|Year : 2016 | Volume
| Issue : 1 | Page : 45-48
Adult-onset Still's disease masquerading as sepsis
Rupesh Gupta, Praveen Tagore, Ritika Dhurwe, Jyotsna Kubre, Vaibhav Ingle, Saurabh Saigal
Department of General Medicine and Critical Care Medicine, AIIMS, Bhopal, Madhya Pradesh, India
|Date of Web Publication||2-Aug-2016|
Department of General Medicine, AIIMS, Saket Nagar, Bhopal, Madhya Pradesh
Source of Support: None, Conflict of Interest: None
This is a case of a 30-year-old female who presented with a recent 4-week history of fever with an underlying chronic illness for the last 6 years for which she got evaluated multiple times and received long treatments but did not get relieved. This time, she presented with high-grade fever and palpitation. Electrocardiogram was suggestive of supraventricular tachycardia which was immediately reverted with intravenous adenosine. She was transferred to the Intensive Care Unit for suspected sepsis. However, after a thorough diagnostic microbiologic, serologic, and immunologic workup, she was diagnosed with adult-onset Still's disease (AOSD) and was managed with steroids and responded well to treatment. AOSD is a rare condition which could present with a variety of clinical features resembling sepsis.
Keywords: Adult-onset Still disease, hyperferritinemia, sepsis, supraventricular tachycardia
|How to cite this article:|
Gupta R, Tagore P, Dhurwe R, Kubre J, Ingle V, Saigal S. Adult-onset Still's disease masquerading as sepsis. Indian J Allergy Asthma Immunol 2016;30:45-8
|How to cite this URL:|
Gupta R, Tagore P, Dhurwe R, Kubre J, Ingle V, Saigal S. Adult-onset Still's disease masquerading as sepsis. Indian J Allergy Asthma Immunol [serial online] 2016 [cited 2020 Mar 28];30:45-8. Available from: http://www.ijaai.in/text.asp?2016/30/1/45/187570
| Introduction|| |
Adult-onset Still's disease (AOSD) is a rare inflammatory systemic condition characterized by a variable clinical expression and progression. Because of the absence of specific markers, the diagnosis of AOSD remains clinical and requires exclusion of various infectious, neoplastic, and autoimmune conditions. The full constellation of clinical and laboratory features of AOSD develops over a period which eventually leads to a delay in diagnosis. Here, we describe a patient with fever admitted to the Intensive Care Unit (ICU) with supraventricular tachycardia and hypotension, where we initially considered Gram-negative sepsis. However, her long history of fever and polyarthralgia spanning a total of 6 years, with much-elevated serum ferritin levels, negative blood cultures, and absence of hemophagocytes on bone marrow examination helped us to make the diagnosis of AOSD.
| Case report|| |
A 30-year-old female was admitted to the medical ward with a history of fever for 4 weeks. She gave history of high-grade intermittent fever that persisted despite on being multiple antibiotics. There were no localizing symptoms or signs and her recent peripheral smear examination, complete blood counts, and chest radiograph all were normal. She had several episodes of fever in previous 6 years. She also had two hospitalizations, 5 and 3 years ago. Fever was accompanied by arthralgias on some occasions. Five years ago, she had a small cervical lymph node, which had nonspecific inflammatory changes on biopsy. Since her fever had persisted, she was also prescribed antitubercular drug therapy then. She continued to have episodes of fever during and after completion of antitubercular drug therapy. A consistent feature on most occasions was mild anemia (hemoglobin [Hb] range: 8-10 g/dL), which was microcytic (mean corpuscular volume 60-66 fL). She twice had a serum ferritin measured in the past, which was elevated (160 and 220 ng/dL). She had elevated C-reactive protein and erythrocyte sedimentation rates on various occasions. Her hemoglobin high-performance liquid chromatography performed twice had shown elevated HbA2 fraction (4.2% and 3.6%), suggestive of thalassemia minor. Two years ago, she had Staphylococcus grown in her blood cultures and had received linezolid for likely Gram-positive sepsis. She never had any constitutional symptoms (such as weight loss, loss of appetite, or vomiting) or localizing symptoms (cough, headache, seizures, yellow eyes, burning micturition, or diarrhea) other than the presence of fever.
