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Table of Contents
Year : 2021  |  Volume : 12  |  Issue : 3  |  Page : 171-174

Adult-onset still's disease masquerading as hemophagocytic lymphohistiocytosis

1 Department of Medicine, Lady Hardinge Medical College and ABVIMS, RML Hospital, New Delhi, India
2 Department of Pathology, Lady Hardinge Medical College, New Delhi, India

Date of Submission10-Mar-2021
Date of Acceptance29-Mar-2021
Date of Web Publication23-Jul-2021

Correspondence Address:
Dr. Aanchal Arora
F11 2nd Floor, Vikas Puri, New Delhi
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Source of Support: None, Conflict of Interest: None

DOI: 10.4103/injms.injms_34_21

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Hemophagocytic lymphohistiocytosis (HLH) is a life-threatening hematological condition caused by the overactivation of macrophages leading to widespread tissue destruction and organ dysfunction. The disease has a clinical overlap with adult-onset still's disease (AOSD) and hence poses a diagnostic challenge. We report the case of a 20-year-old female who presented with prolonged febrile illness, anemia, hepatosplenomegaly, and generalized lymphadenopathy. She was diagnosed with HLH and was readmitted 6 weeks later with recurrent fever, polyarthralgia, and pharyngitis. A diagnosis of AOSD with secondary HLH was made.

Keywords: Adult-onset still's disease, hemophagocytic lymphohistiocytosis, macrophage activating syndrome

How to cite this article:
Gautam P, Gupta N, Arora A, Sharma K, Goel A. Adult-onset still's disease masquerading as hemophagocytic lymphohistiocytosis. Indian J Med Spec 2021;12:171-4

How to cite this URL:
Gautam P, Gupta N, Arora A, Sharma K, Goel A. Adult-onset still's disease masquerading as hemophagocytic lymphohistiocytosis. Indian J Med Spec [serial online] 2021 [cited 2023 Jun 9];12:171-4. Available from: http://www.ijms.in/text.asp?2021/12/3/171/322215

  Introduction Top

Hemophagocytic lymphohistiocytosis (HLH) is a life-threatening hematological condition caused by the overactivation of macrophages leading to widespread tissue destruction and organ dysfunction. First described in 1952 as a familial disorder the disease is now a separate clinical entity which can be primary/familial or secondary to infections, malignancy, immunosuppression, and autoimmune conditions.[1] The exact incidence of HLH is not known; however, as per the Swedish study, the primary autosomal recessive disease has an annual incidence of 1.2/1,000,000 among pediatric population.[2] Common presentations of HLH include prolonged fever, hepatosplenomegaly, pancytopenia, and elevated levels of liver enzymes, ferritin, and triglycerides.[1] The presence of hemophagocytes in various tissues is the pathognomonic hallmark of the disease. Adult-onset still's disease (AOSD) is an autoimmune condition that clinically overlaps with HLH and hence poses a diagnostic challenge.[3] Here, we report a case of 20-year-old female who presented initially with HLH and was later diagnosed as a case of AOSD.

  Case Report Top

A previously healthy 20-year-old unmarried female, resident of Delhi, presented to the emergency with complaints of fever for 2 months, bilateral lower limb swelling, and abdominal distension for 20 days. Fever was low grade and intermittent. She also reported undocumented weight loss. She denied a history of joint pains, rash, photosensitivity, dysuria, oliguria, jaundice, or bleeding from any site. There were no complaints of chest pain, breathlessness, or palpitations. Owing to her illness, she had received four units of blood transfusion and antitubercular treatment in the last 2 months.

On examination, the patient was conscious, normotensive with a blood pressure of 110/70 mmHg, pulse rate of 86/min, and SpO2 of 98% on room air. She was febrile to touch with an oral temperature of 101°F. General physical examination revealed moderate pallor, multiple nontender cervical lymph nodes, largest measuring 1.5 cm. Bilateral pitting pedal edema was present. There was no evidence of rash, swollen, or tender joints. Abdomen examination revealed nontender moderate hepatosplenomegaly and rest systemic examination was unremarkable. A clinical diagnosis of pyrexia of unknown origin with hepatosplenomegaly and anemia was made. Possible differentials were disseminated tuberculosis, lymphoreticular malignancy, Kala Azar, acquired immunodeficiency syndrom-related illness,  Brucellosis More Details, autoimmune disorder, and HLH.

