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Alemtuzumab-induced lung injury in multiple sclerosis: Learning from adversity in three patients

  • Assunta Bianco
    Correspondence
    Corresponding author.
    Affiliations
    Multiple Sclerosis Unit, Fondazione Policlinico Universitario A. Gemelli IRCCS, Roma, Italia. Institute of Neurology, Università Cattolica del Sacro Cuore, Largo Agostino Gemelli n 8, 00168 Rome, Italia
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  • Pier-Valerio Mari
    Affiliations
    Department of Cardiac, Thoracic and Vascular Sciences, Fondazione Policlinico Universitario “A. Gemelli” IRCCS, and Institute of Pneumology, Università Cattolica del Sacro Cuore, Roma, Italia
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  • Anna Rita Larici
    Affiliations
    Department of Diagnostic Imaging, Oncologic Radiotherapy and Hematology, Fondazione Policlinico Universitario “A. Gemelli” IRCCS, and Institute of Radiology, Università Cattolica del Sacro Cuore, Roma, Italia
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  • Matteo Lucchini
    Affiliations
    Multiple Sclerosis Unit, Fondazione Policlinico Universitario A. Gemelli IRCCS, Roma, Italia. Institute of Neurology, Università Cattolica del Sacro Cuore, Largo Agostino Gemelli n 8, 00168 Rome, Italia
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  • Viviana Nociti
    Affiliations
    Multiple Sclerosis Unit, Fondazione Policlinico Universitario A. Gemelli IRCCS, Roma, Italia. Institute of Neurology, Università Cattolica del Sacro Cuore, Largo Agostino Gemelli n 8, 00168 Rome, Italia
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  • Francesco Antonio Losavio
    Affiliations
    Multiple Sclerosis Unit, Fondazione Policlinico Universitario A. Gemelli IRCCS, Roma, Italia. Institute of Neurology, Università Cattolica del Sacro Cuore, Largo Agostino Gemelli n 8, 00168 Rome, Italia
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  • Chiara De Fino
    Affiliations
    Multiple Sclerosis Unit, Fondazione Policlinico Universitario A. Gemelli IRCCS, Roma, Italia. Institute of Neurology, Università Cattolica del Sacro Cuore, Largo Agostino Gemelli n 8, 00168 Rome, Italia
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  • Giuseppe Cicchetti
    Affiliations
    Department of Diagnostic Imaging, Oncologic Radiotherapy and Hematology, Fondazione Policlinico Universitario “A. Gemelli” IRCCS, and Institute of Radiology, Università Cattolica del Sacro Cuore, Roma, Italia
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  • Daniele Coraci
    Affiliations
    Multiple Sclerosis Unit, Fondazione Policlinico Universitario A. Gemelli IRCCS, Roma, Italia. Institute of Neurology, Università Cattolica del Sacro Cuore, Largo Agostino Gemelli n 8, 00168 Rome, Italia
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  • Luca Richeldi
    Affiliations
    Department of Cardiac, Thoracic and Vascular Sciences, Fondazione Policlinico Universitario “A. Gemelli” IRCCS, and Institute of Pneumology, Università Cattolica del Sacro Cuore, Roma, Italia
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  • Massimiliano Mirabella
    Affiliations
    Multiple Sclerosis Unit, Fondazione Policlinico Universitario A. Gemelli IRCCS, Roma, Italia. Institute of Neurology, Università Cattolica del Sacro Cuore, Largo Agostino Gemelli n 8, 00168 Rome, Italia
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Published:October 15, 2019DOI:https://doi.org/10.1016/j.msard.2019.101450

      Highlights

      • We report three cases of severe lung injury in MS patients treated with alemtuzumab.
      • Lung injury was heterogeneous in terms of clinic characteristics, HRCT pattern and onset timing.
      • All cases were reversible after steroid therapy, but re-treatment is challenging.

      Abstract

      Background

      Respiratory alemtuzumab-related adverse events are clinically heterogeneous and include respiratory infections, infusion-related dyspnea, hypoxia and secondary autoimmune disorders.

      Case report

      Here we report three cases of drug-induced lung disease following treatment with alemtuzumab in multiple sclerosis patients. First case was diagnosed as a non-specified intestitial pneumonitis associated with organizing pneumonia with subacute onset, second case was an acute respiratory distress syndrome with onset during second cycle, third case was a diffuse acute alveolar hemorrhage during first cycle infusion. All patients developed acute respiratory failure, reversible after steroid therapy.

