Eur opean Rev iew for Med ical and Pharmacol ogical Sci ences 2013; 17: 3341-3346 An “alternative” clinical course of COPD exacerbation and pulmonary embolism

C. TERZANO, V. CONTI, A. PETROIANNI, G. PAONE 1

Department of Cardiovascular and Respiratory Sciences, Respiratory Diseases Unit, School of Specialization of Respiratory Diseases, Sapienza University of Rome, Fondazione E. Lorillard Spencer Cenci, Rome, Italy 1Department of Cardiovascular and Respiratory Sciences, Sapienza University of Rome, S. Camillo-Forlanini Hospital, Rome, Italy

Abstract. – Patients with chronic diseases, tion of purulent sputum, exertional dyspnea, he - such as Chronic Obstructive Pulmonary Disease moptysis and chest pain arisen seven days before. (COPD) and diabetes mellitus, are exposed to par - Past medical history included arterial hyper - ticular complications that require a careful diagnos - tic algorithm. Pulmonary Embolism (PE) in COPD tension, diabetes mellitus, atrial fibrillation, patients often demands an accurate differential di - glaucoma and prior peptic ulcer, and a chronic agnosis and a prompt therapeutic intervention. pharmacological therapy with oral hypogly - Aspergillus spp. infection comprises a large caemic agents, ticlopidine , nebivolol, digoxin spectrum of pathological manifestations, depend - and ramipril. ing on immune status and the presence of under - The patient was a current smoker since he was lying lung disease. These manifestations may range from invasive pulmonary aspergillosis (IPA) 11 years old (71 pack-years). in gravely immunocompromised patients, to At arrival, his vital signs were: body tempera - chronic necrotizing aspergillosis (CNA) in pa - ture 36.8°C, blood pressure 130/70 mmHg, heart tients with chronic lung diseases and moderately rhythm about 85 beats/min (arrhythmic) and res - compromised immune systems. Aspergilloma is piratory rate 14 breaths/min. generally observed in patients with cavitary lung Examination revealed inspiratory crackles and diseases, and allergic bronchopulmonary as - wheezing after forced expiration. pergillosis (ABPA) is reported in patients with hy - persensitivity to Aspergillus antigens. Investigations showed a neutrophil leukocyto - 3 We report a case with pulmonary aspergillosis sis (total white cells count 13.13*10 / l, with 3 µ arisen on a pulmonary infarction after PE in a neutrophil 9.97*10 /µl), increased erythrocyte patient with COPD and diabetes mellitus. To sedimentation rate (ESR) (86 mm/h) and serum date, report with this clinical evolution was not C-reactive protein (CRP) levels (16.37 mg/dl), reported in literature. normal D-dimer with semiquantitative latex ag - This report is intended to describe an accurate diagnostic path in a complex overlap of different glutination D-dimer assay (204 ng/ml), high lev - pathological conditions, highlighting the great im - els of functional fibrinogen (712 mg/dl). The ar - portance of differential diagnosis and an appropri - terial blood gas analysis revealed normal gas ex - ate diagnostic algorithm. In addition, open issues change at rest on room air (pH 7.43; pO 2 77 on the real diagnostic value of clinical, radiologi - mmHg; pCO 2 38 mmHg). cal, and laboratory features for COPD exacerba - Chest X-ray showed vague COPD signs, with tion, PE and aspergillosis have been discussed. hyperinflated lungs, flattened diaphragm, and Key Words: central pulmonary artery enlargement, and the Chronic obstructive pulmonary disease, Pulmonary pulmonary function test revealed a Stage III embolism, Chronic necrotizing aspergillosis, Voriconazole. COPD, with a severe airflow obstruction (forced expiratory volume in one second (FEV 1): 1.33 L, 46.7% of predicted; forced vital capacity (FVC):

Case Report 2.60L, 67% of predicted; FEV 1/FVC: 51%). Electrocardiography showed atrial fibrillation An 81 year-old man, ex-locksmith, with with normal ventricular response, left axis devia - COPD, was admitted to our Respiratory Disease tion, aspecific alterations of ventricular ripolar - Unit because of cough with increase in produc - ization .