Routine laboratory investigations on day 1 showed pancytopenia with lymphocytosis and deranged liver function tests. Erythrocyte sedimentation rate (ESR), C-reactive protein (CRP), and lactate dehydrogenase (LDH) levels were raised. Considering relevant possible differential diagnosis, other investigations were sent which were HIV, HBs antigen, anti-hepatitis C virus antibody,  Brucella More Details immunoglobulin M (IgM), RK 39 antigen, antinuclear antibody, extractable nuclear antigens, serum ferritin, D-dimer, fibrinogen, and triglyceride levels. Among all serum ferritin, triglyceride, D-dimer values were high along with low levels of fibrinogen. Mantoux test was negative.

She was managed with broad-spectrum antibiotics, antipyretics, and adequate hydration. Simultaneously, a cervical lymph node biopsy was done which revealed paracortical expansion containing high endothelial venules and an admixture of small lymphoid cells, histiocytes, occasional plasma cells, and large cells with vesicular nuclei. Immunohistochemistry revealed CD3- and CD20-positive cells with interspersed CD68-positive cells [Figure 1]a and [Figure 1]b. Acid-fast bacillus stain was negative. Chest imaging and echocardiography were normal. Sonography of the abdomen confirmed the presence of hepatosplenomegaly. In view of pancytopenia, a bone marrow aspiration biopsy was done which revealed the presence of histiocytic cells showing hemophagocytosis [Figure 2].
Figure 1: (a) Lymph Node biopsy showing extensive vascular proliferation with an arborizing network of capillary channels in paracortex. Abortive germinal centers with expanded paracortex containing clear cells and vascular proliferation, along with extracellular deposits of lace-like pink material. (b) Immunohistochemistry of the lymph node biopsy demonstrating CD 68 positivity

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Figure 2: BMA showing hemophagocyte at × 400

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A thorough investigation of the patient suggested a diagnosis of HLH. According to the HLH-2004 protocol,[2] our patient fulfilled seven features out of the eight diagnostic criteria for HLH, including a persistent fever, bicytopenia, hepatosplenomegaly, low fibrinogen levels, raised ferritin levels, elevated triglycerides, and histiocytic activity on a bone marrow aspirate. Further workup to identify secondary causes of HLH was unremarkable. These investigations included blood cultures, urine cultures, Widal test, anti-Ebstein–Barr virus IgM, COVID 19 reverse transcription–polymerase chain reaction and IgG antibodies, and TORCH serology. Genetic analysis could not be done in our resource-limited setting.

The patient had a spontaneous resolution in fever spikes and was discharged to follow-up in our outpatient department. The patient was readmitted 6 weeks later with complaints of new-onset seizure, throat pain, diffuse myalgia, bilateral elbow pain, and weight loss. On examination, she was febrile, conscious, and oriented. There was pallor with palpable cervical and inguinal lymphadenopathy. There was no focal neurological deficit and rest central nervous system examination was unremarkable. On abdomen examination, there was no regression in hepatosplenomegaly. Laboratory investigations revealed persistent anemia with neutrophilic leukocytosis and raised LDH [Table 2]. Blood culture, urine analysis, and culture were sterile, and serum procalcitonin was negative. Chest X-ray and noncontrast computed tomography of the head were normal. Ultrasound of the abdomen revealed hepatosplenomegaly.
Table 1: Laboratory investigations at first admission

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Table 2: Laboratory investigations at second admission

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Hence, the second admission ruled out sepsis as a possible cause of deterioration in the patient's condition. The presence of arthralgias and pharyngitis pointed toward the possibility of AOSD with secondary HLH. The patient fulfilled Yamaguchi criteria[3] (3 major + 3 minor) and was diagnosed as a case of AOSD with macrophage activation syndrome (MAS). The patient was started on intravenous methylprednisolone. However, the patient developed breathlessness and hypoxia on day 4 of admission secondary to probably aspiration pneumonia which required invasive ventilation. She succumbed to her illness on the same day.