      Conclusions

      Clinicians should be aware to early recognize acute and subacute respiratory adverse events for a promptly management. In these patients re-treatment is challenging.

      Keywords

      1. Background

      Alemtuzumab is a humanized anti-CD52 monoclonal antibody approved for the treatment of patients with active relapsing-remitting Multiple Sclerosis (MS) (
      • Berger T.
      • Elovaara I.
      • Fredrikson S.
      • McGuigan C.
      • Moiola L.
      • Myhr K.M.
      • Oreja-Guevara C.
      • Stoliarov I.
      • Zettl U.K
      Alemtuzumab use in clinical practice: recommendations from European multiple sclerosis experts.
      ;
      • Devonshire V.
      • Phillips R.
      • Wass H.
      • Da Roza G.
      • Senior P
      Monitoring and management of autoimmunity in multiple sclerosis patients treated with alemtuzumab: practical recommendations.
      ). Alemtuzumab-related respiratory adverse events, as reported in MS clinical trials, include upper (very common; ≥10%) and lower respiratory infections (common; from 1% to 10%) and infusion-related dyspnea and hypoxia as common. Post-marketing pharmacovigilance described cases of opportunistic respiratory infections (
      • Hazara A.M.
      • Edey M.
      • Roy A.
      • Bhandari S
      Rapidly growing non-tuberculous mycobacterial infection in a renal transplant patient after alemtuzumab induction.
      ), alveolar haemorrhage (
      • Myro A.Z.
      • Bjerke G.
      • Zarnovicky S.
      • Holmøy T
      Diffuse alveolar hemorrhage during alemtuzumab infusion in a patient with multiple sclerosis: a case report.
      ), interstitial pneumonitis (
      • Whiteside D.
      • Barth S.
      • Datta A.
      • Trip S.A
      Pneumonitis secondary to alemtuzumab in a patient with multiple sclerosis - A non-infectious cause of breathlessness.
      ), acute sarcoidosis (
      • Graf J.
      • Ringelstein M.
      • Lepka K.
      • et al.
      Acute sarcoidosis in a multiple sclerosis patient after alemtuzumab treatment.
      ), pulmonary arterial hypertension (
      • Beaumier L.
      • Chanoine S.
      • Camara B.
      • Pison C.
      • Bedouch P
      Alemtuzumab and de novo pulmonary arterial hypertension: a potential association?.
      ) and Goodpasture's syndrome (). We present three cases of alemtuzumab-associated lung disease following treatment with the drug for MS in the form of a pattern of Non-Specific Interstitial Pneumonia (NSIP), Acute Respiratory Distress Syndrome (ARDS) and diffuse alveolar haemorrhage respectively.

