Introduction

Adult-onset Still's disease (AOSD) is a systemic inflammatory disease characterized by prolonged fever, arthritis, evanescent rash, pharyngitis, and leukocytosis with neutrophilia [1–5]. Severe pulmonary involvement remains unusual in this setting. We report three cases of AOSD characterized by febrile acute respiratory failure mimicking sepsis. We emphasize the great diagnostic value of low glycosylated ferritin level.

Case 1

A 39-year-old woman was admitted to the Department of Pulmonary and Critical Care Medicine for fever, cough, and dyspnea. Her medical history was unremarkable. In the 2 weeks prior to her admission, she had fever at 40°C, sore throat, arthralgias involving the hands and knees, and transient skin rash. She was treated with amoxicillin–clavulanic acid, without any improvement, and was finally hospitalized with pulmonary symptoms. She was rapidly transferred to the intensive care unit (ICU), with tachypnea (respiration=30 breaths/min) and severe hypoxemia (p aO2=46 mmHg, p aCO2=39 mmHg, and arterial oxygen saturation=76%). Chest x-ray demonstrated diffuse interstitial opacities with mild pleural effusion. Biologic tests revealed leukocytosis (white blood cells=22,000 mm−3), with polymorphonuclear neutrophils=90%, hemoglobin=8.4 g/l, and platelets=571,000 mm−3. C-reactive protein (CRP) count was 290 mg/l (normal range, <5 mg/l), with hepatic cytolysis and cholestasis. Diagnosis of community-acquired pneumonia was suggested, and antibiotic therapy with ceftriaxone and spiramycin was introduced, without any improvement, after 5 days. Chest CT scan at this time showed parenchymal alveolar densities mainly involving the lower lobes, together with moderate pleural effusion. Abdominal and pelvic CT scans yielded normal results. Bronchoalveolar lavage (BAL) showed normocellular content with 30% neutrophils, and cultures yielded negative results. Echocardiography revealed a diagnosis of moderate pericardial effusion. All other microbiological investigations (including blood, urine, and cerebrospinal cultures; and serological tests for Mycoplasma pneumoniae, Chlamydia pneumoniae, legionellosis, Q fever, HIV, Cytomegalovirus, hepatitis B virus, and hepatitis C virus) yielded negative results. Moreover, antinuclear antibodies, rheumatoid factor, anti-DNA, and anti-neutrophilic cytoplasmic antibodies (ANCAs) were absent. There was no proteinuria, and bone marrow analysis yielded negative results. Ferritinemia was 8,590 μg/l (normal range, 20–300 μg/l) and glycosylated ferritinemia 11% (normal range, 50–80% of total ferritin). A diagnosis of AOSD was suggested, and 1 g of methyl prednisolone pulse i.v. for 3 days was administered, followed by prednisone at 1 mg/kg body weight per day. Her clinical symptoms and chest x-ray results improved dramatically within 2 days. Fever, skin rash, and arthralgias relapsed at 6 months with steroids reduction, but without pulmonary symptoms.

Case 2

A 68-year-old man was admitted to the Pulmonary Department for fever, pleuropneumonitis, and pericarditis. Poliomyelitis, as well as type II diabetes mellitus and epilepsy treated with carbamazepine for several years, was noted in his medical history. His symptoms (fever at 40°C, dry cough, and pain on the right side of the chest) began 10 days after a trip to Russia. Roxithromycin was administered for 15 days, followed by amoxicillin–clavulanic acid, ceftriaxone, and ciprofloxacin. All treatments made no improvements in his condition. At the emergency room, the patient was dyspneic, with bilateral respiratory crackles on chest auscultation. He complained of arthralgias of the knees and wrists. Arterial blood gas analysis showed severe hypoxemia (p aO2=49 mmHg, p aCO2=29 mmHg, and arterial oxygen saturation=78%). Chest x-ray showed mild bilateral pleural effusion and cardiomegaly. Biologic tests revealed leukocytosis (white blood cells=28,000 mm−3), with neutrophils=88%, hemoglobin=12.1 g/l, platelets=220,000 mm−3, CRP=362 mg/l, erythrocyte sedimentation rate=116 mm, hepatic cytolysis, and cholestasis. Abdominal ultrasonogram disclosed hepatomegaly, and chest CT scan showed pericardial and bilateral mild pleural effusion, with alveolar densities involving the lower lobes. Echocardiography confirmed abundant pericardial effusion. Pleural fluid analysis disclosed a sterile exudate with 55 g/l proteins and hypercellularity at 3,000 cells/mm3 (predominantly neutrophils). Cultures for acid-fast bacilli, as well as serological tests for common agents of atypical pneumonia, yielded negative results. Tests for antinuclear antibodies, rheumatoid factor, and ANCA yielded negative results. Levofloxacin, ceftriaxone, and spiramycin were inefficient. His clinical status worsened with the development of acute respiratory failure. Serum ferritin level was 42,600 μg/l and glycosylated ferritin level was 6%. Transient skin rash, arthralgias, and polynucleosis, together with negative results of microbiological tests, failure of antibiotics, ferritinemia, and glycosylated ferritinemia, suggested the diagnosis of AOSD. Methylprednisolone (120 mg, i.v., daily for 3 days) then prednisone (p.o.) improved clinical and radiological symptoms within 3 days, with no recurrence.

