A 20-year-old male patient of Bangladeshi origin was referred to the outpatient clinic of our rheumatology department with polyarthritis (week 0, timeline of events shown in Additional file: Fig. S1). During the first visit, the patient reported polyarthralgia, fatigue and exertional dyspnea for 3–4 weeks. Weight loss, sore throat, and a non-productive cough had been present for 2 months and he had a single episode of elevated temperature one week prior. The patient was non-smoker and did not report any prior diseases, allergies or recent travels. He had moved to Austria 3 years prior and none of the household members shared any similar symptoms at any point in time. On clinical examination, the proximal interphalangeal (PIP), metacarpophalangeal (MCP) and carpo-metacarpal (CMC) joints were swollen and tender, subtle proximal muscular weakness in the lower extremities was noted. The skin over the PIP and DIP joints showed minimal non-palpable brownish discoloration, shoulders and upper arms were covered with small hyperkeratotic papules, Gottron`s sign was present (shown in Fig. a–c). Laboratory investigations showed slightly elevated C-reactive protein (CRP) 0.6 mg/dL, ferritin 3933 μg/L, aspartate aminotransferase (ASAT) 262 U/L, alanine aminotransferase (ALAT) 240 U/L, gamma-glutamyl transferase (GGT) 197 U/L, lactate dehydrogenase (LDH) 575 U/L, creatine kinase (CK) 246 U/L, and aldolase 20.8 U/L. Positive IgG antibodies (Ab) without IgM Ab against cytomegalo-, Epstein-Barr-, herpes simplex 1 and 2 and varicella-zoster-virus were detected. An interferon-releasing assay with mycobacterium tuberculosis ESAT-6 and CFP-10 antigens was non-reactive. Immuno-serology revealed positive anti-nuclear antibodies (ANA) with fine speckled pattern at a titer of 1:320, anti-Ro-60 Ab at 23 U/mL (ULN ≤ 10 U/mL) and, notably anti-MDA-5 Ab at 14 U/mL (ULN ≤ 10 U/mL). Microscopic examination of hematoxylin–eosin (H&E) stained sections of the skin revealed keratotic plugs within dilated follicular ostia similar to that seen in keratosis pilaris (shown in Fig. d). In addition, there was a sparse perivascular lymphocytic infiltrate and a marked perifollicular deposition of acidic mucins as seen in the alcian blue staining (shown in Fig. e). Computed tomography (CT) of the thorax (shown in Fig. I, II) at week 2 showed patchy ill-defined consolidations and areas of ground glass opacifications in the periphery of both lower lobes and subtle thickening of the bronchial walls and hepatic steatosis. Based on the respiratory and musculoskeletal symptoms, skin changes clinically and histologically compatible with dermatomyositis, laboratory, and auto Ab profile, anti-MDA5 associated hypomyopathic dermatomyositis with interstitial lung disease (DM-ILD) was suspected. The patient was admitted to our ward for bronchoscopy with bronchoalveolar lavage (BAL), muscle biopsy, and subsequent initiation of immunosuppressive therapy. A negative rt-PCR test for SARS-CoV-2 was obtained on admission. A 3-Tesla, gadolinium contrast enhanced MRI revealed T2 fat saturated bilateral hyperintense signal alterations of bilateral proximal thigh muscles compatible with myositis (shown in Fig. ). Meanwhile, the patient`s general condition and initial symptoms, including exertional dyspnea, cough and muscle pain had improved spontaneously. A fiberoptic bronchoscopy at week 4 showed multiple white nodular plaques, spanning from the larynx throughout most of the bronchial tract (shown in Fig. VII). Biopsies of the plaque lesions showed a subtle, non-specific lympho- and granulocytic infiltrate, lavage-cytology revealed mixed cell alveolitis. On the first day after bronchoscopy, the patient became subfebrile, and the routinely performed SARS-CoV-2 rt-PCR test was newly found positive, with a cycle threshold of 41.6, and 40.2 a few hours later. The SARS-CoV-2 rt-PCR from the BAL was negative. The patient was isolated under suspicion of an incipient SARS-CoV-2 infection and the muscle biopsy was postponed. Cycle threshold never declined below 40 and all SARS-CoV-2 tests over the following 3 days were negative. Therefore, analysis of IgG Ab against SARS-CoV-2 spike protein and nucleocapsid antigens was performed from a stored biobank sample from a timepoint where no PCR-positivity was yet detected. Both tested antibodies were positive, suggestive of a past COVID-19 infection. On further specific investigation, the patient reported, that 2.5 months prior to the presentation at our clinic, he spent several hours driving a car together with a friend, who was tested positive for SARS-CoV-2 the following day. The patient remembered elevated body temperature, cough, and general weakness after the car drive, retrospectively compatible with a mild course of COVID-19 but was never tested for SARS-CoV-2. The patient has not been vaccinated against SARS-CoV-2 at the time of presentation. Over the next few days, the patient developed severe dyspnea with peripheral oxygen saturations below 85% and required