Corresponding Author: Vittoria Conti, MD; e-mail: [email protected] 3341 C. Terzano, V. Conti, A. Petroianni, G. Paone

AB

Figure 1. Chest CT. A, contrast-enhanced CT scans show a clot in the left pulmonary artery extending into the lower lobar branches. B, lung window setting shows a large consolidation in the upper left lobe resting typically and largely upon scissural, mediastinal, and apical pleura. In addition, several bronchiectasis by retraction are observable in its context.

Two-dimensional echocardiography revealed such as lung cancer, pneumonia, hemorrhagic global left ventricular hypokinesis, increased lung infarct . left and right atrial size, left ventricular ejec - The patient underwent a duplex ultrasonogra - tion fraction 40%; mild mitral and aortic regur - phy of extremity veins, which revealed a deep gitation. vein thrombosis of the popliteal vein. As the initial clinical suspicion was a COPD Immediately we started a treatment with sub - exacerbation, the patient started a standard cutaneous low-molecular-weight heparin treatment with steroids given intravenously (iv (LMWH, Enoxaparin 1 mg/kg every 12 hours); CS, methylprednisolone 20 mg twice a day), an - the therapy with iv CS was then suspended. tibiotics (piperacillin-tazobactam 4.5 g twice a The patient has been discharged a week later day), inhaled bronchodilators and theofilline at with adequate long-term anticoagulant therapy standard dosage. We decided to administer (Acenocoumarol, with doses adjusted in order Enoxaparin at a prophylactic dosage (20 mg, to maintain the INR at a target of 2.5, range 2000 U.I.). After 48 hours of treatment, despite 2.0 -3.0). the improvement in total white cells count 3 3 (10.05 *10 /µl), neutrophils (7.65 *10 /µl), serum CRP (9.12 mg/dl) and ESR (42 mm/h), the pa - tient reported a persistence of the hemoptysis and chest pain. The sputum culture (sample collected at ad - mission) was positive for Escherichia coli sensi - tive to piperacillin-tazobactam. Together with COPD exacerbation we suspect - ed a lung cancer or an acute pulmonary em - bolism. Three other sputum samples were col - lected for the detection of neoplastic cells (nega - tive). Additionally, it seemed to us reasonably to recommend a chest Computed Tomography (CT), which revealed a clot in the left pulmonary artery extending into the lower lobar branches, and an adjacent consolidation in the left upper lobe (Figures 1 and 2). Figure 2. Chest CT, coronal plane . Pulmonary infiltrate The radiological features of the consolida - with pleural evolvement. Infarctioned area shows an ad - tion did not allow us to reach a certain diagno - vanced fibrotic retraction in which a rich vascularization and sis, as they can be seen in different conditions consequent cystic bronchiectasis are evident.

3342 An “alternative” clinical course of COPD exacerbation and pulmonary embolism

Figure 3. Chest CT control after 1 month, coronal plane. In the context of pulmonary infarction (upper left lobe) are observable retraction and pseudo-cavity images. Figure 4. Chest CT control after 4 months, coronal plane. Lung window setting shows a marked cicatricial re - traction in the upper left lobe with associated an empty cavi - One month later a new chest CT control ty. Evident diffuse signs of COPD (phenotype B: emphyse - showed a reduction in size of the thrombus visi - ma and chronic bronchitis) coexist in both lungs. ble in the left pulmonary artery; the focal consol - idated area appeared lowered in size, with some small pseudocavities inside (Figure 3). every 12 hours) was immediately established. The response to the treatment with LMWH Sputum culture turned out negative for As - and then Acenocoumarol allowed us to make a pergillus after 28 days of antifungal therapy. clear diagnosis of PE with hemorrhagic lung in - The clinical course is represented in Figure 5. farction . A new chest CT was performed four months after the discharge: it revealed the complete reso - Discussion lution of the PE and a striking cicatricial retrac - tion in the upper left lobe with associated an This report is intended to describe an accu - empty thin-walled cavity (Figure 4). rate diagnostic path in a complex overlap of dif - We collected a sputum sample and performed ferent pathological conditions, highlighting the a culture for fungal species, resulting positive for importance of differential diagnosis and of an Aspergillus Sp. appropriate diagnostic algorithm, to discrimi - As in routine clinical practice most Aspergillus nate proven and probable pulmonary aspergillo - isolates from non-sterile body sites do not repre - sis from Aspergillus colonization, as previously sent disease, the patient underwent fiberoptic described 1. bronchoscopy to perform a brochoalveolar lavage This case clearly describes the difficulty that culture, which confirmed a positive result for As - clinicians encounter in clinical practice when pergillus Sp. predisposing diseases coexist in a single patient. We observed in a patient with COPD and dia - What is your Diagnosis? betes mellitus, diseases with high prevalence, a Diagnosis: Chronic Necrotizing Aspergillosis clinically underhand event of PE. The application (CNA) in an elderly, previously hospitalized pa - of an accurate diagnostic algorithm, using CT tient, with underlying pulmonary disease scan, as well as BAL, with semiquantitative cul - (COPD), diabetes mellitus, previous low-dose ture and cytological examination, made us able corticosteroid use, and a pulmonary infarction to carry out appropriate diagnostic exams, inden - with ischemic necrosis of the lung parenchyma. tify the onset of pulmonary infarction and conse - quent superimposition of Aspergillus infection Clinical course: An anti-fungal therapy with and chronic necrotizing aspergillosis 1-3 , and es - intravenous Voriconazole (400 mg every 12 tablish a prompt therapy in a complex process of hours in the first 24 hours, and then 200 mg differential diagnosis (Figure 5) .

