Eosinophilic Pleural Effusion Secondary to Infection in a Patient with Systemic Sclerosis: A Case Report

Introduction

Scleroderma is a chronic disease characterized by 3 pathological mechanisms: small-vessels angiopathy, autoimmunity, and excessive fibrosis. It can be classified into 2 forms based on the extension of the disease: localized scleroderma and systemic scleroderma (systemic sclerosis, SSc) [1,2].

SSc is clinically characterized by skin lesions (skin thickening of the fingers, digital ulcerations, telangiectasias), Raynaud’s phenomenon, and respiratory dysfunction (eg, interstitial lung disease, pulmonary arterial hypertension). Elevated levels of anti-centromere and anti-topoisomerase I antibodies are related to the presence of the disease. Disorders such as gastroesophageal reflux disease, myocardial disease, arrhythmias, pericardial disease, and renal involvement are complications of SSc [1,2]. Pleural involvement (eg: pleural effusion, diffuse pleural thickening, subpleural micronodular lesions) is not specific to SSc but can occur and is usually associated with pulmonary arterial hypertension (PAH). While pleural effusion and pleural thickening are general findings in SSc, they are not common findings on chest radiography, and significant pleural effusion is considered to be uncommon [3].

Eosinophilic pleural effusion (EPE) is defined by an eosinophil count of at least 10% in the pleural fluid cytology analysis [4]. EPE is a rare manifestation with a broad spectrum of etiologies, such as malignancy (metastatic carcinoma, malignant mesothelioma, malignant lymphoma, malignant myeloma), blood/air in the pleural space, infectious diseases (Paragonimus spp. infections, Dracunculus medinensis infection, sparganosis, toxocariasis, cutaneous myasis, loiasis, strongyloidiasis, echinococcosis, lymphatic filariasis, ascariasis, amebiasis), autoimmune disorders (rheumatoid arthritis, Churg-Straus disease, sarcoidosis, systemic lupus erythematosus, eosinophilic fasciitis) and it can even be idiopathic [4–7]. Eosinophilia, which is defined as the elevation of the eosinophil count in the peripheral blood above 0.5×103/μL [8], can be associated with EPE and usually disappears after the pleural effusion resolves [5]. The peripheral blood eosinophil percentage is usually less than the pleural eosinophil percentage [4,7]. While eosinophilia is a common finding in a large variety of diseases, it is not helpful for finding the etiology of EPE [4].

In this report we present a case of systemic sclerosis complicated with Trichinella spiralis infection in which their association led to the development of eosinophilic pleural effusion, a rare complication.

Case Report

A 49-year-old man with a past medical history of arterial hyper-tension presented for bilateral inflammatory radio-ulnar-carpal joint pain, paresthesia of the hands and forearms, and fatigue. He also had a 6-month history of Raynaud’s phenomenon and a 2-week history of right posterior aching thoracic pain and night sweats. Additionally, he did not present a history of parasitic infections or of travel outside of Europe. The patient was stable, with heart rate of 98 beats/minute, blood pressure of 114/70 mmHg, and oxygen saturation of 94%. The initial physical exam was notable for substantial sclerodermatous skin involvement of the fingers (mRSS=3), hands (mRSS=2), forearms (mRSS=1), and forehead (mRSS=2), with a total of 14 points of mRSS score, sclerodactyly, Raynaud’s phenomenon, telangiectasias (Figure 1), metacarpophalangeal (MCP), proximal interphalangeal (PIP), and distal interphalangeal (DIP) swelling. A closer evaluation revealed diffuse reduction of the vesicular breath sounds, bilateral basal dullness to percussion and basal abolishment of the vesicular breath sounds, and edema of the hands and legs. He was a former smoker (35 pack-years) and a chronic alcohol consumer, and he was exposed to toxic substances due to work (construction).

Table 1 shows the laboratory findings at admission. Antinuclear antibodies (ANAs) and anti-topoisomerase I antibodies (anti-Scl 70) levels were significantly elevated (ANA=554.27 IU/mL, anti-Scl 70=179.19 IU/mL). Other tests, including blood urea nitrogen (BUN), uric acid, creatinine, serum complement proteins (C3, C4), creatine-kinase (CK), lactate dehydrogenase (LDH), thyroid-stimulating hormone (TSH), free thyroxine (fT4), and the electrolyte panel were normal. At admission, the ECG showed sinus rhythm with micro-voltage QRS complexes. A chest X-ray revealed accentuation of interstitial lung tissue and left diaphragmatic flattening and left costophrenic recess obstruction, spirometry and diffusing capacity of the lungs for carbon monoxide were within normal parameters (forced vital capacity 109%, forced expiratory volume in 1 s 98%, diffusing capacity of the lungs for carbon monoxide [DLCO] 91%, total lung capacity during DLCO 90%) and a thorax high-resolution CT (HRCT-scan) showed bilateral pleurisy, pericardial effusion, and minimal nonspecific interstitial lesions (Figures 2, 3). The nonspecific interstitial lung impairment was analyzed as pulmonary involvement, possibly due to toxic exposure (materials and substances used in construction, nicotine) and re-evaluation of the pulmonary system was scheduled as an integral part of the monitoring plan. Under those circumstances, based on the clinical presentation and the imaging findings, the preliminary diagnosis was scleroderma.

