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Abstract

Adult-onset Still’s disease (AOSD) is an inflammatory disorder characterized by recurrent fevers, arthralgia, leukocytosis, and a salmon-colored rash. Diagnosis is made based on the Yamaguchi criteria. Various cardiac and pulmonary manifestations have been described in association with AOSD, including acute respiratory distress syndrome (ARDS) and pulmonary arterial hypertension (PAH). We describe the first case of both PAH and ARDS in a patient with AOSD who, despite aggressive therapy, declined rapidly and ultimately died. There was concern for pulmonary veno-occlusive disease given the rate of her decompensation, but this was found not to be the case on autopsy. Treatment of AOSD with cardiopulmonary involvement requires rapid identification of AOSD followed by aggressive immunosuppression.

Keywords

pulmonary arterial hypertension adult-onset Still’s disease acute respiratory distress syndrome pulmonary veno-occlusive disease

Introduction

Adult-onset Still’s disease (AOSD) is an inflammatory disorder characterized by recurrent fevers, arthralgia, leukocytosis, and a salmon-colored rash. Diagnosis is made based on the Yamaguchi criteria.¹ Various cardiac and pulmonary manifestations have been described in association with AOSD, including acute respiratory distress syndrome (ARDS) and pulmonary arterial hypertension (PAH).^2–5 We present a case of a young woman who developed PAH and ARDS as a consequence of her AOSD, where her clinical course was initially concerning for pulmonary veno-occlusive disease (PVOD), which was ruled out on autopsy.

Case presentation

A 31-year-old African American woman presented with a two-week history of rapidly progressive shortness of breath on exertion and leg swelling. Prior to her presentation, she could complete activities of daily living without any difficulty but experienced dyspnea while climbing stairs and lifting heavy objects for the last year. Despite multiple hospitalizations for these issues at an outside community institution, an etiology for these symptoms was never fully evaluated or determined. The patient was diagnosed with AOSD at the age of 24 years and had previously been managed with various immunosuppressive therapies including prednisone and mycophenolate mofetil. Upon presentation to our institution, she was receiving prednisone and methotrexate for the management of her AOSD symptoms and was prescribed trimethoprim-sulfamethoxazole for prophylaxis. Physical examination was notable for hyperpigmented macules of the bilateral upper arms, lower extremity pitting edema, distended jugular venous pulse with accentuated hepatojugular reflex, and a loud P2 on cardiac auscultation.

Her chest radiograph (CXR) is shown in Fig. 1. A transthoracic echocardiogram showed normal left ventricular size and function with an ejection fraction of 55–60%, severe enlargement of the right ventricle and atrium, flattening of the interventricular septum in systole and diastole, and severe tricuspid regurgitation (Fig. 2). Right ventricular systolic pressure was estimated at 70–80 mmHg and there was evidence of a small pericardial effusion. A non-contrasted CT of the chest on admission revealed extensive mediastinal and hilar lymphadenopathy with some axillary lymphadenopathy, an enlarged pulmonary artery of approximately 39 mm, and extensive mosaic attenuation throughout the bilateral lungs (Fig. 3) with no evidence of pulmonary embolism.

Fig. 1

CXR on day of admission showing clear lung fields, cardiomegaly, and a slightly widened mediastinum.

Fig. 2

Apical four-chamber view showing right atrial and ventricle dilation and a small pericardial effusion.

Fig. 3

Chest CT without contrast performed on day of admission showing evidence of mild bilateral mosaic attenuation throughout the lungs.

