key: cord-0851305-wg1rudhc
authors: Ashtari, Fereshteh; Soltani, Rasool; Shokouhi, Shervin; Rismanbaf, Ali; Hajiahmadi, Somayeh; Hakamifard, Atousa
title: Adverse reaction of methylprednisolone pulse therapy: Acute respiratory distress syndrome
date: 2021-07-16
journal: Clin Case Rep
DOI: 10.1002/ccr3.4468
sha: 1bd143f06cf3704ae3695bc0418bc12056ee31c0
doc_id: 851305
cord_uid: wg1rudhc

Methylprednisolone pulse therapy has significant anti‐inflammatory effects in multiple sclerosis. Acute respiratory distress syndrome as a probable adverse effect of methylprednisolone pulse therapy in MS patients should be considered.

Methylprednisolone pulse therapy is one of the most common treatments in exacerbation of multiple sclerosis. In this case report, we present a 25-year-old woman with a 5-year history of MS, who developed acute respiratory distress syndrome after methylprednisolone succinate pulse therapy.

Glucocorticoids are a class of corticosteroids first identified in the 1940s. 1 These agents have significant antiinflammatory effects and were introduced as an effective multiple sclerosis (MS) treatment due to their beneficial effects on autoimmune diseases in the clinical practice. 1 Mechanisms that may be involved in the therapeutic effects of glucocorticoids in patients with MS include inhibitory effects on pro-inflammatory cytokines, inflammatory T cells, and phagocytic antigen-presenting cells, such as macrophages. 2 Today, the use of glucocorticoids in MS treatment is limited to manage the symptoms of exacerbations. Among the glucocorticoids, methylprednisolone pulse therapy (MPPT), 1 g daily intravenously (IV) for 3-5 days, is one of the most common and effective treatments of MS flare-ups. In addition to its beneficial effects, MPPT has several side effects including psychiatric abnormalities, sleep disorders, hyperglycemia, hypertension, hypokalemia, and peptic ulcer. 1,2 However, to our knowledge, pulmonary complications, including acute respiratory distress syndrome (ARDS), have not been reported as adverse drug reactions (ADR) for methylprednisolone pulse therapy in the treatment of MS exacerbation. In this case report, we present a patient with a 5-year history of MS who developed ARDS after methylprednisolone succinate pulse therapy for controlling disease flare. Written informed consent was obtained from the patient. This case report was approved by the ethics committee of Isfahan University of Medical Science.

In May 2019, a 25-year-old woman with a 5-year history of relapsing-remitting MS being under treatment with glatiramer acetate (40 mg SC three times weekly) was referred to our hospital due to an exacerbation of MS. The patient's vital signs were stable (PR: 83/min, RR: 16/min, T: 37℃, and BP: 110/70 mm Hg) at the time of admission; however, paresthesia and paraparesis were detected on physical examination.

Upon admission and evaluation, intravenous methylprednisolone succinate was started at a daily dose of 1 g for 3 days to control the exacerbated MS symptoms. On the first day of receiving methylprednisolone, the patient developed mild dyspnea, while her vital signs were stable and other aspects of physical examination including cardiac exam were unremarkable. On the second day, following the injection of methylprednisolone, she developed severe dyspnea, respiratory distress, decreased O 2 saturation (SpO 2 ) to 65% (Table 1) . Consequently, because of respiratory failure, she was admitted to Intensive care unit and intubated for mechanical ventilation. Chest radiography and computerized tomography (CT) scan were performed with the results interpreted as bilateral lung involvement ( Figure 1 ). According to a chest CT scan following pulse therapy, she received empiric IV cotrimoxazole (for possible Pneumocystis jiroveci pneumonia), meropenem, and vancomycin. Also, furosemide was initiated. However, endotracheal secretions gram staining and bronchoalveolar lavage (BAL) evaluation were with negative results. D-dimer's test was negative. Furthermore, no cardiac dysfunction was observed in echocardiography. On day 6, the patient was extubated with stable vital signs. Finally, on the 12th day, the patient was discharged.