      2. Description of cases

      A 31-year-old non-smoker male with relapsing-remitting MS diagnosed on 2015 and previously treated with dimethyl fumarate for one year and subsequently fingolimod, withdrawn for clinical and radiological disease activity, underwent first cycle of alemtuzumab 12 mg/day for five days. Six weeks later, he reported dyspnea on exertion and cough without fever and was admitted to the Emergency Room. Physical examination showed fine velcro-like crackles bilaterally and an oxygen saturation of 70% breathing room air. A chest X-ray documented an opacity in the right lower lobe. Therapy with 35% oxygen and levofloxacin 750 mg/day was started, but symptoms worsened the day after. Treatment with piperacillin/tazobactam was added despite neutrophil count, C-reactive protein and pro-calcitonin within the normal range. Axial High-Resolution Computed Tomography HRCT image (Fig. 1-a) showed bilateral ground-glass opacities (GGO) with superimposed thickening of the interlobular septa and small focal consolidations in both lower lobes, with no traction bronchiectasis and no subpleural involvement. This pattern is consistent with NSIP, associated with foci of organizing pneumonia (OP). Bronchoalveolar lavage (BAL) demonstrated 55% lymphocytes while microbiological cultures were raised negative. A diagnosis of drug-induced interstitial pneumonia pattern was made. Treatment with methylprednisolone IV 1000 mg/day for three days was started with subsequent tapering, with promptly clinical improvement. After one week of treatment with high-dose steroids, HRCT scan (Fig. 1-b) demonstrated the almost complete resolution of the abnormalities. The patient was discharged home with a prescription of predisone 50 mg/day; scheduled monthly controls were unremarkable and prednisone was withdrawn after tapering two months later. After 30 months follow-up patient shows no evidence of MS disease activity without any Disease-Modifying-Drug (DMD).
      Fig 1
      Fig. 1(a–d). High-Resolution Computed Tomography (HRCT) scans of the chest at lung window setting (a, b) performed in the first patient. Axial image (a) shows bilateral ground-glass opacities with superimposed thickening of the interlobular septa in the lower lobes, and small focal consolidations predominantly in the right lower lobe, with a relative subpleural sparing and without traction bronchiectasis or bronchiolectasis. This HRCT pattern is suggestive of cellular non specific interstitial pneumonia (NSIP), associated with foci of organizing pneumonia (OP). The follow-up HRCT scan (b) demonstrates the almost complete resolution of the abnormalities after one week of treatment with high-dose steroids. HRCT scan of the chest at lung window setting (c) performed in the third patient immediately after the onset of symptoms. Axial image depicts bilateral centrilobular and confluent ground glass opacities, predominantly in the lower lobes with a dependent distribution, due to a subtotal alveolar filling with fluid. This HRCT pattern, associated with patient clinical signs and symptoms, is suggestive of diffuse acute alveolar hemorrhage. The follow-up HRCT scan (d) performed one month later demonstrates a complete resolution of the lung abnormalities.
      A 16-year-old non-smoker girl with high-active pediatric onset relapsing-remitting MS diagnosed on 2013 and previously treated with beta-1a interferon and subsequently with 12 infusion of natalizumab, without complete disease control, started treatment with alemtuzumab on march 2017. One year later, she underwent second cycle of alemtuzumab 12 mg/day. On the third day of drug administration, infusion was promptly halted due to rapidly progressive dyspnea, fatigue, dry cough without fever. Bilateral fine inspiratory crackles were predominant in the left lower lung areas. Oxygen saturation was 90% breathing room air and she was started on supplemental oxygen. Chest X-ray was consistent with acute respiratory distress syndrome. C-reactive protein and pro-calcitonin were normal. Amoxicillin-clavulanate 1000 mg p.o. t.i.d. plus IV methylprednisolone 1000 mg for three days were started. There was dramatic improvement in her clinical status and oxygen supplementation was stopped. HRCT scan performed five days later was negative. The patient was discharged with a diagnosis of drug-induced acute respiratory distress syndrome. No further DMD was started and patient remains without evidence of MS disease activity after 18 months follow-up.
      A 28-year-old non-smoker female with relapsing-remitting MS diagnosed on 2010 and previously treated with beta-1b interferon until 2013 and subsequently fingolimod withdrawn after a severe relapse, underwent first cycle of alemtuzumab 12 mg/day. On the second day, she reported the acute onset of chest pain associated with dyspnea and hemoptysis. Blood pressure was 125/85 mmHg and heart rate 52 bpm. Arterial saturation was 94% while breathing 24% oxygen. Chest auscultation showed fine inspiratory crackles in the middle and lower lung fields. Blood chemistry and complete blood cell count were normal. Autoantibodies (ANA, ANCA and anti- GBM) were negative and renal function was normal. HRCT scan of the chest (Fig. 1-c) immediately after the onset of symptoms depicted bilateral, centrilobular and confluent GGO in both lower lobes with a dependent distribution, due to a subtotal alveolar filling with fluid. This HRCT pattern, associated with patient clinical signs and symptoms, is suggestive of diffuse acute alveolar hemorrhage. Alemtuzumab infusion was promptly stopped. Methylprednisolone IV 1000 mg/day was started in combination with trimethoprim/sulfamethoxazole as prophylaxis against Pneumocystis jiroveci and rapid clinical improvement was noted. Oxygen therapy was discontinued. Patient was discharged with a diagnosis of alveolar haemorrage after confirmation of increasingly blood-stained BAL lavage aliquot, and she was given a two-month-tapering regimen of oral corticosteroids. One month later, lung function tests yielded normal results with a normal diffusion for carbon monoxide and follow-up HRCT scan (Fig. 1-d) demonstrates a complete resolution. No further DMD was started and patient remains without evidence of MS disease activity after 16 months follow-up.