3343 C. Terzano, V. Conti, A. Petroianni, G. Paone

Figure 5. Diagnostic course of case report. COPD: Chronic obstructive pulmonary disease; ESR: erythrocyte sedimentation rate; CRP: C reactive protein; ABG: arterial blood gas analy - sis; iv CS: intravenous corticosteroids; LMWH: low-molecular-weight heparin; PE: Pulmonary embolism; BAL: bronchoalveolar lavage.

3344 An “alternative” clinical course of COPD exacerbation and pulmonary embolism

Table I. Diagnostic criteria for chronic pulmonary aspergillosis (CNA).

Denning’s Criteria 9 Kohno’s Criteria 10

Clinical Chronic (41 month) pulmonary or systemic symptoms, Chronic symptoms with fever, cough, including at least one of: weight loss; productive cough; haemoptysis hemoptysis, and body weight loss No overt immunocompromising conditions (e.g. haematological malignancy, neutropenia, organ transplantation) No dissemination Radiological Cavitary pulmonary lesion with evidence of paracavitary infiltrates Chest X-ray and CT scan abnormalities New cavity formation, or expansion of cavity size over time showing infiltrates and cavities in the upper lobes Laboratory Elevated levels of inflammatory markers (C-reactive protein, Positive levels of serum plasma viscosity, or erythrocyte sedimentation rate) precipitation antibody for Isolation of Aspergillus spp from pulmonary Aspergillus and β-Dglucan or pleural cavity, or Isolation of Aspergillus spp. Positive serum Aspergillus precipitin test exclusion of other from lung specimens, pulmonary pathogens, by results of appropriate cultures and e) failure to detect other bacterial, and serological tests, that are associated with similar disease fungal, or mycobacterial pathogens presentation, including mycobacteria and endemic fungi

Today, the use of modern diagnostic tech - Table II. Differential diagnosis of pulmonary aspergillosis niques let us assess the possible alternative diag - (aspergilloma and necrotizing pneumonia). nosis up to reach the certain diagnosis. Infectious pulmonary diseases Pulmonary aspergillosis may be under-recog - Anaerobic bacterial infections nized in patients with COPD; the factors con - Gram negative bacterial infection tributing to its development in these patients have Influenza pneumonia not been yet entirely defined. In addition, clini - Staphylococcus aureus infection Streptococcus pyogenes pneumonia cians should consider PE in a diagnostic workup Tuberculosis of COPD exacerbations, especially in patients Mycobacterium avium where the underlying aetiology is not apparent Mycobacterium Kansasii and in whom there is a history of additional risk Atypical mycobacteria Legionaires disease factors that may increase the clinical likelihood Pseudomonas infection of PE 4-6 . Amebiasis Aspergillus spp are ubiquitous fungi acquired Hydatid cyst by inhalation of airborne spores and may cause Actinomycosis Blastomycosis lifethreatening infections, especially in immuno - Coccidioidomycosis compromised hosts. The spores are commonly Histoplasmosis isolated from the soil, plant debris, and the in - Nocardiosis door environment, including hospitals. Abscesses Aspergillus spp . infection comprises a large Septic Pulmonary Embolism Granulomatous inflammatory diseases spectrum of pathological manifestations, depend - Sarcoidosis ing on immune status and the presence of under - Wegeners granulomatosis lying lung disease 7. These manifestations may Neoplastic diseases range from invasive pulmonary aspergillosis Carcinoma lung squamous cell/large cell (IPA) in gravely immunocompromised patients, Metastatic lung disease Pulmonary lymphoma to chronic necrotizing aspergillosis (CNA) in pa - Vascular diseases tients with chronic lung diseases and moderately Pulmonary infarction compromised immune systems. Aspergilloma is Pulmonary infarction with cavitation generally observed in patients with cavitary lung Trauma diseases, and allergic bronchopulmonary as - Pulmonary contusion Pneumoconiosis and poisoning pergillosis (ABPA) is reported in patients with Silicosis 8 hypersensitivity to Aspergillus antigens . Talc dust mining exposure Tables I and II describe diagnostic criteria for Silico-tuberculosis CNA and differential diagnosis of pulmonary as - Chemical pneumonitis pergillosis. Chemical fumes inhalation

