Chronic conventional disease-modifying anti-rheumatic drugs masking severe SARS-CoV-2 manifestations in an elderly rheumatic patient.

Dear Editor,

In early 2020 a new beta-corona virus (SARS-CoV-2) spread all over the world, and with a high incidence in Europe, especially in Italy [1,2]. SARS-CoV-2 infection may lead to a wide range of clinical presentations, from an asymptomatic form to a severe acute respiratory syndrome [3]. The symptoms more frequently observed were fever, chills, myalgia or fatigue, followed by a dry cough and dyspnea 3-7 days later. The age and the presence of chronic comorbidities (hypertension, cardiovascular disease, diabetes, chronic lung, kidney or cerebrovascular disease or malignancy) have been considered as the major risk factors for acute respiratory distress syndrome (ARDS) and the need for intensive care in COVID-19 patients [4]. ARDS is an immunopathologic event with hyper-activity of the systemic inflammatory response that induces cytokine storm, that increase pro-inflammatory cytokines like interferons, interleukins (IL), tumor necrosis factor and chemokines, suggesting the use of anti-inflammatory agents for SARS-CoV-2 pulmonary symptoms [5]. Few data are available on SARS-CoV-2 infection in rheumatological patients chronically treated with immunosuppressive therapy.

We present a clinical case of an 82-year-old Caucasian woman with a history of rheumatoid arthritis (RA) and idiopathic arterial hypertension hospitalized for SARS-CoV-2 pneumonia. The diagnosis of RA was performed in 2007 for the appearance of rheumatoid factor and anti-citrullinated protein antibody-positive symmetrical polyarthritis, without signs of pulmonary or systemic disease. She had been under methotrexate, 10 mg/weekly (cumulative dose 6080 mg) and methylprednisolone (4 mg/day) treatment for two years, with a low disease activity status (DAS 28 PCR 2.9).

A week before admission, the patient had low grade fever (37.5°C) and a dry cough; she had stopped methylprednisolone and had started antibiotic treatment, without improvement; on 27 March, she underwent nasopharyngeal SARS-CoV-2 swab, which resulted positive, and was hospitalized on 30 March. Despite the absence of any pulmonary symptoms, a lung CT scan showed interstitial bilateral pneumonia (Fig. 1 ), and a thoracic ultrasound with lung ultrasound reaeration score (LUS) of four. Hydroxycloroquine, lopinavir/ritonavir, and low molecular weight heparin (LMWH, 4000 UI/die) were started. Two days later, although afebrile, she presented dyspnea (respiratory rate-RR 32) with SpO2 of 93% in FiO2 21% and PaO2 / FiO2 309 mmHg and Oxygen therapy was started. High values of D-dimer and C-reaction protein were observed, a CT angiography excluded embolism, but showed a worsening of pneumonia (Fig. 1), and the LUS score was 10. Because of the persistence of signs of cytokine storm, without worsening in respiratory function, tocilizumab was administered (Fig. 2 ). The next day she worsened (PaO2 / FiO2 137.8 mmHg), so another dose of tocilizumab was administered, and methylprednisolone was started. A gradual clinical and biochemical improvement was observed (Fig. 2). On 12 and 14 April, nasopharyngeal-oropharyngeal swabs resulted negative. On 16 and 22 April, a LUS score of eight and two was observed, respectively, and the patient was discharged in good general condition.

Fig. 1

Axial non-contrast CT scans of the upper chest in the lung in an 82-year-old woman with COVID-19 pneumonia.

A: Single sub-pleural thin band-like consolidation in the right upper lobe associated with ground-glass opacities (GGO). A small GGO is also seen in the left upper lobe, 7 days after the onset of symptoms.

B: Scan showed an increased extension of GGO in the right upper lobe associated with septal thickening (crazy paving) and posterior consolidations. Two smaller GGO are also visible in the left upper lobe, 10 days after the onset of symptoms.

C: Axial non-contrast CT image obtained below the carina showed bilateral multifocal GGO in both lower lobes with prevalence of the peripheral regions, 7 days after the onset of symptoms.

D: Scan showed a mixed pattern with parenchymal consolidations and parenchymal bands in both lower lobes with sub-pleural and posterior distribution. The perilobular bands of consolidation associated with thickening of the interlobular septa suggested the presence of organizing pneumonia, 10 days after the onset of symptoms.

Fig. 2

D-Dimer, CRP and PAO2/FO2% and therapy in a 82-year-old woman.

Our clinical case teaches to pay particular attention in the management of COVID-19 infection in the rheumatological field: in the absence of fever during the entire hospitalization period and clinical signs of pulmonary failure, the patient developed severe pneumonia. In most of case, the COVID-19 is asymptomatic or oligosymptomatic; while in a low percentage of case the fever persist up to 14 days from the onset of symptoms with clinical and radiological evidence of pneumonia from the day 7 and 14 and sometimes with a pulmonary failure. In the present case, in the absence of fever during the entire hospitalization and clinical signs of pulmonary failure, the patient developed a severe pneumonia. Thus, a close and continuous monitoring of PaO2 / FiO2, of biochemical signs of cytokine storm (D-dimer and CRP) and of imaging signs of pneumonia are needed to identify the initial signs of the respiratory failure.

We can hypothesize that by controlling the excessive activation of the immune system, chronic cDMARD treatment may mask the clinical presentation of COVID-19 with a silent development of severe acute pneumonia. In fact, although the immunological mechanism behind the risk of greater severity of COVID-19 infection is unknown, the coronavirus infection (SARS and MERS) may induce a cytokines storm especially in patients who developed fatal complications. Moreover, the pathological findings associated with acute respiratory distress syndrome in COVID-19 showed abundant interstitial mononuclear inflammatory infiltrate in the lungs, dominated by lymphocytes, once again implying that the immune hyperactivation mechanisms are at least partially accountable for COVID-19 severity 7, 8, 9.

Thus, close and continuous clinical, biochemical and imaging monitoring are needed to identify the initial signs of respiratory failure.

Our case shows a different course from that described by Mihan et al.[6], who reported a peculiar SARS-CoV-2 with mild symptoms in a 57-year-old woman with systemic sclerosis (SSc) with interstitial lung disease as main organ manifestation of SSc and chronically treated with tocilizumab (8 mg/kg body weight every 4 weeks iv). A month after the last infusion of tocilizumab, the patient developed a SARS-Cov-2 infection. However, her symptoms remained mild and she was monitored from home, resulting negative at the nasal swab after 14 days since symptoms had started [6]. The authors hypothesized that IL-6 blocking treatment given for chronic autoimmune diseases, such as rheumatoid disease, may even prevent the development of severe COVID-19. [6].

In our case, although the patient had negative prognostic factors (older age, chronic disease and arterial hypertension), the use of tocilizumab and corticosteroid was associated with the control of severe pneumonia, supporting the role of tocilizumab in controlling severe SARS-CoV-2-related life-threatening conditions.

Declaration of Competing Interest

All the authors of the manuscript declare they have no conflict of interest in connection with this paper.

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