Adult-onset Still’s disease in a 73-year-old Maltese man

Background

Adult-onset Still’s disease (AOSD) is a rare polygenic, systemic autoinflammatory condition, which is reported in 1.6 cases/million1 and tends to predominate in two main age groups: 16–26 years and 36–46 years. Despite its rarity outside this age group, we report a case of an elderly man who presented with AOSD symptoms preceded by the occurrence of Epstein-Barr virus (EBV), which responded immediately to low-dose steroids. Despite that concomitant infection precludes the diagnosis of AOSD according to Yamaguchi criteria,2 there are various case reports identifying a viral trigger preceding the onset of classical symptoms.

Case presentation

A 73-year-old Maltese man presented with a 3-day history of fever up to 39°C, associated with a 1-week history of sore throat and cough productive of green sputum. He denied any rashes, joint pains and oral ulcers. In addition, he also reported an unintentional weight loss of 8 kg over the previous 2 weeks. His medical history included thalassaemia trait and renal colic. His surgical history and drug history were unremarkable. He was a lifelong non-smoker and denied drug use or regular alcohol intake. He did not report any recent travel. Family history, including a history of malignancy, was unremarkable. No close contact members were similarly affected.

On clinical assessment, the patient was afebrile with stable parameters. Full physical examination, including chest examination, was normal. At this point, a provisional diagnosis of a lower respiratory tract infection was made and he was discharged on oral antibiotics.

Few days later, he returned to the emergency department with persistent quotidian fever, highest in the evenings reaching up to 39°C. Four weeks into the disease course, the patient reported increasing malaise, myalgias and arthralgias involving bilateral shoulders, hips, hands and wrists. A diffuse salmon-coloured non-pruritic coalescent maculopapular rash developed a few days after, which intensified during febrile episodes and settled after 48 hours.

Investigations

On presentation, blood investigations revealed a raised white cell count (80% neutrophils), microcytic anaemia with a haemoglobin (Hb) of 95 g/L and mean cell volume (MCV) of 59.3 fL (79–93 fL). Blood film showed longstanding microcytic hypochromic anaemia in keeping with haemoglobinopathy and reactive neutrophils with no immature granulocytes. C reactive protein (CRP) of 206 mg/L (0–5 mg/L) and erythrocyte sedimentation rate of 50 mm first hour (28–32 mm first hour). Liver function tests (LFTs) and chest X-ray were normal.

A respiratory screen tested positive for Staphylococcus aureus, and though EBV viral capsid antigen (VCA) IgM, VCA IgG and nuclear antigen-1 IgG were negative, Epstein-Barr antigen was detected by PCR at 6747 copies/mL. The rest of the septic screen was negative, including blood and urine cultures and viral and bacterial screens for Cytomegalovirus (CMV), parvovirus, HIV, Mycoplasma and Legionella. Immunology testing, including Rheumatoid Factor (RhF), antinuclear antibodies (ANA), antineutrophil cytoplasmic antibodies, anti-cyclic citrullinated peptide and immunoglobulins were all negative. A multiple myeloma screen, including serum protein electrophoresis (SPE) and serum free light chains (SFLC), was negative. Transthoracic and transoesophageal echocardiograms ruled out the possibility of infective endocarditis.

Repeat LFTs during the second admission revealed a mildly deranged mixed picture with alanine aminotransferase (ALT) of 72 U/L (5–41 U/L), alkaline phosphatase (ALP) of 180 U/L (40–129 U/L) and gamma-glutamyl transferase (GGT) of 76 U/L (8–61 U/L). Haematinics, including vitamin B₁₂, folate and iron profile, were unremarkable except for an elevated ferritin of 3028 ng/mL (22–322 ng/mL), later rising further to 12 868 ng/mL. Lactate dehydrogenase was minimally raised (359 U/L (135–220 U/L)). The patient subsequently developed symptomatic anaemia (Hb of 7.0 g/dL) that required transfusion of red cell concentrate. A full summary of relevant blood investigations is outlined in table 1.

Plain X-rays performed for arthralgias excluded any evidence of bone pathology and the absence of synovitis or tendinitis were confirmed on ultrasonography of the hands and wrists. CT of the thorax, abdomen and pelvis showed non-specific bilateral small pleural effusions not amenable for tapping and a small pericardial effusion. An MRI of the whole spine was performed in view of intermittent non-limiting back pain, which showed only osteoarthritic changes. This modality was selected over myelography as it is less invasive, and no contraindications were present. Following this, a positron emission tomography–computed tomography (PET-CT) was then performed, which excluded malignant processes and systemic vasculitides. Repeated respiratory screen and Epstein-Barr antigen PCR after 1 week turned negative.

Differential diagnosis

This case described a healthy elderly man who presented with initial symptoms of a lower respiratory tract infection, in addition to a significant 8 kg weight loss over a span of 2 weeks. Given the initial presenting features, a bacterial lower respiratory tract infection was the primary provisional diagnosis and was, therefore, prescribed antibiotics. However, despite treatment, the patient returned with persistent high-grade quotidian fevers, which were unresponsive to further antibiotic treatment.

Given the history of significant weight loss on presentation, the possible diagnosis of an underlying haematological and solid organ tumour were excluded through CT of the thorax, the abdomen and the pelvis. Multiple myeloma was excluded through normal SPE and SFLC and an MRI of the whole spine. Furthermore, a PET scan was performed, which further excluded any underlying malignancy, which was possibly missed on other radiological investigations. There was no indication for a bone marrow aspirate or trephine in this case given that there was no evidence of haematological malignancies on intensive biochemical and radiological investigations and the patient satisfied the Yamaguchi criteria for a diagnosis of AOSD.

The possibility of EBV-related prolonged viral infection was raised following the detection of EBV viral load via PCR. However, this case did not fulfil criteria neither for protracted course of infectious mononucleosis (IM) nor for chronic active EBV infection and had tested negative on repeat tests.

Other EBV-associated diseases include malignancies (Burkitt’s and Hodgkin’s lymphoma, and nasopharyngeal carcinoma), which were excluded following a thorough investigation. Autoimmune diseases are also described, and these include Sjögren’s syndrome, rheumatoid arthritis and systemic lupus erythematosus,3 but in the presented case, there were neither the symptoms nor repeat immunology testing present to satisfy any such criteria.

Four weeks into the disease, the patient developed arthralgia and a typical diffuse salmon-coloured non-pruritic rash, which in addition to fever of 39°C for at least 1 week, granulocytic leucocytosis, abnormal LFTs and negative tests for RhF and ANA satisfied the Yamaguchi criteria for a diagnosis of AOSD.

Treatment

Initially, the patient was treated with a 7-day course of co-amoxiclav (1.2 g three times per day intravenously for 4 days, then changed to an oral dose of 1 g two times per day for another 3 days) with no beneficial effect. This was followed by oral doxycycline (200 mg stat day one followed by 100 mg two times per day) for a total of 10 days, and piperacillin/tazobactam (4.5 g three times per day) for another 7 days also to poor effect. Once Yamaguchi criteria was satisfied, antibiotic treatment was stopped and oral prednisolone (40 mg/day) was initiated at 0.5 mg/kg/day.

Outcome and follow-up

There was immediate resolution of symptoms on initiation of prednisolone with significant biochemical improvement in the following days (table 1). The patient regained independence since arthralgias resolved. The patient was given a tailing down regiment of prednisolone with an outpatient follow-up appointment in 3 months. On review at the outpatient clinic, the patient had remained very well, completely asymptomatic with no further febrile episodes or recurrence of rash.