The patient was clinically fluid overloaded on presentation (elevated jugular venous pulsation, bilateral lower extremity edema) requiring diuresis to optimize her fluid status prior to right heart catheterization (RHC). Laboratory evaluation revealed an elevated NT-pro-BNP of 1566 pg/mL, transaminitis (AST and ALT were 790 and 697 U/L, respectively, total bilirubin 1.0 mg/dL and alkaline phosphatase 81 U/L), elevated C-reactive protein (105.2 mg/L), and a leukocytosis (16.9 thou/cu mm with 90% PMNs). The patient’s transaminitis was new when compared with values from a few months prior. An ANA titer was positive at 1:160; however, the rest of her autoimmune workup and HIV status were negative. Right upper quadrant ultrasound showed mild hepatomegaly without cirrhosis consistent with hepatic congestion. Her RHC findings were consistent with pre-capillary PAH. Pulmonary artery pressures were measured to be 52/30 mmHg with a mean of 38 mmHg. Her pulmonary artery occlusion pressure was normal at 8 mmHg (Table 1). Given that the patient was functional class IV and had a high-risk hemodynamic pulmonary profile according to 2015 ESC/ERS guidelines for the diagnosis of pulmonary hypertension,⁶ given the high right atrial pressure, low cardiac index, and low mixed venous oxygen saturation, she was initiated on intravenous epoprostenol and oral tadalafil, with plans to add an endothelial receptor blocker as a third agent. Additionally, as she continued diuresis, she experienced hypotension with systolic pressures as low as 70 mmHg with a lactic acidosis as high as 4.9 mmol/L (which later resolved with the addition of a dobutamine infusion).

Table 1

Right heart catheterization.

Measurement	Value
Right atrium	23 mmHg
Right ventricle	50/21 mmHg
Pulmonary artery	52/30 mmHg
Mean pulmonary artery pressure	38 mmHg
Pulmonary artery occlusion pressure	8 mmHg
Cardiac output (thermodilution)	2.9 L/min
Cardiac index (thermodilution)	1.6 L/min/m²
Pulmonary vascular resistance	10.3 Woods Units
Pulmonary arterial oxygen saturation	97%
Pulmonary venous oxygen saturation	40%
Hemoglobin	9.5 g/dL

Over the subsequent three days, the patient began to decline, exhibiting symptoms of right ventricular failure. Inhaled epoprostenol at 50 ng/kg/min was initiated and epoprostenol infusion was gradually increased to a rate of 8 ng/kg/min. Despite this, she exhibited worsening hypoxia on serial arterial blood gas measurements despite increasing her inhaled FiO2. Due to her hemodynamic instability, the patient was worked up for an infectious etiology and broad-spectrum antimicrobial coverage was initiated.

Despite these interventions, the patient continued to deteriorate. She ultimately required endotracheal intubation and mechanical ventilation due to her worsening hypoxia (desaturations as low as 70% on 100% inhaled FiO2 non-rebreather mask) in conjunction with tachycardia to 160 beats per minute. Her lactic acidosis returned as well, peaking at 3.6 mmol/L. Complete blood count revealed a worsening leukocytosis 24.9 thou/cu mm with 15% bands. The patient’s CXR prior to intubation (Fig. 4) and clinical picture at the time of this decompensation was consistent with ARDS. Shortly after intubation, the patient experienced pulseless electrical activity and despite advanced cardiovascular life support she ultimately died. The rapid decline after initiating pulmonary arterial hypertension therapy was concerning for possible underlying pulmonary veno-occlusive disease (PVOD) or pulmonary capillary hemagiomatosis (PCH). Additionally, her rapid decline precluded the possibility of any repeat imaging or advanced monitoring of cardiac output.

Fig. 4

CXR three days after admission revealing diffuse bilateral infiltrates.

Autopsy revealed right ventricular hypertrophy and moderately dilated right ventricle and right atrium. Additionally, the patient’s lungs were significant for diffuse alveolar damage with prominent hyaline membrane formation with edema and a prominent neutrophilic alveolar infiltrate. There was both intimal thickening of the pulmonary arteries and arterioles (Fig. 5). Features suggestive of the presence of PVOD and PCH were not present on pathological examination. Pathology slides were sent out for a second opinion that confirmed the initial report. Regardless, all cultures and staining performed on lung samples did not identify any infectious organisms. The final diagnosis was PAH and ARDS in the setting of AOSD. Considering the right ventricular hypertrophy present on autopsy and her report of dyspnea on exertion for the year prior to her decompensation, it is likely the patient’s PAH had been present for some time and not recognized during her previous hospitalizations.