In October 2019, the patient was again referred to our hospital due to MS flare-up. As in the previous episode, the patient was prescribed methylprednisolone succinate at a daily dose of 1 g for three days to control her exacerbation symptoms. The Chest X-ray was performed before pulse therapy ( Figure 2 ) and was normal. On the second day of receiving methylprednisolone, severe dyspnea and reduced SpO 2 (80%) occurred again with similar chest CT results compatible with ARDS ( Figure 3) , hence, antibiotics were not prescribed. Supportive oxygen therapy with face mask and supportive care was initiated. Also, the methylprednisolone was discontinued and for eliminating alternative diagnoses as the cause of lung disease, the same workup was performed as in the previous hospitalization with the results of bronchoscopy and BAL gram staining for bacteria and Pneumocystis jirovecii, acid-fast staining, BAL fluid culture for bacteria and fungi and PCR for Mycobacterium tuberculosis and Pneumocystis jirovecii all being negative. We also checked the BAL specimen for respiratory viruses by PCR including respiratory syncytial virus, influenza, adenovirus, parainfluenza, coronavirus, and rhinovirus, all were negative. Serum galactomannan and aspergillus smear and culture in the BAL specimen were negative. We found no evidence of viral, fungal, or bacterial infection. In addition, the patient's echocardiography was normal. In the next visits for the patient when steroids were indicated, dexamethasone was used and no side effects were observed. The patient is off methylprednisolone pulse therapy for almost 11 months with no similar events. The patient is currently receiving glatiramer acetate ( Figure 4 ).

This case presents the possibility of ARDS following MPPT. ARDS is a consequence of an alveolar epithelium and capillary endothelium injury-producing diffuse alveolar damage. Septic shock, pancreatitis, and massive transfusion are examples that can cause this condition. 3, 4 We know that drugs can also cause lung disease by injury to the airways or alveoli and create interstitial patterns in the lungs. 5 Often pathophysiologic mechanisms for ARDS including direct damage (by producing reactive oxygen) or indirect damage (by releasing inflammatory cytotoxic mediators) remain unknown for most of the drugs; hence most cases of drugassociated ARDS are considered probable or possible rather than definitive. 3 Diffuse alveolar damage (DAD) is defined as a pathological finding for ARDS and clinically DAD is associated with diffuse pulmonary infiltration with respiratory failure. Till now some cases of DAD related to drugs have been reported. 5, 6 To our knowledge, there is no previous report of such an adverse effect by MPPT. Of note, glucocorticoids are used in the treatment of ARDS or drug-induced lung injury in many cases. 7 F I G U R E 2 CXR before methylprednisolone pulse therapy In our case, diffuse pulmonary infiltration with respiratory failure (ARDS, clinically DAD), the exclusion of other etiologies including PCP and other infectious agents, acute course of dyspnea with its relatively fast improvement following cessation of the MPPT and recrudescence with rechallenge make the diagnosis of possibility of adverse drug reaction (ADR) with MPPT. On the other hand, from the radiological point of view, it is necessary to mention few points: in a patient with acute symptoms, differential diagnosis of ground-glass opacities is broad such as atypical pneumonia, pulmonary edema, and either hydrostatic or increased permeability edema; diffuse alveolar damage, pulmonary hemorrhage and acute eosinophilic pneumonia. In the acute setting, appearance and distribution of ground-glass opacities are of limited use in narrowing differential diagnosis. Cardiogenic pulmonary edema usually presents with a history of acute cardiac events, so that physical examination reveals jugular venous distention and fine rales. 8 The normal echocardiography rules out the possibility of cardiac origin for pulmonary edema. No one was detected in our case.

We cannot accurately justify the exact mechanism of this complication, but MPPT may be the cause of direct lung endothelial damage in this case. Using Naranjo scale for estimating the probability of this adverse reaction, 9 the score 8 is obtained and interpreted as "probable" ADR. Therefore, ARDS should be considered as a probable ADR of high-dose glucocorticoids. 

Mechanistic insights into corticosteroids in multiple sclerosis: War horse or chameleon?

Corticosteroids and multiple sclerosis: to treat or not

to treat? pharmacists can be the front-line resource for MS patients

Drug-associated acute lung injury: a population-based cohort study

The acute respiratory distress syndrome

Diffuse alveolar damage and recurrent respiratory failure secondary to sertraline

Drug induced lung disease: high-resolution CT and histological findings

Pharmacological agents for adults with acute respiratory distress syndrome

Diagnosis and management of cardiogenic pulmonary edema

A method for estimating the probability of adverse drug reactions

The authors declare that they have no competing interests.

A.H; F.A; R.S; and S.S acquired data, analyzed and interpreted the data. A.H; R.S; A.R; and S.H assisted in drafting the manuscript. All authors have read, revised, and approved the final manuscript.

This research was approved by the ethics committee of Isfahan University of Medical Sciences and written informed consent was obtained from the patient.

Data sharing is not applicable to this case report article as no new data were created or analyzed in this study.

Atousa Hakamifard https://orcid.org/0000-0001-9456-2239