Case 3

A 43-year-old man was admitted to the ICU for acute respiratory distress and pericarditis. He had no remarkable past medical history. He was initially admitted for fever at 40°C, diffuse myalgias, disability, and sore throat starting 10 days prior to admission. He was treated with amoxicillin on the impression of bacterial tonsillitis. After 3 days, he was still febrile and dyspneic. Physical chest examination disclosed bilateral crackles. Chest x-ray and CT scan displayed bilateral pleural effusion and alveolar syndrome. The pleural fluid was sterile, with 3,300 cells/mm3 and 80% neutrophils. Echocardiography showed pericardial effusion. Cefotaxim, ofloxacin, and gentamicin were ineffective. His condition continued to deteriorate, and he was then transferred to the ICU due to acute respiratory distress syndrome. On admission, white blood cells=15,600 mm−3, neutrophils=91%, and CRP=471 mg/l. Arterial blood gases disclosed severe hypoxemia (p aO2=40 mmHg, p aCO2=36 mmHg). Chest CT scan demonstrated pleural and pericardial effusion, without tamponade on echocardiography. Invasive assisted ventilation, together with broad-spectrum antibiotic treatment (cefotaxime, metronidazole, vancomycin, and vibramycin), was begun on the impression of nosocomial pleuropneumonitis. BAL was sterile, with normocellular content. Large infectious checkup, as well immunological investigations, yielded negative results. Aspirin (3 g/day) was initiated on the impression of viral pericarditis, but was rapidly withdrawn due to hepatitis. Pericardial effusion worsened, requiring pericardial drainage. The pericardial fluid was a sterile hemorrhagic exudate, with 9,100 cells/mm3 and 95% polymorphonuclear neutrophils. Pericardial biopsy showed unspecific inflammatory lesions. He had transient maculopapular rashes on the trunk and arms. Ferritin level was 25.195 μg/l and glycosylated ferritin level was 12%, suggesting the diagnosis of AOSD. Administration of methylprednisolone (1 g daily for 3 days), followed by prednisone (1.5 mg/kg daily) and immunoglobulins (administered intravenously), dramatically improved his clinical and biological status within 2 days. He relapsed 6 months later, with prolonged fever and arthralgias but without pulmonary symptoms, requiring weekly oral methotrexate.

Discussion

Despite the availability of classification criteria [4], there is still no specific hallmark for AOSD and clinical manifestations of this disease could mimic an infectious syndrome. Thus, AOSD is still an exclusion diagnosis. However, recently, Fautrel et al. [6] reported the stringent value of a low (<20%) glycosylated ferritin level as a marker of this disease. They proposed new classification criteria for AOSD [7], including four or more major criteria (spiking fever ≥39°C, arthralgia, transient erythema, pharyngitis, polymorphonuclear neutrophils ≥80%, and glycosylated ferritin ≤20%) or three major and two minor criteria (maculopapular rash and white blood cells≥10,000 mm−3).

Our three patients fulfilled the Yamaguchi and Fautrel classification criteria for AOSD, with low glycosylated ferritin levels. However, they had atypical clinical presentations with acute respiratory distress and systemic inflammatory response syndrome, requiring admission to the Pneumology Department. These three patients had severe hypoxemic pulmonary involvement with bilateral alveolar opacities, which are associated with pleural and pericardial effusion. Two of them required observation in the ICU due to their respiratory status, and mechanical ventilation was necessary for one. It is interesting to notice that, at the onset of the disease, these three patients had sore throat (an unspecific but frequent feature of AOSD) [2, 3] and skin rash (misinterpreted as allergy). An infectious cause seems unlikely because of the presence of prolonged fever without any microbiological documentation, resistance to broad-spectrum antibiotics, associated clinical features such as arthralgias, dramatic improvement with steroids, and long-term relapses. Only a few cases of AOSD with severe respiratory involvement have been reported so far in the literature [8–15]. In a retrospective series of AOSD, pulmonary involvement remained unusual [1–5]. A precise description of pulmonary manifestations and their severity was generally not mentioned in these publications, but clinical and radiological presentations seemed unspecific, mimicking a severe infectious disease.

In conclusion, AOSD may have atypical presentations with pulmonary involvement and acute respiratory failure, mimicking a severe infectious disease. Clinicians must be aware of this rare exclusion diagnosis and must look for suggestive clinical symptoms. A low glycosylated ferritin level should be a useful tool in these atypical forms of such disease.