Fig. 5

Pulmonary histology showing evidence of pulmonary arteriole intimal thickening (blue arrow) and hypertrophy as well as prominent alveolar edema and neutrophilic alveolar infiltrate (red arrow).

Discussion

AOSD is a rare systemic autoinflammatory disease whose prevalence is roughly 0.16/100,000.⁷ The disease usually presents in young individuals, but there is a degree of bimodality to the age distribution.^8,9 AOSD with PAH typically occurs in young women and to date 12 cases have been published (Table 2).

Table 2

Cases of AOSD and PAH.

Authors	Age	Sex	Fever	WBC (thou/mm³)	Arthralgia	Rash	Therapy for PH/AOSD	Outcome
Zen et al., 1990¹⁸	29	F	+	Elevated	+	+	None/none	Died
Chen et al., 2006¹⁹	41	F	NA	NA	NA	NA	None/none	Survived
Chen et al., 2006¹⁹	27	F	NA	NA	NA	NA	None/none	Survived
Mubashir et al., 2007²⁰	29	F	+	Elevated	+	+	Nifedipine 60 mg daily/ corticosteroids, anakinra	Died
de Siqueira et al., 2009²¹	18	F	+	32.6	+	+	None/indomethacin, corticosteroids, methotrexate	Survived
Khattri et al., 2011²²	26	F	+	16.3 (87% PMNs)	+	+	None/corticosteroids, naproxen	Survived
Campos et al., 2012¹²	27	F	+	Elevated	+	+	Amlodipine/corticosteroids, azathioprine, anakinra	Survived
Ibarra et al., 2013²³	43	F	−	11.8	−	+	Sildenafil/corticosteroids, cyclophosphamide, rituximab	Survived
Thakare et al., 2013⁵	18	F	+	23.2	−	+	None/none	NA
Kadavath et al., 2014²⁴	38	F	+	27.1	+	+	None/corticosteroids, toclizumab	Survived
Guilleminault et al., 2016³	19	F	+	“Normal”	+	+	Ambrisentan, tadalafil/ corticosteroids, methotrexate, anakinra	Died
Wong et al., 2016¹³	24	F	+	NA	+	+	Epoprostenol, tadalafil, treprostinil, ambrisentan, tadalafil/corticosteroids, methotrexate	Survived
Our case	31	F	+	16.9 (90% PMNs)	+	+	Epoprostenol, tadalafil/ corticosteroids, methotrexate	Died

F, female; +, present; −, not present; NA, not available.

Although the mortality in AOSD is low,¹⁰ it increases dramatically in cases where the disease is complicated by cardiopulmonary abnormalities.¹¹ PAH and ARDS are rare complications of AOSD. We report the first case where both complications occurred in a patient with AOSD. The presence of mediastinal adenopathy on chest imaging and the patient’s clinical decline after initiation of PAH-specific therapy was concerning for PVOD/PCH. However, autopsy failed to show evidence suggestive of either. To date, there have been no cases of PVOD/PCH reported in association with AOSD.

The exact pathophysiology of AOSD is unknown, but much of the disease seems to involve macrophage and neutrophil activation. Furthermore, therapy for AOSD can involve inhibition of IL-1, IL-18, and TNFα, implicating their role in the disease.^12–14 With regards to PAH, there is a consensus that dysregulation of these cytokines plays a role in the remodeling of the pulmonary vasculature via recruiting of inflammatory cells. It seems reasonable to conclude that this similarity between AOSD and PAH could represent a reasonable mechanism for the pathophysiology of the disease; however, more research is necessary.

The mainstay of treatment of AOSD involves immunosuppression. Specifically, inhibition of IL-1 with anakinra has been associated with improved outcomes in AOSD and PAH.^12,14 In this case, the patient was continued on her prior immunosuppressive regimen for AOSD. Escalation of her immunosuppressive therapy was considered; however, due to her rapid hemodynamic decline and the possibility of an infectious etiology, we decided the benefit did not outweigh the risk at that time. Furthermore, the choice was made to prioritize treatment of the patient’s right-sided heart failure as a consequence of her PAH given her rapidly progressing hemodynamic instability and eventual hypoxic respiratory failure.