An ultrasound examination was conducted and confirmed the presence of pleural and pericardial effusion. The following day, an ultrasound re-examination revealed fluid volume expansion in the right pleural cavity and a diagnostic thoracentesis was performed. The pleural fluid analysis was negative for a bacterial infection but the presence of an exudate with high concentration of eosinophils on the fluid cytology analysis was observed (LDH=1387.00 IU/mL, C3=0.51 g/L, C4=0.05 g/L, 10% eosinophils). Blood tests were repeated and showed an elevated level of IgE (346.00 IU/mL), together with a decrease of the white blood cells level (13.40×103/μL) and an increase of the eosinophils count (1.38×103/μL). We tried to integrate hypereosinophilia etiologically. The patient underwent specialty parasitological consultation and had a stool ova and parasite (O&P) examination, but the results were negative, with no ova, larvae, or parasite cysts being identified. Additionally, no familial epidemiologic context was found. A hematology consultation was recommended, and a bone marrow biopsy examination was done to rule out a myelodysplastic syndrome (MDS). The bone marrow was cellular-rich, had polymorphic appearance, and was characterized by a hyperplastic granulocytic series with present maturation and mild eosinophilia, with no signs of atypical cytology. We considered testing for FIP1L1-PDGFRA fusion gene, but once the eosinophilia improved under corticosteroid and anthelmintic therapy, we ruled out hypereosinophilic syndrome as an etiology. Multiple ultrasound examinations were done and each showed slightly progressive bilateral pleural fluid volume expansion.

Although the clinical presentation and evolution of the patient were not specific, we again searched for a cause of the parasitosis. As a result, we re-evaluated the patient, with a major focus on targeting his activities and recent history, and we discovered a history of raw meat consumption in January, 7 months prior to his admission. We tested him for specific anti-trichinella IgG antibodies and the results were positive; therefore, after another parasitological consultation, it was decided that the history of raw meat consumption, eosinophilia, and positive serology (IgG antibodies) were enough for a diagnosis of Trichinella spiralis infection, and the patient started treatment with albendazole. After therapy, his symptoms improved: the sclerodermatous skin involvement was reduced, the hand and forearms edema disappeared, and the radio-ulnar-carpal joint pain diminished. The patient was discharged with the diagnosis of scleroderma and Trichinella spiralis infection. After 3 weeks, he was admitted for re-evaluation. At this time, there were still reactive changes in the full blood count, but the eosinophils count was in normal range and no anti-trichinella IgG antibodies were identified. He showed no signs of articular involvement, such as the initial arthralgias and articular edema, but the specific sclerodermatous cutaneous involvement was still present. No signs of pleural effusion could be identified and the pericardial fluid was significantly reduced.

Initially, we attempted addressing the symptomatology; therefore, nonsteroidal inflammatory drugs and vasodilator agents, such as pentoxifylline 400 mg per day, ketoprofen 100 mg/2 ml per day, and acetaminophen 1000 mg/100 mL per day were administered. After Strongyloides stercoralis infection was excluded, the symptomatic treatment was replaced with cortico-therapy, initially dexamethasone 8 mg/2 mL per day and later methylprednisolone 32 mg per day. After the identification of anti-trichinella IgG antibodies, the treatment scheme was completed with albendazole 200 mg tablets, 1 tablet 3 times per day, for 14 days. With this therapeutic approach, significant clinical improvement was observed. We decided to postpone disease-modifying antirheumatic drugs (DMARDs) administration due to the presence of active infection, but this step is certainly going to be a part of the therapeutic management. After the next pulmonary reassessment, if the patient has no signs of pulmonary fibrosis, we plan to initiate methotrexate.

Discussion

Systemic sclerosis is a rare autoimmune condition with a broad range of age onset (30–50 years) [2]. It is most common in the indigenous population in Canada (47/100.000), followed by Europeans, and affects more females than males (4.6: 1) [9]. Men are prone to have diffuse form, pulmonary, cardiac and renal impairment, while women are more likely to have the limited form [2]. This connective tissue disorder remains, nonetheless, a rare disease well known for its heterogeneity regarding clinical manifestations, organ involvement, progression, severity, and outcomes [10]. The diagnosis and classification of SSc is based on the ACR-EULAR score. Our patient presented bilateral skin thickening of the fingers that extended proximally to the MCP joints, which is sufficient to make the diagnosis of SSc [1]. Additionally, he had fingertip pitting scars, telangiectasia, Raynaud’s phenomenon, anti-topoisomerase I antibodies, and a potential interstitial lung disease (based on the chest X-ray), with a total score of 22, more than enough to make the diagnosis of systemic sclerosis [1]. The disease is characterized by vasculopathy, produced by antibody-mediated endothelial apoptosis and endothelial dysfunction, the latter causing an imbalance between vasoconstrictor and vasodilator agents [11,12]. This triggers Raynaud’s phenomenon early in the disease progression, before the onset of sclerosis, as seen in our case [11]. Cardiac complications can be present as a primary heart impairment, but most frequently they are encountered in association with pulmonary hypertension, being clinically silent in over 70% cases [13]. Pericarditis is common (up to 70%), can be acute or chronic, and often arises in the form of pericardial effusion [14]. Our patient showed no signs of increased blood pressure in the arteries of the lung and no symptoms of pericardial inflammation, but the abnormalities of cardiac auscultation, ECG, and echocardiography proved the moderate accumulation of pericardial fluid.