On admission to hospital, she was febrile, had pulse rate of 120/min, blood pressure of 100/60 mmHg, and saturations of 97-98% on room air. She was pale and had mild splenomegaly. We ordered for a fresh hematology, blood chemistry, urine, and blood cultures. In addition, we also ordered for antinuclear antibody (ANA), thyroid profile, and serum ferritin. The same evening, she developed high-grade fever and palpitations. At this time her pulse was 220/min, and blood pressure was 80/50 mmHg. Her electrocardiogram (ECG) showed supraventricular tachycardia, which was reverted with injection adenosine. However, she continued to have sinus tachycardia and hypotension. At this time, she was shifted to ICU.
In view of high-grade fever, persistent hypotension, and tachycardia, she was managed as sepsis. We initiated volume resuscitation and subsequently vasopressors support. Her complete blood counts drawn in the afternoon had leukocyte count of 17,000, and her liver function and renal function tests were normal. Her arterial blood gas drawn in the ICU was suggestive of metabolic acidosis. She was initiated on injectable carbapenems (meropenem) and aminoglycosides (amikacin) considering blood stream infection with septic shock. To maintain her blood pressure, vasopressor support in the form of noradrenaline and vasopressin was added. In view of refractory shock, intravenous (i.v.) hydrocortisone in a dose of 100 mg i.v. 8 hourly was also added. Echocardiography revealed hyperkinetic myocardium with an ejection fraction of 60-65%. The next day, her leukocyte counts were 34,000 with 85% of cells being polymorphs and 15% lymphocytes. On day 3, her leukocyte counts had decreased to 11,600, and vasopressor support was tapered and withdrawn. Metabolic acidosis had resolved, and serum chemistry remained normal. Her blood and urine cultures drawn on the 1 st day came back as sterile. Imaging of thorax and abdomen (radiographs, computed tomography-scan, and ultrasound) was normal.
Her serum ferritin was markedly high (47,890 ng/mL). Her ANA, rheumatoid factor, and anticyclic citrullinated peptide antibodies were negative. In view of the prolonged history of fever, evidence of a persistent inflammatory state and current episode of supraventricular tachycardia with leukocytosis and hyperferritinemia, we considered the possibilities of macrophage activation syndrome. We performed bone marrow aspiration, and it had no evidence of hemophagocytes. Another differential diagnosis was AOSD, which is largely a diagnosis of exclusion. An episode of supraventricular tachycardia and hypotension was likely due to myocarditis, for which this patient survived. Her fever had also responded, likely due to hydrocortisone infusion. On day 5, we stopped antibiotics and initiated her on 1 mg/kg of oral prednisolone (PO). She was shifted back to the medical ward where she remained afebrile for next 3 days. She remained hemodynamically stable and did not develop any leukocytosis. She was discharged and on follow-ups at 4 and 8 weeks; she remained asymptomatic. We have tapered her oral steroids to 30 mg PO and planned to reduce dosage further based on the clinical and inflammatory response.
| Discussion|| |
AOSD is a rare differential diagnosis for fever of unknown origin (FUO). Because of the particular complexity of biological and clinical data, diagnosis of adult Still's disease is one of exclusion. Lack of specific biomarkers and its similarity to infectious, malignant and rheumatic diseases may lead to a delay in its diagnosis.  In our case, primary differential diagnosis kept was sepsis due to the way of her recent presentation, but at the same time, autoimmune diseases or malignancy was kept in mind because of her associated chronic history.
Various investigations were sent in our patient for likelihood possibility of sepsis/autoimmune disease/malignancy, but all of them were negative. Excessive hyperferritinemia, FUO, history of polyarthralgia, and rash in our case gave us clue toward the diagnosis of AOSD. Based on the criteria proposed by Yamaguchi et al. [Table 1] which require >5 criteria (>2 being major criteria and no exclusion criteria), the diagnosis was positive for AOSD as our patient fulfilled three major and four minor criteria. 