AOSD does have an established relationship with ARDS (Table 3), having now been published in 18 cases. ARDS is known to occur because of the pathogenic production of cytokines, such as TNFα and IL-1.^15–17 This has been established in the context of sepsis, but as previously mentioned, these cytokines are implicated in the development of PAH from AOSD. It stands to reason that the pathogenic release of these cytokines from AOSD could also result in ARDS and PAH, such as in this case.

Table 3

Cases of AOSD and ARDS.

Authors	Age, years	Sex	Fever	WBC (thou/mm³)	Arthralgia	Rash	Therapy for AOSD	Outcome
Hirohata et al., 1986⁴	65	F	+	14	+	−	Corticosteroids, cyclophosphamide	Died
Pederson et al., 1991²⁵	40	M	+	33	+	+	Corticosteroids, azathioprine	Survived
Gibbs et al., 1993²⁶	21	F	+	NA	+	−	Corticosteroids	Survived
Yokoyama et al., 1995²⁷	71	M	+	NA	−	+	Corticosteroids, nafamostat mesilate	Survived
Iglesias et al., 1999²⁸	29	F	+	16.6	+	−	Corticosteroids	Survived
Shinohara et al., 1999²⁹	54	F	+	17.7 (84% PMNs)	+	+	Corticosteroids	Survived
Mito et al., 2002³⁰	24	F	+	NA	−	+	Corticosteroids, cyclosporine	Survived
Suleiman et al., 2002³¹	36	F	+	30.9	−	−	Corticosteroids, methotrexate	Survived
Hagiyama et al., 2003³²	24	F	+	12.9 (95% PMNs)	−	−	Corticosteroids, cyclophosphamide	Survived
Hagiyama et al., 2003³²	20	M	+	12.2 (88% pmns)	−	+	Corticosteroids	Survived
Manganelli et al., 2003³³	17	F	+	NA	−	+	Corticosteroids, 6-mercaptopurine, cyclosporine, IVIG	Died
Biron et al., 2006³⁴	39	F	+	22 (90% PMNs)	+	+	Corticosteroids	Survived
Biron et al., 2006³⁴	68	F	+	28 (88% PMNs)	+	+	Corticosteroids	Survived
Biron et al., 2006³⁴	43	M	+	15.6 (91% PMNs)	−	−	Corticosteroids, IVIG	Survived
Guignard et al., 2007¹⁴	23	M	+	21	−	+	Corticosteroids, methotrexate	Survived
Chvojka et al., 2009³⁵	24	M	+	NA	−	−	Corticosteroids	Died
Dua et al., 2013²	26	F	+	20 (92% PMNs)	−	−	Corticosteroids	Died
Our case, 2016	31	F	+	16.9 (90% PMNs)	+	+	Corticosteroids, methotrexate	Died

F, female; M, male; +, present; −, not present; NA, not available.

What is not clear is why, exactly, ARDS and PAH tends to be so fulminant in cases of AOSD. It has been noted that any pulmonary complication has been associated with a poorer outcome and our patient experienced two concomitant severe pulmonary complications.¹¹ Considering the pathophysiology of extremely rapid decline is unclear, it perhaps highlights avenues for further research to elucidate a mechanism beyond that of the release of cytokines.

As in our case, patients with AOSD are frequently empirically treated with broad-spectrum antimicrobial therapy, but tend to ultimately be transitioned to aggressive immunosuppression. Our case differs in that the patient’s clinical status was more fulminant given her severe right heart failure due to PAH. This precluded the possibility of definitively excluding infectious etiologies and allowing for adequate and timely treatment with immunosuppression.

Conclusion

We describe the first case of both PAH and ARDS in a patient with AOSD who, despite aggressive therapy, declined rapidly and ultimately died. Treatment of AOSD with cardiopulmonary involvement requires rapid identification of AOSD as the etiology for decompensation followed by aggressive immunosuppression. Considering this, we recommend early involvement of rheumatology specialists in cases where patients present with new onset respiratory failure with a history of rheumatologic disease in which pulmonary hypertension is in the differential diagnosis. This case also highlights how the concomitant presentation of these two conditions may be mimicking the clinical presentation of PVOD or PCH. No standard of care for the management of these conditions currently exist.

