A 61-year-old lady with acute-onset wheeze and hypoxemia

Sir,

Wheezing is a common respiratory symptom. Acute-onset wheezing could indicate acute severe asthma, foreign body aspiration, and others. Uncommonly, wheezing may be the presenting symptom of pulmonary thromboembolism (PTE). Herein, we describe a case of acute on chronic PTE presenting with wheezing while on therapeutic anticoagulation.

A 61-year-old lady presented with a history of sudden onset of dyspnoea for one day. There was no cough, haemoptysis, chest pain, palpitation, altered sensorium, aspiration, or fever. She denied orthopnoea, stridor, hoarseness of voice, previous endotracheal intubation, or a similar episode in the past. The patient was a non-smoker and had never experienced wheeze prior to the current illness. Two months earlier, she was evaluated for abdominal pain and was diagnosed with adenocarcinoma of the gall bladder. Simultaneously, she was also detected to have pulmonary embolism in the segmental and subsegmental branches of both pulmonary arteries [Figure 1] for her symptoms of exertional breathlessness. Therapeutic anticoagulation with rivaroxaban and chemotherapy (gemcitabine and carboplatin) was initiated one month before the current presentation.

Figure 1.

Computed tomography pulmonary angiography (CTPA) images (a-c) showing acute pulmonary thromboembolism (white arrows in a and b) with maintained right ventricle to left ventricle (RV-LV) ratio and convex interventricular septum (small black arrows)

On examination, the patient had tachycardia (135 beats/minute), tachypnoea (26 breaths/minute), blood pressure of 90/60 mmHg, and a resting pulse oximetric oxygen saturation of 86% on room air. Jugular venous pressure was not elevated. There was non-pitting pedal oedema and bilateral wheeze (right > left). The rest of the physical examination was unremarkable. Chest radiograph was normal. Electrocardiography showed sinus tachycardia. Cardiac markers (myoglobin, troponin-I, and CK-MB) were within normal limits. Liver and renal function tests were normal. D-dimer was 3100 ng/mL.

Computed tomography (CT) pulmonary angiography revealed pulmonary thromboembolism with an increased clot burden and evidence of right heart dysfunction on imaging [Figure 2]. Compression ultrasonography showed acute thrombus in the left popliteal, anterior, and posterior tibial veins. We diagnosed acute on chronic PTE. Thrombolysis was performed with half dose of alteplase (50 mg intravenously administered over two hours). Post-thrombolysis, she had immediate relief from breathlessness. One hour following thrombolysis, she had no wheeze, her blood pressure normalized (120/80 mmHg), and her resting oxygen saturation improved to 96% on room air.

Figure 2.

CTPA images (a-c) showing recurrent pulmonary thromboembolism (white arrows in a and b) with increasing thrombus burden and features of RV strain (RV-LV ratio >1 with septal bowing towards left (small black arrows)

New-onset wheeze could indicate severe acute asthma, central airway obstruction including foreign body aspiration, malignant or benign central airway obstruction, and others.[1] In the index case, there was no history of asthma or aspiration, and the CT done a month earlier did not show a mediastinal mass or endotracheal growth, excluding a malignant central airway obstruction. Exertional dyspnoea or sudden onset breathlessness is characteristic of PTE. Uncommonly, acute PTE can present with wheezing. In the Prospective Investigation of Pulmonary Embolism Diagnosis (PIOPED) study, approximately 5% of patients with acute PTE presented with wheezing.[2] In another retrospective study of 154 patients with acute PTE, wheezing was the presenting feature in 9.1%.[3] The mechanism of wheezing in patients with PTE is unclear. First, the thrombus could release pharmacologically active substances (e.g., acetylcholine, serotonin, histamine, and plasma kinins), resulting in bronchoconstriction. An animal experiment suggested that the bronchospasm could be due to the release of serotonin from platelets in the clot.[4] A few studies reported improvement in bronchospasm with intravenous heparin, and the effect was attributed to inhibiting serotonin release from the clot.[5] Secondly, temporary occlusion of the pulmonary artery can lead to a sudden decline in the partial pressure of carbon dioxide and precipitate bronchoconstriction, secondary to local airway hypocapnia.[6] In another animal experiment, bronchospasm in experimental embolism was abolished following vagus nerve transection.[7] It was hypothesized that bronchoconstriction could result from elevated pressures in the right-sided chambers of the heart, leading to a reflex bronchoconstriction mediated through the vagus nerve. All the above mechanisms indirectly suggest that wheezing might be associated with a more severe PTE. In the index case, the acute-onset wheeze could thus reflect the severe clot burden, which was also evident by features of right ventricular strain noted on the CT scan. Also, the wheezing in the current case improved with thrombolysis without nebulization or intravenous glucocorticoids.

The index case had developed deep vein thrombosis and PTE despite being treated with rivaroxaban for one month. Failure of anticoagulant therapy and breakthrough PTE is known with rivaroxaban as well as low molecular weight heparin. In the EINSTEIN-PE trial, recurrent PTE was 2.1% in the rivaroxaban group versus 1.8% in the enoxaparin therapy group.[8] Underdosing, non-compliance, underlying cancer, and drug interactions are a few causes that could result in therapeutic failure with rivaroxaban.[9] Generally, chemotherapeutic agents are safely administered with oral anticoagulants. Rarely, drugs such as paclitaxel (CYP3A4 inducer) may cause failure of rivaroxaban therapy, resulting in thrombosis.[10] However, the index patient was on gemcitabine and carboplatin therapy, which do not have significant interactions with rivaroxaban. The cause of recurrent PTE in patients with malignancy could be related to higher disease burden and prothrombotic state of malignancy. Finally, although unlikely, we have not excluded additional underlying conditions (apart from malignancy), such as antiphospholipid antibody syndrome, wherein an increased rate of recurrent thrombosis (especially on newer oral anticoagulants) is well known.

Wheezing could rarely be the presenting feature of acute pulmonary thromboembolism (PTE), and alternate causes, such as severe acute asthma, should be excluded. PTE presenting with wheezing could indicate greater severity of illness or a higher clot burden and needs urgent management.

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Conflicts of interest

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