapital, Dubai Health Authority, Dubai, U.A.E
2 Department of Dermatology, MIMS Hospital, Calicut, Kerala, India
3 Department of Pathology, MIMS Hospital, Calicut, Kerala, India
4 Department of Paediatrics, MIMS Hospital, Calicut, Kerala, India

Date of Web Publication26-Nov-2013

Correspondence Address:
Jaheersha Pakran
Department of Dermatology, Hatta Hospital, Dubai Health Authority, Dubai, U.A.E

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Source of Support: None, Conflict of Interest: None

DOI: 10.4103/2319-7250.122174

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The aim is to report a case of fatal hemophagocytic syndrome (HS) which developed in a patients with sepsis and Stevens-Johnson syndrome (SJS). A 12-year-old girl with chronic renal failure was admitted for catheter site infection related sepsis. Patient was treated with meropenem, vancomycin and sodium valproate. After this, she developed purpuric skin lesions and mucosal erosions consistent with SJS. Further investigations were performed due to rapid clinical deterioration, hepatosplenomegaly and resistant pancytopenia. We found elevated serum triglyceride and serum ferritin and evidence of hemophagocytosis in bone marrow aspirate. She was diagnosed as sepsis related HS with coexistent SJS and started on injection methylprednisolone. Despite treatment, she expired on the eighth day of admission. HS or hemophagocytic lymphohistiocytosis comprises a heterogeneous group of primary and secondary disorders characterized by the proliferation of activated macrophages, associated with generalized hemophagocytosis. The fact that HS is being reported with an ever-increasing list of dermatological and rheumatological diseases should make us vigilant to this immunological complication. Treatment of the precipitating events and timely administration of immunosuppressive drugs could be life-saving in this situation.

Keywords: Hemophagocytic lymphohistiocytosis, macrophage activation syndrome, Stevens-Johnson syndrome, toxic epidermal necrolysis

How to cite this article:
Pakran J, Pavithran K, Kuruvila S, Anand M. Coexistence of Stevens-Johnson syndrome and hemophagocytic syndrome. Indian J Paediatr Dermatol 2013;14:83-7

How to cite this URL:
Pakran J, Pavithran K, Kuruvila S, Anand M. Coexistence of Stevens-Johnson syndrome and hemophagocytic syndrome. Indian J Paediatr Dermatol [serial online] 2013 [cited 2022 Jun 28];14:83-7. Available from: https://www.ijpd.in/text.asp?2013/14/3/83/122174

  Introduction Top

Hemophagocytic syndrome (HS) or hemophagocytic lymphohistiocytosis (HLH) comprises a heterogeneous group of primary (familial) and secondary (non-familial) disorders characterized by the proliferation of activated macrophages associated with generalized hemophagocytosis. [1] Due to the association of HS with several diseases that dermatologists encounter, increasing awareness of this potentially lethal condition is critical for early detection and treatment. In this article, we report a 12-year-old girl on dialysis that developed HS in association with  Stevens-Johnson syndrome More Details-toxic epidermal necrolysis (SJS-TEN) overlap syndrome following "methicillin resistant Staphylococcus aureus" (MRSA) sepsis.

  Case Report Top

Our patient, a 12-year-old girl was on maintenance hemodialysis and awaiting a renal transplantation, after being diagnosed with the chronic renal failure secondary to medullary cystic kidney disease 4 months back. During the treatment period, she developed high fever and was admitted in her treating hospital. Patient was diagnosed with sepsis due to the jugular venous catheter site infection. Blood culture grew MRSA sensitive to vancomycin. She was treated with meropenem, vancomycin and sodium valproate (for metabolic seizures). During the treatment, she developed global left ventricular dysfunction, progressive anemia and neutropenia for which blood transfusion and granulocyte macrophage-colony stimulation factor (GM-CSF) was started. At this point, patient was referred to our hospital.

