Successful Recovery of COVID-19 Associated With Cardiomyopathy in Advanced Breast Cancer Patient With Pulmonary Lymphangitis Carcinomatosis

Introduction

In early December 2019, the first confirmed SARS-CoV-2 infection was reported in China. ¹ SARS-CoV-2 rapidly spread worldwide and was declared a pandemic by WHO in March 2020. ² The virus can cause mild to severe symptoms, and patients undergoing chemotherapy are at high risk of severe infection due to the cytotoxic effects of chemotherapy on the immune system. ³ he mortality rate among oncology patients with SARS-CoV-2 infection is high, with breast cancer patients being at a greater risk due to the prevalence of this malignancy.^4,5 A large percentage of this population is patients with breast cancer, the most prevalent malignancy and the most common cause of death among women worldwide.^6,7 Breast cancer commonly metastasizes to the lungs, regional lymph nodes, and central nervous system. ⁸ Pulmonary lymphangitis carcinomatosis (PLC) is a rare but fatal sign of advanced breast cancer that can lead to a poor prognosis with limited treatment options. ⁹ Corticosteroids have been used to treat hypoxia in patients with PLC; however, the evidence to support this is limited. ¹⁰ Corticosteroids have been used to manage hypoxia in patients with PLC, although evidence to support their use is limited. In contrast, low doses of corticosteroids have been found effective in managing severe COVID-19 pneumonia, and dexamethasone has been reported to decrease mortality in ICU patients.^11,12 Additionally, tocilizumab has been used to treat severe SARS-CoV-2 infection with elevated levels of IL-6, which has been linked to a severe cytokine storm, a condition associated with severe disease and the need for assisted respiration.^{13 -17} The REMAP-CAP trial showed that patients who received tocilizumab and sarilumab had significantly lower risks of in-hospital death, improved in-hospital survival, and more organ support-free days. ¹⁸

In this case report, we discuss the outcome of a breast cancer patient with PLC who was admitted with severe COVID-19 pneumonia and was treated with dexamethasone, tocilizumab, and broad-spectrum antibiotics.

Case Description

A 43-year-old female presented with shortness of breath at rest on October 1, 2019, and a large left breast mass with skin involvement. She was diagnosed with estrogen and progesterone receptor-positive and human epidermal growth factor receptor 2-negative invasive ductal carcinoma. Computed chest, abdomen, and pelvis tomography revealed a left breast mass with extension to the skin and right breast, bilateral local lymphadenopathy, left chest wall metastases, and mediastinal lymphadenopathy with bilateral lymphadenitis carcinomatosis. It also revealed multiple hepatic metastases, intra-abdominal metastatic lymphadenopathy, bone metastases, and pleural metastases with moderate pleural effusion.

She was started on a systemic anthracycline-based chemotherapy protocol as she was in a visceral crisis. Initially, she showed a reasonable clinical response. Follow-up chest X-ray and CT chest (Figure 1A and B) showed stable PLC with significant regression in the size of axillary and mediastinal lymph nodes and bilateral breast tumors. After completion of a total of 6 cycles, she again presented with respiratory distress, and disease progression was confirmed radiologically. Her echocardiogram and ejection fraction were within the normal range. She received docetaxel and showed a partial clinical response. However, she presented to the emergency department on June 14, 2020, with new respiratory distress, high-grade fever, dry cough, and hypoxia requiring oxygen. Her laboratory tests showed an absolute neutrophil count (ANC) of 0.23 × 10⁹/L, and high inflammatory markers, including ferritin and C-reactive protein (CRP), which were 675 µg/L (normal range 13-150 µg/L) and 289 mg/L (negative is <3 mg/L), respectively. Chest X-ray revealed intermittent development of left lower lobe airspace opacity and mild to moderate left-sided pleural effusion. Chest CT (Figure 2) also showed multiple bilateral ground-glass airspace opacities consistent with COVID-19 pneumonia. The COVID-19-PCR nasal swab confirmed the diagnosis. She was given hydroxychloroquine, azithromycin, and ceftriaxone according to the hospital management guidelines for moderate COVID-19 infections. She continued to have fever spikes with oxygen desaturation that required a high-flow nasal cannula (HFNC).

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Figure 1.

Baseline chest CT w/contrast in March 2020 before SARS-CoV-2 infection (A and B).

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Figure 2.

Diagnostic chest CT showing multiple bilateral ground glass airspace opacities (Blue arrows), Left pleural effusion (Red arrow), and mild pericardial effusion (Orange arrow) in June 2020.