3345 C. Terzano, V. Conti, A. Petroianni, G. Paone

In a hospitalized COPD patient with severe pergillosis: a discrete clinical entity. Medicine (Bal - nosocomial pneumonia, we ought to exclude as - timore) 1982; 61: 109-124. pergillosis, so corticosteroid therapy should be 3) SARACENO JL, P HELPS DT, F ERRO TJ, F UTERFAS R, revaluated and systemic antifungal therapy con - SCHWARTZ DB . Chronic necrotizing pulmonary as - pergillosis: approach to management. Chest sidered. Outcomes can be improved by rapid di - 1997; 112: 541-548. agnosis and prompt therapy with voriconazole. 4) TERZANO C, C ONTI V, D I STEFANO F, P ETROIANNI A, CECCARELLI D, G RAZIANI E, M ARIOTTA S, R ICCI A, VITARELLI A, P UGLISI G, D E VITO C, V ILLARI P, A LLEGRA Conclusions L. C OMORBIDITY , hospitalization, and mortality in COPD: results from a longitudinal study. Lung To our best knowledge cases with aspergillosis as 2010; 188: 321-329. complication of pulmonary infarction from PE were 5) RIZKALLAH J, M AN SF, S IN DD . Prevalence of pul - monary embolism in acute exacerbations of not yet reported in literature. Instead cases of pul - COPD: a systematic review and metaanalysis. monary aspergillosis causing infarction with pul - Chest 2009; 135: 786-793. monary necrosis and PE were relatively frequent . 6) SIDNEY S, S OREL M, Q UESENBERRY CP J R, D ELUISE C, This case report is interesting as well as exclu - LANES S, E ISNER MD. COPD and incident cardiovas - sive for its clinical evolution and, thus, may be a cular disease hospitalizations and mortality: Kaiser Permanente Medical Care Program. Chest typical example of clinical practice. 2005; 128: 2068-20675. 7) ZMEILI OS, S OUBANI AO . Pulmonary aspergillosis: a ––––––––––––– –– –––– – clinical update. Q J Med 2007; 100: 317-334. Conflict of Interest 8) SOUBANI AO, C HANDRASEKAR PH. The clinical spec - The Authors declare that there are no conflicts of interest. trum of pulmonary aspergillosis. Chest 2002; 121: 1988-1999. 9) DENNING DW, R INIOTIS K, D OBRASHIAN R, S AMBATAKOU References H. Chronic cavitary and fibrosing pulmonary and pleural aspergillosis: Case series, proposed 1) VANDEWOUDE KH, B LOT SI, D EPUYDT P, B ENOIT D, T EM - nomenclature and review. Clin Infect Dis 2003; 37: MERMAN W, C OLARDYN F, V OGELAERS D. Clinical rele - S265-280. vance of Aspergillus isolation from respiratory 10) KOHNO S, M ASAOKA T, Y AMAGUCHI H, M ORI T, U RABE tract samples in critically ill patients. Crit Care A, I TO A, N IKI Y, I KEMOTO H. A multicenter, open-la - 2006; 10: R31. bel clinical study of micafungin (FK463) in the 2) BINDER RE, F ALING LJ, P UGATCH RD, M AHASAEN C, treatment of deep-seated mycosis in Japan. SNIDER GL. Chronic necrotizing pulmonary as - Scand J Infect Dis 2004; 36: 372-379.

3346