Eosinophilic pleural effusions (EPE) represent 5% to 16% of exudative pleural effusions [4]. In a 2012 meta-analysis, the most common causes of EPE were malignancy (26%), idiopathic (25%), and parapneumonic (13%) effusions, followed by pleural air/blood (13%), tuberculosis (7%), collagen vascular diseases (3%), as well as eosinophilic lung disease or infections [6].

A recent retrospective study observed a higher prevalence of malignancy (52.94%) and of pleural parasitic infestations (8.82%) [7]. In our patient, no malignant formation could be seen on the thorax CT scan, and no other imaging evaluation showed the presence of a tumoral process. The patient’s history, clinical presentation, and laboratory findings were not consistent with pneumonia, tuberculosis, or systemic autoimmune diseases associated with EPE. Although an autoimmune disease, scleroderma has not been reported to cause EPE to the best of our knowledge. As such, we searched for the presence of a parasitic infection. Among the parasitic diseases, the most associated with EPE is paragonimiasis; other diseases include cutaneous myiasis, echinococcosis, strongyloidiasis, amebiasis, toxocariasis, and filariasis [4,15]. Initially, the patient had a stool O&P examination, which tested the presence of Strongyloides stercoralis, Toxocara canis, and Toxoplasma, and the results were negative. The history of raw meat consumption indicated the need of testing for trichinosis. Trichinella spiralis infection is a food-borne disease that develops due to consumption of raw or semi-raw meat (eg: pork, wild boar, dog). Its diagnosis is usually based on clinical presentation and on serological tests, enzyme-linked immunosorbent assay (ELISA) being the test recommended by the International Commission on Trichinosis. This investigation tests for specific seric anti-trichinella IgG antibodies by excretory secretion (E/S) antigens of Trichinella spiralis larvae [15]. Increased parasite-specific IgG, IgM, and IgA antibodies are seen in most trichinellosis cases. Seroconversion occurs between the third and the fifth weeks of infection [16]. While our patient did not present the usual symptoms of trichinosis (periorbital and facial edema, muscle pain, subconjunctival hemorrhage, allergic rash) [15], we detected eosinophilia and specific anti-trichinosis IgG antibodies by ELISA, with which we could diagnose the infection. Testing for anti-trichinella IgM antibodies was not done due to the possible seroconversion and lack of diagnostic value at that time. To the best of our knowledge, there have been only 2 reported cases of pleural effusions caused by Trichinella spiralis, but both were unilateral and had a predominant lymphocyte cytology of the fluid [15], while our patient had bilateral eosinophilic pleural effusion.

While SSc and trichinosis are 2 etiologically different diseases, they show similarities regarding their immune system activation pathway, the most evident being the amplified response of type 2 T helper cells (Th2). This translates to an elevated level of cytokines, especially of interleukins 4 (IL-4) and inter-leukin 13 (IL-13), which are observed in high titers in both conditions [17–19]. On the one hand, both these cytokines are fibrogenic factors in SSc, by stimulating the B cells production of immunoglobulins and activating the fibroblast proliferation and differentiation pathways, thus enhancing the fibrosis [19]. Additionally, they have been observed to enhance a series of inflammation-related mechanisms [19]. On the other hand, in trichinellosis, immune cells populations, such as T cells, fibro-blasts, eosinophils, basophils, and macrophages, are recruited by specific antibody subclasses and the elevated IL-4 and IL-13, which in turn determine the development of hypersensitivity reactions. Our hypothesis was that by having these similarities in the immune system activation, the concomitant presence of the 2 diseases determined an amplified inflammatory response. It is not certain if the specific combination of the 2 diseases led to the heterogeneity of clinical manifestations or if one of them is associated with the rarer clinical presentations, such as EPE. To the best of our knowledge, there are no reported cases of SSc or Trichinella spiralis infection associated with the presence of EPE. The heterogeneous clinical presentation is exemplified by the association of articular involvement (arthralgias, articular swelling), pericarditis, and eosinophilic pleural effusion with the usual findings of SSc.

Conclusions

We presented a case of a man with systemic sclerosis and Trichinella spiralis infection, in which the association of the diseases led to the development of rare complications, one of them being eosinophilic pleural effusion. This condition has not previously been associated with systemic sclerosis or Trichinella spiralis infection. Even when confronted with an uncommon clinical presentation, the physician should try to discover the underlying issues. Although patient management can be more complicated, by treating the initial causes no additional treatment usually needs to be given other than the patient’s baseline medication.