Footnotes

Conflict of interest

The author(s) declare that there is no conflict of interest.

Funding

This research received no specific grant from any funding agency in the public, commercial, or not-for-profit sectors.

References

Yamaguchi

Ohta

Tsunematsu

et al.

Preliminary criteria for classification of adult Still’s disease. J Rheumatol 1992; 19: 424–430.

Dua

Manadan

Case

. Adult onset Still’s disease presenting with acute respiratory distress syndrome: case report and review of the literature. Open Rheumatol J 2013; 7: 125–128.

Guilleminault

Laurent

Foucher

et al.

Pulmonary arterial hypertension in adult onset Still’s disease: a case report of a severe complication. BMC Pulm Med 2016; 16: 72.

Hirohata

Kamoshita

Taketani

et al.

Adult Still’s disease complicated with adult respiratory distress. Arch Intern Med 1986; 146: 2409–2410.

Thakare

Habibi

Agrawal

et al.

Pulmonary arterial hypertension complicating adult-onset Still’s disease. Clin Rheumatol 2013; 32: S1–2.

Galiè

Humbert

Vachiery

et al.

2015 ESC/ERS Guidelines for the diagnosis and treatment of pulmonary hypertension: The Joint Task Force for the Diagnosis and Treatment of Pulmonary Hypertension of the European Society of Cardiology (ESC) and the European Respiratory Society (ERS): Endorsed by: Association for European Paediatric and Congenital Cardiology (AEPC), International Society for Heart and Lung Transplantation (ISHLT). Eur Respir J 2015; 46: 903–975.

Magadur-Joly

Billaud

Barrier

et al.

Epidemiology of adult Still’s disease: estimate of the incidence by a retrospective study in west France. Ann Rheum Dis 1995; 54: 587–590.

Sakata

Shimizu

Hirano

et al.

Epidemiological study of adult-onset Still’s disease using a Japanese administrative database. Rheumatol Int 2016; 36: 1399–1405.

Ohta

Yamaguchi

Kaneoka

et al.

Adult Still’s disease: review of 228 cases from the literature. J Rheumatol 1987; 14: 1139–1146.

10.

Uppal

Al-Mutairi

Hayat

et al.

Ten years of clinical experience with adult onset Still’s disease: is the outcome improving?

Clin Rheumatol 2007; 26: 1055–1060.

11.

Zeng

Zou

et al.

Clinical features and prognosis of adult-onset Still’s disease: 61 cases from China. J Rheumatol 2009; 36: 1026–1031.

12.

Campos

Schiopu

. Pulmonary arterial hypertension in adult-onset Still’s disease: rapid response to Anakinra. Case Rep Rheumatol 2012; 2012: 537613.

13.

Wong

Ytterberg

Frantz

. Resolution of severe pulmonary arterial hypertension complicating adult-onset Still’s disease. J Heart Lung Transplant 2016; 35: 1140–1144.

14.

Guignard

Dien

Dougados

. Severe systemic inflammatory response syndrome in a patient with adult onset Still’s disease treated with the anti-IL1 drug anakinra: a case report. Clin Exp Rheumatol 2007; 25: 758–759.

15.

Colletti

Remick

Burtch

et al.

Role of tumor necrosis factor-alpha in the pathophysiologic alterations after hepatic ischemia/reperfusion injury in the rat. J Clin Invest 1990; 85: 1936–1943.

16.

Meduri

Headley

Kohler

et al.

Persistent elevation of inflammatory cytokines predicts a poor outcome in ARDS. Plasma IL-1 beta and IL-6 levels are consistent and efficient predictors of outcome over time. Chest 1995; 107: 1062–1073.

17.

Tracey

Beutler

Lowry

et al.

Shock and tissue injury induced by recombinant human cachectin. Science 1986; 234: 470–474.