Literature had proved AOSD masquerading as sepsis. Hypotension, leukocytosis in ASOD is because of excessive release of inflammatory cytokines. There is increasing evidence that circulating ferritin levels may not only reflect an acute phase response but may play a pathogenic role in inflammation. A novel role for extracellular ferritin as a pro-inflammatory signaling molecule in hepatic stellate cells has been proposed. Ruddel et al observed that cells treated with ferritin activated a pathway comprising PI3 kinase phosphorylation, protein kinase C zeta activation, and mitogen-activated protein kinase, ultimately culminating in activation of nuclear factor-kB (NF-kB). Activation of NF-kB, in turn, enhanced the expression of pro-inflammatory mediators, including interleukin (IL)-1 beta, inducible nitric oxide synthase, and others. These ILs had proven in the pathogenesis of AOSD. , Based on various studies, causes of hyperferritinemia can be divided according to its level. Only a few differentials when the levels were >10,000 mcg/L, which includes fulminant hepatic failure, hemophagocytic lymphohistiocytosis (HLH) and AOSD. In our case, serum ferritin was 47,859 ng/mL. The patient had normal coagulation profile, normal bilirubin level, mildly elevated transaminases, normal imaging which ruled out fulminant hepatic failure. HLH is a hyperinflammatory syndrome with high mortality. Although literature supports the association of HLH in AOSD in our case, on day 4 ICU, the patient developed relative cytopenia which created the possibility of HLH; hence, bone marrow was planned but had normal with no evidence of phagocytosis is hence not fulfilling the criteria for HLH. These all findings support the diagnosis of AOSD. 
In juvenile idiopathic arthritis (JIA), myocarditis is a well-known complication often associated with pericardial effusion, which can lead to congestive heart failure and arrhythmias. On the contrary, myocarditis has been rarely described in AOSD. To the best of our knowledge, only a few cases of myocarditis were reported during the course of AOSD. , Literature had reported various nonspecific ECG changes of myocarditis in AOSD such as nonspecific ST segment and T wave abnormalities.  Clinical reports show a good response of acute myocarditis to systemic steroids with complete and quick regression of cardiac failure. , In this case, the patient had sinus tachycardia initially but later developed narrow complex tachycardia which reverted with injection adenosine, but sinus tachycardia still persisted. Incidentally in ICU, we had started systemic steroid in view of refractory shock that might helped the patient.
Regarding available data on AOSD, the risk/benefit ratio is not favorable with regard to nonsteroidal anti-inflammatory drugs (NSAIDs). Indeed, more than 80% of AOSD patients did not achieve remission with NSAIDs and approximately 20% suffered adverse events. Nevertheless, temporary use of NSAIDs can be considered during diagnostic workup or for early relapse of the disease.  Corticosteroids remain the first-line treatment for AOSD, regardless of the clinical presentation. Nevertheless, studies of systemic-onset JIA are providing evidence that some biologics should be used earlier in the course of the disease.  In addition, new treatment plans for systemic-onset JIA have placed methotrexate, anakinra, and tocilizumab as possible first-line treatments.  Corticosteroids control symptoms in about 60% of patients and they show greater efficacy with regard to control of systemic symptoms than articular ones. Steroid dependency occurs in approximately 45% of cases. In the event of failure of corticosteroid treatment or steroid dependence, disease-modifying antirheumatic drugs can be considered.  In this case, at the time of acute illness in ICU, we had given i.v. hydrocortisone 100 mg 8 hourly later on shifted the patient on oral PO and patient responded clinically. In her past admissions to various hospitals, she was treated with NSAIDs and got only temporarily relieved but never achieved full remission.
| Conclusion|| |
AOSD is a diagnosis of exclusion; high ferritin levels along with history of polyarthralgia and negative microbiologic, immunologic and radiological markers pointed us to this diagnosis.
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Conflicts of interest
There are no conflicts of interest.
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