      3. Discussion

      We report three cases of adverse pulmonary reactions to alemtuzumab in patients with highly-active MS showing heterogeneous lung injury in terms of clinic characteristics, HRCT pattern, and onset timing. We reported an unspecified interstitial pneumonitis, an ARDS and acute alveolar hemorrhage. The absence of an evident infective cause, the temporal association with alemtuzumab administration, the lymphocytosis in the BAL and also the dramatic improvement after high-dose corticosteroid therapy all support an immunologically-mediated lung disease, probably without an autoimmune mechanism. In fact, the most accredited mechanism for the onset of new autoimmune disease after alemtuzumab therapy is an unbalanced B cell than T cell recovery during reconstitution phase, with subsequent unregulated B-cell expansion and antibody-production in response to self-antigens. However, this mechanism does not seem to be involved in any of our three cases because of the rapid time of onset (B-cell mediated new autoimmune disease develop over months to years from the infusion). In our view, the pathogenesis of such reactions, probably different case by case, may be due to activation of resident cytotoxic T lymphocytes and persistent cytokine release, resulting in alveolar and/or interstitial lung disease. Type III/IV hypersensitivity reaction to this monoclonal antibody characterized by an aberrant Th1/Th17 response is another possibility. The presence of a bronchoalveolar lavage lymphocytosis in the context of peripheral lymphopenia is paradoxical and suggest a compartimentalization of the immune response after alemtuzumab exposure. Whether or not steroid sensitivity and response to steroids indicate an immunological mechanism remains unclear at the present time. It should also be noted that empirical use of methylprednisolone 1000 mg/day for three days has not received experimental or clinical support compared to more conventional dosages (e.g. 120–240 mg daily for three days). Sensitization to alemtuzumab cannot be excluded on the basis of relapse upon rechallenge in one case in the literature (
      • Blasco M.R.
      • Ramos A.
      • Malo C.G.
      • García-Merino A
      Acute pneumonitis and pericarditis related to alemtuzumab therapy in relapsing-remitting multiple sclerosis.
      ).
      All cases promptly resolved after steroid treatment, but probably rechallenge with alemtuzumab is discouraged as the event could be repeated even with a more severe clinical presentation. Since all monoclonal antibodies present a potential lung toxicity, with different damage patterns, the most relevant clinical challenge is represented by which DMD to choose for these patients with very active disease and when restart a new treatment.
      Postmarketing surveillance detected some other rare side effects of Alemtuzumab (
      • Whiteside D.J
      • Trip S.A
      Reader response: Rare side effects of alemtuzumab remind us of the need for postmarketing surveillance.
      ) and European Medicines Agency started a review on April 2019 to overview the drug safety, including CMV pneumonia and bleeding in the lungs (
      • Buonomo A.R.
      • Saccà F.
      • Zappulo E.
      • De Zottis F.
      • Lanzillo R.
      • Gentile I.
      • Carotenuto A.
      • Borgia G.
      • Russo C.V
      Bacterial and CMV pneumonia in a patient treated with alemtuzumab for multiple sclerosis.
      ,

      EMA review 220110/2019, 12 April 2019. www.ema.europa.eu.

      ).
      In conclusion, it is important for neurologists, pulmonologists and emergency or ICU physicians to be knowledgeable in alemtuzumab pulmonary toxicity, diagnose the condition early and integrate these toxicities into the risk-benefit decision-making prior to instituting such therapy.

      Funding Source

      None.

      Informed Consent

      Informed consent for publication of report and images was given by each patient.

      Declaration of Competing Interest

      Dr. Richeldi reports personal fees from Sanofi-Aventis, grants and personal fees from Roche, personal fees from Immune Works, grants and personal fees from Boehringer Ingelheim, personal fees from Celgene, personal fees from Nitto, personal fees from Fibrogen, personal fees from Promedior, personal fees from Bristol Myers Squibb, personal fees from DynaMed, personal fees from Pliant Therapeutics, outside the submitted work.

      Acknowledgment

      The authors would like to acknowledge and sincerely thank Professor Philippe Camus (Centre Hospitalier Universitaire, Dijon, France). We are very grateful for his contributions and the comprehensive Pneumotox website support during the writing of this manuscript (www.pneumotox.com).

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