The pro-BNP level increased to 21 716 pg/mL (negative is <155 pg/mL), CK-MB was 252 U/L (normal range 24-195 U/L), and troponin T was 79 ng/L (negative is <14 ng/L). Echocardiography revealed a severely reduced ejection fraction = 25%-30% and severe global hypokinesis. Serum ferritin increased to 1733 µg/L.

The patient was urgently admitted to the ICU, and hydroxychloroquine and azithromycin were discontinued as the patient had a prolonged QT interval. The patient was started on dexamethasone 6 mg intravenous, meropenem, and tocilizumab 400 mg single dose along with granulocyte colony-stimulating factor (G-CSF). The patient’s condition deteriorated the next day, and she required intubation with mechanical ventilation and inotropic support. The second dose of tocilizumab 400 mg was given, and the dexamethasone dose was increased to 20 mg IV for 5 days. Fortunately, the patient had clinical and biochemical improvement and hemodynamic stability, did not require inotropic support and underwent successful extubation, and steroid tapered by 5 mg every 3 days. In addition, ferritin decreased to 91 µg/L, and CRP decreased to 0.8 mg/L. Furthermore, she was asymptomatic and off oxygen with a confirmed negative COVID-PCR nasal swab before being discharged home.

Two months after discharge, the CT scan of the chest (Figure 3) showed partial response in primary and metastatic sites. There was still a diffuse ground-glass appearance in both lungs that was associated with inflammatory opacities, thus implying the persistence of the post-SARS-CoV-2 infection sequence. She was started on hormonal therapy with tamoxifen, and response evaluation revealed stable disease at the 3-month follow-up.

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Figure 3.

Post-COVID-19 infection follow-up chest CT scan showing significant improvement and resolution of pulmonary infiltrates (Blue arrows) and left pleural effusion (Red arrow) in October 2020.

Discussion

Many factors contributed to cardiomyopathy in this patient. However, what is notable here is the recovery of cardiac function upon controlling her cytokine storm using dexamethasone and tocilizumab. Despite having a COVID-19 infection with underlying breast cancer and PLC, the patient had an excellent clinical response. Her outcome and treatment response corresponded with the effect of dexamethasone on 28-day mortality in COVID-19-infected patients in the RECOVERY trial, which proved that dexamethasone decreased the risk of mortality in those receiving either noninvasive or invasive ventilation. ¹⁹ Viral myocarditis induced by SARS-CoV2 can induce severe cardiac damage or even sudden death if left untreated. This is related to the downstream effect of low oxygen or cytokine storm on cardiac muscle or secondary to the direct invasion of cardiac cells by binding S-spike to the angiotensin-converting enzyme 2 (ACE-2) receptors. ²⁰ PLC is a severe and challenging manifestation of metastatic cancer with a high mortality rate. ¹¹ Low-dose corticosteroids decrease mortality risk and improve respiratory conditions. ¹⁰ However, this does not lead to significant radiological improvement, as seen in this patient. A systematic review and meta-analysis of case reports on PLC from 1970 to 2018 showed that glucocorticoids, in addition to other supportive treatments (such as oxygen and morphine), helped relieve the respiratory symptoms without affecting the imaging findings of PLC. ¹¹

Adjacent to the radiological findings of PLC, the residual pulmonary changes in diffuse ground-glass appearance and inflammatory opacities are related to post-COVID-19 pneumonia. These changes may persist for more than 26 days after the onset of symptoms, as reviewed in the time course of lung changes at chest CT during recovery from coronavirus Disease 2019. ²¹ Tocilizumab is an immunosuppressive drug that works against the interleukin 6 receptor (IL-6R). Furthermore, tocilizumab proved effective in both COVID-19-associated cytokine storms and breast cancer. One explanation is that IL-6 is one of the immune modulator cytokines with a proven onco-proliferative effect that tocilizumab could suppress. ²² The combination of azithromycin and hydroxychloroquine was thought to impact the COVID-19 viral load and management. ²³ Further studies showed that the combination did not decrease morbidity or mortality associated with SARS-CoV-2 infection nor improve respiratory status. ²⁴

Conclusion

The combination of dexamethasone and tocilizumab showed successful recovery of life-threatening COVID-19-induced cardiomyopathy in metastatic breast cancer patient with PLC. Higher doses of dexamethasone and supplemental doses of tocilizumab might be required to achieve better recovery.