intensified oxygen therapy. Increasing CRP and LDH levels accompanied by dry cough raised the suspicion of pneumocystis pneumonia (PCP). Trimethoprim/sulfamethoxazole was initiated before the results from testing for beta-D-Glucan, galactomannan, and PCR and cultivation for pneumocystis were available. All of these came back negative. A second diagnostic bronchoscopy was performed and showed progressive areas of leukoplakia and a highly vulnerable mucosa. There was no presence of pneumocystis or other relevant pathogens in the BAL. Lung biopsy revealed acute bronchitis with complete squamous metaplasia, and findings which were consistent with organizing pneumonia (OP), or diffuse alveolar damage (DAD), as seen in both DM-ILD and COVID-related ARDS (shown in Fig. VIII). A follow-up CT of the chest at week 6 (shown in Fig. III, IV) revealed a progression of the ground glass opacities and consolidations in both lower lobes as well as a mediastinal lymphadenopathy. The emergence of blisters on the lips and oropharyngeal pain raised a suspicion of a herpetiform infection. Additional microbial tests were ordered and in the light of the rapid deterioration of the patient’s general and respiratory condition, a multifaceted approach was established with glucocorticoid pulse therapy (250 mg intravenous prednisolone), acyclovir and continued trimethoprim/sulfamethoxazole. Despite this and the high-flow nasal oxygen therapy, the respiratory condition worsened, requiring transfer to intensive care unit (ICU) at week 7. The continuous respiratory deterioration led to an invasive ventilation. CRP and IL-6-levels rose excessively (shown in Additional file: Fig. S2), while procalcitonin remained within normal limits, suggesting a hyperinflammatory state without relevant bacterial infection. The patient did not fulfill the criteria of a hemophagocytic lymphohistiocytosis diagnosis. The differential diagnosis of a COVID-19 relapse was also considered. We performed a thorough literature review of therapy for RP-ILD in DM [–] and COVID-19 cytokine storm and associated lung injury [–] that was available by March 2021. After an interdisciplinary discussion, we continued high-dose glucocorticoids and started cyclophosphamide and tacrolimus because of the rapid disease progression. Colchicine was added due to the hyperinflammatory state. The administration of caspofungin, piperacillin/tazobactam and doxycycline followed for infection prophylaxis under strong immunosuppression. Intravenous immunoglobulins as well as tocilizumab and JAK inhibitors were debated. However, as already implemented aggressive immunosuppressive combination remained without desired effect and there was a serious concern about potential harm of further escalation, we did not proceed with expansion of the immunosuppression, for which we only had insufficient evidence at the time of the event. Despite high ventilation efforts, initiation of veno-venous extracorporal membrane oxygenation (ECMO) was inevitable. Considering the fulminant diffuse bilateral lung damage and the patient`s young age, listing for a highly urgent lung transplantation was the ultima ratio. A compatible organ was allocated to the patient after a short waiting period, and the transplantation was successfully performed at week 11, after 4,5 weeks on ECMO. The primary organ function was excellent and the ECMO could be removed at the end of the operation. Pathological examination of the H&E and SFOG trichrome stained sections of explanted organ showed extensive fibrosis with a mixed pattern of organized diffuse alveolar damage and organizing pneumonia (shown in Fig. a, b). Moreover, thrombotic occlusions of multiple vessels were present, which is compatible with both, a COVID-19 associated lung disease and a myositis-associated ILD []. Standard triple immunosuppression, including tacrolimus, mycophenolate mofetil, as well as glucocorticoids was established. The respiratory situation improved steadily, and the patient could be weaned fast. Early physiotherapy contributed to the patient`s rapid recovery and he was transferred to a rehabilitation center and further outpatient care. One month after the lung transplantation, the antibody profile turned negative for ANA- and anti-MDA5 Ab, the anti-Ro-60 Ab were only marginally elevated (12 U/mL). On the follow-up visit, five months after the transplantation, ANA, anti-Ro Ab and anti-MDA5 Ab were negative. The patient did not report any symptoms on the follow-up visit twelve months after the lung transplantation. Using whole exome sequencing, we investigated genetic predisposition for “myositis” phenotype according to Human Phenotype Ontology (HPO) and Online Mendelian Inheritance in Man (OMIM) database and frequency of a sequence change in the population as per findings of various databases. An extended analysis of the associated genes (shown in Additional file: Supplement 3) did not detect any pathogenic mutation in our patient. A pre-transplantation HLA typing was also performed.