On admission in pediatric intensive care unit, she was sick looking, febrile, pale but hemodynamically stable, conscious and oriented. She had hepatosplenomegaly with liver palpable 3 cm below right costal margin. Patient was noted to have purpuric lesions on face, trunk and extremities involving approximately 25% of body surface area, hemorrhagic crusting of lips and oral mucosal erosions with white curdy precipitates and genital erosions. The clinical findings were consistent with SJS/TEN overlap syndrome with mucosal candidiasis. She was continued on hemodialysis while the suspected offending drugs sodium valproate and vancomycin were stopped and substituted with cefoperazone-sulbactam combination, clobazam, fluconazole, metronidazole and other supportive measures. Her laboratory reports showed pancytopenia, serum creatinine of 5.8 mg/dl, erythrocyte sedimentation rate of 66, mildly elevated liver enzymes. The coagulation parameters became progressively deranged; initial prothrombin time of 13.8 s became 20 s over 3 days (control 11 s) and international normalized ratio prolonged from 1.23 to 1.73. The activated partial thromboplastin time was 52.5 s (control 24 s). Though initial blood culture was negative, her serum procalcitonin titers were more than 100 ng/ml (normal < 0.15 ng/ml), which is highly indicative of sepsis. She had elevated serum triglyceride (288 mg/dl) and serum ferritin (18,396 ng/ml against a normal value of <200 ng/ml). Anti-nuclear antigen, rheumatoid factor and human immunodeficiency virus serology were negative. Bone marrow aspiration showed hypoplastic marrow with suppressed erythropoiesis, myelopoiesis and megakaryocytes; the predominant cells were lymphocytes and macrophages showing phagocytosis and there was increased iron staining of the marrow, suggesting a diagnosis of HLH [Figure 1]. She was diagnosed as sepsis related HS and started on injection methyl prednisolone 750 mg daily. Her pancytopenia worsened over the subsequent days (total leucocyte count of 1500 cells/dl to 50 cells/dl over 7 days) despite recombinant - granulocyte colony stimulating factor and multiple blood and blood component transfusions. Subsequent bone marrow culture grew Candida tropicalis sensitive only to Amphotericin B, which could not be started due to pancytopenia and renal impairment. She developed protracted diarrhea and hypotension and finally expired on the 8 day of admission from the combined assault of renal failure, HS and sepsis.
Figure 1: Bone marrow aspirate (a) shows phagocytosis of RBC (R), myeloid precursor cells (P) and lymphocytes (L) by macrophages; Giemsa stain ×100 magnification (MN-macrophage nucleus). (b) There is increased iron staining (blue dots) in the marrow; Perl's iron stain ×100 magnification

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  Discussion Top

SJS and HS are two complex immunological diseases whose pathogenesis is not fully elucidated yet. In this report, both diseases co-existed in the same patient. SJS and TEN are severe idiosyncratic reactions, most commonly triggered by medications. [2] While several systemic complications are well-recognized in SJS/TEN, association with HS is only recently reported. Zeng and Chen [3] reported a previously healthy 7-year-old boy who developed SJS following ceftriaxone injections for bronchitis. When ceftriaxone was substituted with vancomycin, patient developed macrophage activation syndrome (MAS), which was successfully treated with steroids and cyclosporine. [3]

HS/HLH comprises a heterogeneous group of disorders featuring sepsis-like clinical characteristics with high fever, hepatosplenomegaly and lymphadenopathy. The ingestion of cellular blood components and their precursors by normal appearing macrophages is called hemophagocytosis and forms the pathognomonic feature of HS. It is typically combined with dysfunctional cellular cytotoxicity, hypercytokinemia, hemophagocytosis, variable cytopenias, coagulation disorders, elevated triglycerides and hyperferritinemia (above 10,000 ng/ml), often resulting in multiple organ failure and high mortality rate. [4],[5] The most common histopathologic finding in patients with MAS is tissue infiltration with T lymphocytes and cytologically benign yet actively phagocytic macrophages in bone marrow and other tissues such as liver, lymph nodes, skin, lungs etc. [6]

There is some confusion in the literature regarding the terminologies of MAS and HS/HLS, which needs clarification. The term MAS was initially used in pediatric patients suffering from the disorder as a complication of autoimmune disease. This terminology remains prevalent in the rheumatology literature, whereas syndromes described in the hematology and infectious disease literature often describe a similar phenomenon as secondary HLH. Subsequent work has demonstrated that it may be appropriate to classify MAS as a secondary form of HLH. [7]