  Discussion Top

AOSD is an autoimmune disease with bimodal age distribution, affecting people among 15–25 years and 36–46 years of age.[4] The exact etiology of AOSD is still not clear, but several factors such as genetic, immunological, bacterial, and viral infections contribute to the pathogenesis. It commonly presents with high spiking fevers, transient nonpruritic salmon/maculopapular rash, nonsuppurative pharyngitis, multiple joint pains, nontender lymphadenopathy, and hepatosplenomegaly.

Common laboratory findings include elevated leukocyte count, deranged LFT, elevated ESR, and serum ferritin levels. Lymph node biopsies demonstrate paracortical T-cell hyperplasia, and increased number of CD 68-positive cells.[5] The disease is a diagnosis of exclusion and is diagnosed after ruling out other autoimmune, infective conditions, malignancies, and connective tissue diseases.[4] The disease can be diagnosed utilizing various criteria such as Yamaguchi criteria. HLH/MAS is the most serious complication of AOSD and shares many clinical laboratory features with it thus posing a diagnostic challenge[6] and is associated with higher mortality.[7]

Our patient had presented initially with a febrile illness with hepatosplenomegaly, pancytopenia, and hemophagocytosis on bone marrow examination and was subsequently diagnosed as a case of HLH since autoimmune diseases and malignancy were excluded; lymph node biopsy demonstrated paracortical T-cell hyperplasia likely to be a reactive lymph node and the patient had spontaneous improvement, it was assumed to be a case of secondary HLH due to a viral illness and the patient was discharged. However, during the second admission, the patient had a history of joint pains, throat pain, and high spiking fever with neutrophilic leukocytosis. With sepsis in the current admission excluded, the possibility of AOSD was kept. The patient fulfilled the Yamaguchi criteria and the disease was diagnosed and treatment was started.

  Conclusion Top

AOSD is a rare autoimmune condition which often presents as a diagnostic challenge. It has a poor prognosis when complicated by HLH. Hence, the present case report highlights the overlapping manifestations of both the conditions and helps the clinician to suspect it as a possible etiology of HLH.

Declaration of patient consent

The authors certify that they have obtained all appropriate patient consent forms. In the form the patient (s) has/have given his/her/their consent for his/her/their images and other clinical information to be reported in the journal. The patients understand that their names and initials will not be published and due efforts will be made to conceal their identity, but anonymity cannot be guaranteed.

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Conflicts of interest

There are no conflicts of interest.

  References Top

Thomas M, Robert A, Kuruvilla N, Uthamanand C. An unusual presentation of systemic lupus erythematosus as hemophagocytic lymphohistiocytosis in a male. Cureus 2019;11:E5427.  Back to cited text no. 1
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. 2
Yamaguchi M, Ohta A, Tsunematsu T, Kasukawa R, Mizushima Y, Kashiwagi H, et al. Preliminary criteria for classification of adult Still's disease. J Rheumatol 1992;19:424-30.   Back to cited text no. 3
Agha-Abbaslou M, Bensaci AM, Dike O, Poznansky MC, Hyat A. Adult-onset still's disease: Still a serious health problem (a case report and literature review). Am J Case Rep 2017;18:119-24.  Back to cited text no. 4
Ruscitti P, Ciccia F, Cipriani P, Guggino G, Di Benedetto P, Rizzo A, et al. The CD68(+)/H-ferritin(+) cells colonize the lymph nodes of the patients with adult onset Still's disease and are associated with increased extracellular level of H-ferritin in the same tissue: Correlation with disease severity and implication for pathogenesis. Clin Exp Immunol 2016;183:397-404.  Back to cited text no. 5
Bae CB, Jung JY, Kim HA, Suh CH. Reactive hemophagocytic syndrome in adult-onset Still disease: Clinical features, predictive factors, and prognosis in 21 patients. Medicine (Baltimore) 2015;94:e451.  Back to cited text no. 6
Wang R, Li T, Ye S, Tan W, Zhao C, Li Y, et al. Macrophage activation syndrome associated with adult-onset still's disease: A multicenter retrospective analysis. Clin Rheumatol 2020;39:2379-86.  Back to cited text no. 7


  [Figure 1], [Figure 2]

  [Table 1], [Table 2]

This article has been cited by
1 Hemophagocytic Lymphohistiocytosis Secondary to Adult-Onset Stillís Disease
Bhupen Barman,Md Jamil,Pranjal Kalita,Biswajit Dey
Cureus. 2021;
[Pubmed] | [DOI]


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