18.

Zen

Yamashita

Ueda

et al.

[A case of adult Still’s disease with pulmonary hypertension]. Ryumachi 1990; 30: 45–52.

19.

Chen

Wang

et al.

Pulmonary arterial hypertension in autoimmune diseases: an analysis of 19 cases from a medical center in northern Taiwan. J Microbiol Immunol Infect 2006; 39: 162–168.

20.

Mubashir

Ahmed

Hayat

et al.

Pulmonary hypertension in a patient with adult-onset Stills disease. Clin Rheumatol 2007; 26: 1359–1361.

21.

de Siqueira

Rodrigues

Kormann

APM

. Adult-onset Still’s disease and pulmonary arterial hypertension. Respiratory Medicine CME 2009; 2: 70–72.

22.

Khattri S and Barland P. Pulmonary hypertension in a patient with adult-onset Still disease: a rare entity or an overlooked complication? J Muscoskel Med 2011: 388.

23.

Padilla-Ibarra

Sanchez-Ortiz

Sandoval-Castro

et al.

Rituximab treatment for pulmonary arterial hypertension in adult-onset Still’s disease. Clin Exp Rheumatol 2013; 31: 657–658.

24.

Kadavath

Zapantis

Zolty

et al.

A novel therapeutic approach in pulmonary arterial hypertension as a complication of adult-onset Still’s disease: targeting IL-6. Int J Rheum Dis 2014; 17: 336–340.

25.

Pedersen

. ARDS - associated with adult Still’s disease. Intensive Care Med 1991; 17: 372–373.

26.

Gibbs

Foord

Lee

et al.

Disseminated intravascular coagulation in adult-onset Still’s disease with neurological, respiratory and hepatic sequelae. Br J Hosp Med 1993; 50: 278–279.

27.

Yokoyama

Suwa

Shinozawa

et al.

[A case of adult onset Still’s disease complicated with adult respiratory distress syndrome and disseminated intravascular coagulation]. Nihon Rinsho Meneki Gakkai Kaishi 1995; 18: 207–214.

28.

Iglesias

Sathiraju

Marik

. Severe systemic inflammatory response syndrome with shock and ARDS resulting from Still’s disease: clinical response with high-dose pulse methylprednisolone therapy. Chest 1999; 115: 1738–1740.

29.

Shinohara

Hidaka

Matsuki

et al.

Calcinosis cutis and intestinal pseudoobstruction in a patient with adult onset Still’s disease associated with recurrent relapses of disordered coagulopathy. Intern Med 1999; 38: 516–520.

30.

Mito

Yamakami

Mizunoe

et al.

[A case of adult-onset Still’s disease complicated with acute respiratory distress syndrome]. Nihon Kokyuki Gakkai Zasshi 2002; 40: 894–899.

31.

Suleiman

Wolfovitz

Boulman

et al.

Adult onset Still’s disease as a cause of ARDS and acute respiratory failure. Scand J Rheumatol 2002; 31: 181–183.

32.

Hagiyama

Koike

Nagasaka

et al.

Two cases of acute respiratory distress syndrome resulting from adult-onset Still’s disease. Mod Rheumatol 2003; 13: 76–80.

33.

Manganelli

Fietta

Zuccoli

. Adult-onset Still’s disease with respiratory distress syndrome, polyserositis and disseminated intravascular coagulation: a case with a fatal outcome. Clin Exp Rheumatol 2003; 21: 139.

34.

Biron

Chambellan

Agard

et al.

Acute respiratory failure revealing adult-onset Still’s disease: diagnostic value of low glycosylated ferritin level. Clin Rheumatol 2006; 25: 766–768.

35.

Chvojka

Krouzecký

Radej

et al.

[24-year old male with fever, multi-organ dysfunction and fast progressing ARDS]. Vnitr Lek 2009; 55: 991–994.

Pulmonary arterial hypertension and acute respiratory distress syndrome in a patient with adult-onset stills disease

Abstract

Keywords

Introduction

Case presentation

Discussion

Conclusion

Footnotes

Conflict of interest

Funding

References