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Can infections trigger sarcoidosis?

      Highlights

      • Amongst infectious pathogens, Mycobacterium tuberculosis and Propionibacterium acnes have most widely been associated with the development of sarcoidosis but other infections such as hepatitis C virus have also shown association
      • Three cases of coronavirus disease 2019 (COVID-19) associated with a subsequent sarcoid reaction (only one case with radiological pulmonary involvement) have now been reported ranging from 2 weeks to 1 year after the COVID-19 illness
      • Increased clinico-radiological vigilance and further investigation into the potential association of COVID-19 with sarcoid is needed

      Keywords

      To the Editor,
      We read with interest the article by Capaccione et al. on coronavirus disease 2019 (COVID-19)-induced pulmonary sarcoidosis.
      • Capaccione K.M.
      • McGroder C.
      • Garcia C.K.
      • Fedyna S.
      • Saqi A.
      • Salvatore M.M.
      COVID-19-induced pulmonary sarcoid: a case report and review of the literature.
      As this is a single case report of COVID-19-induced pulmonary sarcoidosis on a background of over 300 million severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infections worldwide to date,
      WHO Coronavirus (COVID-19) Dashboard
      one must be cautious in attributing the development of sarcoidosis to their SARS-CoV-2 infection in patients with prior SARS-CoV-2 infection. Sarcoidosis poses a diagnostic challenge given the overlapping clinico-radiological features with lymphoma, tuberculosis and certain autoimmune diseases.
      WHO Coronavirus (COVID-19) Dashboard
      Therefore, it is often a diagnosis of exclusion taking into consideration clinical (although often asymptomatic), biochemical (e.g., elevated serum angiotensin-converting enzyme levels [ACE] and hypercalcaemia), radiological (such as bilateral hilar lymphadenopathy and pulmonary infiltrates) and histological findings (e.g., well-formed noncaseating granulomas), most if not all of which were present in the case by Capaccione and colleagues, thus strongly supporting the diagnosis. Although the authors report the first case of pulmonary sarcoidosis following COVID-19 (occurring one year after being critically unwell with COVID-19), prior to this in September 2020, Behbahani et al. reported a case of a “sarcoid-like reaction” occurring two weeks after a hospital admission with COVID-19.
      • Behbahani S.
      • Baltz J.O.
      • Droms R.
      • Deng A.C.
      • Amano S.U.
      • Levin N.A.
      • et al.
      Sarcoid-like reaction in a patient recovering from coronavirus disease 19 pneumonia.
      The sarcoid-like features in this patient were erythema nodosum and skin biopsy findings of well-formed noncaseating granulomas in subcutaneous tissue suggestive of sarcoidosis. Unlike the case reported by Capaccione et al. however, serum ACE levels and chest imaging were normal (although these findings do not rule out sarcoidosis). In May 2021, Polat Ekinci et al. reported a similar cutaneous/subcutaneous, biopsy-confirmed sarcoid-reaction with no radiological evidence of pulmonary sarcoid in a patient 1 month after the onset of her COVID-19 illness.
      • Polat Ekinci A.
      • Büyükbabani N.
      • Meşe S.
      • Pehlivan G.
      • Okumuş N.G.
      • Ağaçfidan A.
      • et al.
      COVID-19-triggered sarcoidal granulomas mimicking scar sarcoidosis.
      We do agree that the mechanism postulated by Capaccione et al. by which COVID-19 could potentially trigger sarcoidosis (an inflammatory condition characterised by increased inflammatory cytokine release) through COVID-19 induced cytokine-mediated immune stimulation, is plausible given the now widely recognised cytokine storm that occurs with COVID-19,
      • Del Valle D.M.
      • Kim-Schulze S.
      • Huang H.-H.
      • Beckmann N.D.
      • Nirenberg S.
      • Wang B.
      • et al.
      An inflammatory cytokine signature predicts COVID-19 severity and survival.
      which has led to widespread use of anti-cytokine monoclonal agents (such as the interleukin-6 receptor monoclonal antibody drug tocilizumab) in the treatment of COVID-19.
      • Schulert G.S.
      Can tocilizumab calm the cytokine storm of COVID-19?.
      It is also supported by the fact that there are data to support the triggering of sarcoidosis by other infections, the most extensively studied of which are Mycobacterium tuberculosis and Propionibacterium acnes, which in animal (murine) studies have both been shown to stimulate the development of granulomas with corresponding increases in the concentrations of inflammatory cytokine-producing immune cells within the affected tissues/organs.
      • Starshinova A.A.
      • Malkova A.M.
      • Basantsova N.Y.
      • Zinchenko Y.S.
      • Kudryavtsev I.V.
      • Ershov G.A.
      • et al.
      Sarcoidosis as an autoimmune disease.
      However, there are a lack of studies demonstrating the direct effects of infectious pathogens on the development of granulomas in humans. There are case reports/series' of sarcoidosis with biopsy-confirmed hepatic sarcoid involvement in patients with hepatitis C virus infection
      • Brjalin V.
      Sarcoidosis and chronic hepatitis C: a case report.
      • Ramos-Casals M.
      • Mañá J.
      • Nardi N.
      • Brito-Zerón P.
      • Xaubet A.
      • Sánchez-Tapias J.M.
      • et al.
      Sarcoidosis in patients with chronic hepatitis C virus infection: analysis of 68 cases.
      and in one patient with hepatitis B
      • Patel S.
      • Patel P.
      • Jiyani R.
      • Ghosh S.
      • Patel D.
      A rare case of hepatic sarcoidosis caused by hepatitis B virus and treatment-induced opportunistic infection.
      virus infection, thus supporting a role for viral infections as direct triggers for sarcoidosis.
      A meta-analysis which investigated whether there is any association between infectious agents and sarcoidosis not only found a strong etiological link of sarcoidosis with mycobacteria and Propionibacterium acnes but also with Borrelia, human herpes virus-8, Rickettsia helvetica, Chlamydia pneumoniae, Epstein-barr virus and HIV.
      • Esteves T.
      • Aparicio G.
      • Garcia-Patos V.
      Is there any association between sarcoidosis and infectious agents?: a systematic review and meta-analysis.
      However, this study was performed prior to the declaration of the COVID-19 pandemic, therefore data specifically relating to any potential association between SARS-CoV-2 infection and sarcoidosis are lacking. Given that sarcoidosis is frequently asymptomatic and the fact that most individuals with SARS-CoV-2 infection during this ongoing pandemic do not undergo post-infection imaging (given that only a minority are admitted to hospital), there may be additional cases of COVID-19-associated sarcoidosis that remain undiagnosed or that are yet to develop. If sarcoidosis with pulmonary involvement potentially triggered by SARS-CoV-2 infection can occur relatively shortly after their infection, identification of sarcoid features on chest imaging may be made more challenging by the fact that sarcoidosis and COVID-19 can have similar radiological features in certain cases, partly dependent on the radiological stage of sarcoidosis.
      • Tana C.
      • Mantini C.
      • Cipollone F.
      • Giamberardino M.A.
      Chest imaging of patients with sarcoidosis and SARS-CoV-2 infection. Current evidence and clinical perspectives.
      The cases by Capaccione et al., Behbahani et al. and Polat Ekinci et al. however, will widen awareness of COVID-19 associated sarcoid disease thus helping to increase clinical and radiological vigilance and lead to greater consideration amongst physicians and radiologists of this potential association. It may also give the impetus for further scientific and clinical studies of this largely unrecognised potential complication of COVID-19.