In the most recent classification of the Histiocyte Society, HLH is included under "disorders of varied biologic behavior" of macrophages and it is further subdivided into primary or familial HLH and secondary or reactive HLH. [6] Clinically, however, these disorders may be difficult to distinguish from each other. Familial HLH is a constellation of rare autosomal recessive immune disorders, which usually presents within the first 2 months of life and are rapidly fatal unless treated. [8] Secondary, HLH occurs in association with a variety of diseases, which are summarized in [Table 1]. [4] [Table 2] shows a simplified model for the proposed pathogenic mechanisms of HLH. [7]
Table 1: Simplified classification of hemophagocytic lymphohistiocytosis showing diseases associated with it

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Table 2: Simplified model for pathogenesis of hemophagocytic lymphohistiocytosis: One model proposes that over-stimulation of innate immunity by tolllike receptors is sufficient for development of macrophage activation syndrome. In the second model the adaptive immunity is abnormal with decreased number or function of natural killer and cytotoxic T lymphocytes. This either hinders the elimination of antigens or impairs the contraction of the immune response after the clearance of antigen. The final common pathway is uncontrolled proliferation of T-cells and macrophages, with overproduction of cytokines by these cells (cytokine storm), which cause hemophagocytosis

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Although several medications including disease-modifying antirheumatic drugs have been implicated to trigger MAS, whether these drugs or the initial rheumatological condition for which they are prescribed is the actual trigger in these cases is not known for sure. [8] There is a report of hemophagocytosis exacerbated by G-CSF/GM-CSF treatment in a patient with myelodysplasia. [9] MAS in a child as a probable side-effect of antiepileptic drug have also been reported. [10] Olgar et al. [11] described four patients who developed MAS during or after vancomycin treatment and they concluded that vancomycin should be used with great care in patients with systemic juvenile idiopathic arthritis. A role for vancomycin in precipitating HS in our patient cannot be ruled out, which would mean co-occurrence of two drug related diseases in our patient.

It awaits to be seen whether every inflammatory disease, which generates a suitable cytokine milieu in the susceptible host, can potentially lead to HS because interferon-γ (IFN-γ) is the cytokine with the highest concentration, in blister fluid of TEN. [2] IFN-γ has also been demonstrated to be the major mediator of macrophage activation in the perforin knockout mouse model of infection-induced HLH [4] as well as the toll-like receptor-9 over-stimulation model. [12] Thus, whether the association between SJS and HS in is genuine or spurious is debatable.

The clinical findings in overt HS are often dramatic and evolve rapidly. Typically, patients with a chronic condition become acutely ill with persistent fever, mental status changes, lymphadenopathy, hepatosplenomegaly and liver dysfunction. A hemorrhagic syndrome resembling disseminated intravascular coagulopathy is another striking feature of HS. Encephalopathy, renal dysfunction and pulmonary infiltrates have been frequently reported in HS. Though, hemorrhagic skin rashes from mild petechiae to extensive ecchymotic lesions are commonly seen in these patients. [5] In our patient the involvement of two mucosal sites with crusting of lips, genital erosions, purpuric and necrotic skin lesions over the face and upper trunk and limbs tilt the diagnosis for the skin lesions in favor of SJS.

In HLH-94, the first prospective international treatment study for HLH, diagnosis was based on five criteria, persistent fever, splenomegaly, bicytopenia, hypertriglyceridemia (≥265 mg/dl) and/or hypofibrinogenemia (≤1.5 g/L) and hemophagocytosis. In HLH-2004, three additional criteria were introduced; low/absent natural-killer cell-activity, hyperferritinemia (>500 ng/ml) and high-soluble interleukin-2-receptor levels. Altogether, five of these eight criteria must be fulfilled, unless family history or molecular diagnosis is consistent with HLH. [13] Our patient fulfilled all of the HLH-94 criteria along with hyperferritinemia, which aided in the diagnosis.

Critical points of successful management of HS are early clinical suspicion in high-risk patients and appropriate screening with serum ferritin and other markers of the disease. Upon diagnosis, treatment of the causative disorder, avoidance/removal of triggering drugs/insults and appropriate supportive measures are needed. Definitive treatment includes appropriate antibiotics, corticosteroids (high dose oral steroids or intravenous methyl prednisolone pulses) and immunosuppressive drugs such as cyclosporin, cyclophosphamide and intravenous immunoglobulin. [14] Although the reported mortality rates of MAS reach 20%, due to increasing awareness, it is now diagnosed relatively early and the outcome is improving. [5] However despite treatment, our patient succumbed to the disease due to the insurmountable level of multiple comorbidities.