      Funding

      No specific funding was received for this study.

      Declaration of competing interest

      None of the authors have any competing interests to declare.

      References

        • Capaccione K.M.
        • McGroder C.
        • Garcia C.K.
        • Fedyna S.
        • Saqi A.
        • Salvatore M.M.
        COVID-19-induced pulmonary sarcoid: a case report and review of the literature.
        Clin Imaging. 2022; (S0899707121004976)https://doi.org/10.1016/j.clinimag.2021.12.021
        • WHO Coronavirus (COVID-19) Dashboard
        https://covid19.who.int/n.d
        Date accessed: January 13, 2022
        • Behbahani S.
        • Baltz J.O.
        • Droms R.
        • Deng A.C.
        • Amano S.U.
        • Levin N.A.
        • et al.
        Sarcoid-like reaction in a patient recovering from coronavirus disease 19 pneumonia.
        JAAD Case Rep. 2020; 6: 915-917https://doi.org/10.1016/j.jdcr.2020.07.026
        • Polat Ekinci A.
        • Büyükbabani N.
        • Meşe S.
        • Pehlivan G.
        • Okumuş N.G.
        • Ağaçfidan A.
        • et al.
        COVID-19-triggered sarcoidal granulomas mimicking scar sarcoidosis.
        J Eur Acad Dermatol Venereol. 2021; 35https://doi.org/10.1111/jdv.17286
        • Del Valle D.M.
        • Kim-Schulze S.
        • Huang H.-H.
        • Beckmann N.D.
        • Nirenberg S.
        • Wang B.
        • et al.
        An inflammatory cytokine signature predicts COVID-19 severity and survival.
        Nat Med. 2020; 26: 1636-1643https://doi.org/10.1038/s41591-020-1051-9
        • Schulert G.S.
        Can tocilizumab calm the cytokine storm of COVID-19?.
        Lancet Rheumatol. 2020; 2: e449-e451https://doi.org/10.1016/S2665-9913(20)30210-1
        • Starshinova A.A.
        • Malkova A.M.
        • Basantsova N.Y.
        • Zinchenko Y.S.
        • Kudryavtsev I.V.
        • Ershov G.A.
        • et al.
        Sarcoidosis as an autoimmune disease.
        Front Immunol. 2020; 10: 2933https://doi.org/10.3389/fimmu.2019.02933
        • Brjalin V.
        Sarcoidosis and chronic hepatitis C: a case report.
        WJG. 2012; 18: 5816https://doi.org/10.3748/wjg.v18.i40.5816
        • Ramos-Casals M.
        • Mañá J.
        • Nardi N.
        • Brito-Zerón P.
        • Xaubet A.
        • Sánchez-Tapias J.M.
        • et al.
        Sarcoidosis in patients with chronic hepatitis C virus infection: analysis of 68 cases.
        Medicine. 2005; 84: 69-80https://doi.org/10.1097/01.md.0000157577.69729.e6
        • Patel S.
        • Patel P.
        • Jiyani R.
        • Ghosh S.
        • Patel D.
        A rare case of hepatic sarcoidosis caused by hepatitis B virus and treatment-induced opportunistic infection.
        Cureus. 2020; https://doi.org/10.7759/cureus.10454
        • Esteves T.
        • Aparicio G.
        • Garcia-Patos V.
        Is there any association between sarcoidosis and infectious agents?: a systematic review and meta-analysis.
        BMC Pulm Med. 2016; 16: 165https://doi.org/10.1186/s12890-016-0332-z
        • Tana C.
        • Mantini C.
        • Cipollone F.
        • Giamberardino M.A.
        Chest imaging of patients with sarcoidosis and SARS-CoV-2 infection. Current evidence and clinical perspectives.
        Diagnostics. 2021; 11: 183https://doi.org/10.3390/diagnostics11020183