  Summary Top

We report a case of fatal HS developing in a patient with sepsis and SJS. The coexistence is significant because it is possible that many cases of HLH developing in SJS/TEN are either misdiagnosed or masked by sepsis, due to overlapping clinical features. Due to the several comorbidities and drugs given we are unable to pinpoint the specific inciting agent for HS in our patient. The fact that HS is being reported with an ever-increasing list of dermatological and rheumatologic diseases should make us vigilant to this immunological catastrophe.

  References Top

1.Penchansky L. Macrophage and dendritic-cell related disorders including the lysosomal storage disorders. In: Penchansky L, editor. Pediatric Bone Marrow. Berlin: Verlag, Springer; 2004. p. 64.  Back to cited text no. 1
2.Khalili B, Bahna SL. Pathogenesis and recent therapeutic trends in Stevens-Johnson syndrome and toxic epidermal necrolysis. Ann Allergy Asthma Immunol 2006;97:272-80.  Back to cited text no. 2
3.Zeng H, Chen X. First case report of Stevens-Johnson syndrome complicated with macrophage activation syndrome. Rheumatol Rep 2009;1:e9.  Back to cited text no. 3
4.Emmenegger U, Schaer DJ, Larroche C, Neftel KA. Haemophagocytic syndromes in adults: Current concepts and challenges ahead. Swiss Med Wkly 2005;135:299-314.  Back to cited text no. 4
5.Grom AA. Macrophage activation syndrome a review of diagnosis, treatment, and prognosis. The Rheumatologist 2010. Available from: http://www.the-rheumatologist.org/details/article/973181/Macrophage_Activation_Syndrome.html. [Last accessed on 2011 Aug 30].  Back to cited text no. 5
6.Jaffe R. The histiocytoses. Clin Lab Med 1999;19:135-55.  Back to cited text no. 6
7.Behrens EM, Canna SW, Slade K, Rao S, Kreiger PA, Paessler M, et al. Repeated TLR9 stimulation results in macrophage activation syndrome-like disease in mice. J Clin Invest 2011;121:2264-77.  Back to cited text no. 7
8.Grom AA. Natural killer cell dysfunction: A common pathway in systemic-onset juvenile rheumatoid arthritis, macrophage activation syndrome, and hemophagocytic lymphohistiocytosis? Arthritis Rheum 2004;50:689-98.  Back to cited text no. 8
9.Wang S, Degar BA, Zieske A, Shafi NQ, Rose MG. Hemophagocytosis exacerbated by G-CSF/GM-CSF treatment in a patient with myelodysplasia. Am J Hematol 2004;77:391-6.  Back to cited text no. 9
10.Cwikliñska M, Czoga³a M, Balwierz W, Hnatko-Ko³acz M, Moryl-Bujakowska A, Malinowska I, et al . Hemophagocytic syndrome in children with different underlying conditions. Przegl Lek 2010;67:430-5.  Back to cited text no. 10
11.Olgar S, Ertugrul T, Devecioglu O, Nisli K, Omeroglu RE. Does red-man reaction stimulate macrophage activation syndrome in children with systemic juvenile idiopathic arthritis? J Rheumatol 2007;34:2491-4.  Back to cited text no. 11
12.Deane S, Selmi C, Teuber SS, Gershwin ME. Macrophage activation syndrome in autoimmune disease. Int Arch Allergy Immunol 2010;153:109-20.  Back to cited text no. 12
13.Henter JI, Horne A, Aricó M, Egeler RM, Filipovich AH, Imashuku S, et al. HLH-2004: Diagnostic and therapeutic guidelines for hemophagocytic lymphohistiocytosis. Pediatr Blood Cancer 2007;48:124-31.  Back to cited text no. 13
14.Joshi VR. Macrophage activation syndrome. J Assoc Physicians India 2007;55:183-4.  Back to cited text no. 14


  [Figure 1]

  [Table 1], [Table 2]

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