A 36-year-old female presented to the Emergency Department of the University Clinical Centre of Serbia in August 2020 with bilateral weakness and aches in the proximal muscles of the upper and lower extremities, limited limb movement, and poor tolerance of physical exertion. Symptoms had developed 4 weeks after hospitalisation for coronavirus disease 2019 (COVID-19) pneumonia and progressed rapidly over the next weeks (Fig). During her hospitalisation for COVID-19, she was treated with the corticosteroid (CS) methylprednisolone 0.5 mg/kg for 10 days, and prophylactic low-molecular-weight heparin, azithromycin (500 mg/day for 3 days), and antipyretics. Physical examination revealed weakness of the proximal muscles (grade 3/5) but no other abnormalities. Nasal swab screening for severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) by polymerase chain reaction test was negative. Blood work-up showed elevated levels of creatine kinase (CK) [28 731 U/L], myoglobin, and troponin (Table). Renal function tests were normal (blood urea nitrogen: 8.0 mmol/L, serum creatinine: 45 μmol/L, estimated glomerular filtration rate: >60 mL/min). Immunoserological analysis was positive for assessment of antinuclear antibodies (1:640) and myositis profile (Mi-2++ and Ro-52++). The patient was then referred to the Clinic of Allergy and Immunology of the same centre for further evaluation. Electromyoneurography of the upper and lower extremities revealed moderate-to-severe myopathic lesions in the proximal muscles with a pattern characteristic of inflammatory myopathies. Testing of respiratory muscle strength revealed decreased maximal inspiratory pressure of 62%. Lung computed tomography scan and echocardiography were normal. Muscle biopsy and magnetic resonance imaging were not performed due to temporary restrictions during the pandemic. The remainder of a thorough work-up was normal. Autoimmune myopathy associated with COVID-19 was suspected and the patient was prescribed high-dose CS (1 mg/kg/day) followed by pulse therapy of 500 mg/day methylprednisolone for 3 consecutive days. Methotrexate (22.5 mg/week) was introduced. No clinical or laboratory improvement was evident after 2 weeks, hence intravenous immunoglobulins (0.4 g/kg/day) were given for 5 days. This therapy led to significant clinical improvement and a gradual decline in muscle enzymes. During follow-up, a trial of CS withdrawal and methotrexate dose reduction resulted in worsening of proximal muscle weakness and rise in serum CK. After 1 year of follow-up, the patient remained on methotrexate 20 mg/week and prednisone 5 mg/day. Repeated immunoserological analysis was still positive for antinuclear antibodies (1:640) and anti–Mi-2 antibodies.

Myalgias, muscle weakness, and elevation of muscle enzymes are commonly seen in COVID-19 patients, but are typically resolved within a few weeks with conservative treatment. Direct viral invasion of muscles, toxic effects of cytokines and dysregulated immune stimulation have been proposed as possible mechanisms. There are several reports of COVID-19–related myositis/rhabdomyolysis with serum CK level as high as 427 656 U/L.1 2 Most patients recover with conservative treatment. In our patient, a mild increase in muscle enzymes was noticed during COVID-19 infection. Nonetheless early signs of myopathy may have been masked by the CS therapy prescribed for COVID-19 pneumonia. Due to the presence of anti–Mi-2 and anti–Ro-52 antibodies, which are characteristic of dermatomyositis, we carefully examined the skin and nailfolds, but there were no suggestive findings at first presentation or subsequent follow-up. A limitation of our work was the lack of muscle histopathology or magnetic resonance imaging. Nonetheless the clinical picture, 1-year disease course, electromyographic pattern typical of inflammatory myopathies, and persistent positivity for anti–Mi-2 antibodies suggest that SARS-CoV-2 infection may have triggered the development of autoimmune myopathy in our patient.

A case of COVID-19–associated inflammatory myopathy with severe facial, bulbar, proximal limb weakness, and elevated CK level, suggestive muscle biopsy and positive anti-SSA, anti–SAE-1, and anti-Ku antibodies, has been reported. The patient was successfully treated with a 5-day course of 1000 mg methylprednisolone.3 Nonetheless there are no data on the subsequent clinical course.

Recently, a COVID-19–associated myopathy caused by type I interferonopathy has been described.4 The patient presented with general weakness, myalgias, fever, bibasilar lung infiltrates, and significantly elevated serum CK and troponin levels. Immunohistochemical analysis of deltoid muscle biopsy specimen revealed abnormal expression of major histocompatibility complex class I antigen on sarcolemma and sarcoplasm, and presence of myxovirus resistance protein A on muscle fibres and capillaries. The authors speculated that increased expression of type I interferon was responsible for SARS-CoV-2 myopathy in their patient through up-regulation of proteins that are toxic to muscle cells.4 Nonetheless deposition of myxovirus resistance protein A in muscle fibres and capillaries is also an early feature of dermatomyositis. Given the lack of data on immunoserological analysis and follow-up of the patient, an early phase of dermatomyositis cannot be excluded.

The number of reports of autoimmune disease developing in patients with COVID-19 is increasing. Molecular mimicry has been proposed as a potential mechanism.5 A recent study identified three immunogenic linear epitopes with high sequence identity to SARS-CoV-2 proteins in patients with dermatomyositis, implying a possible contribution of SARS-CoV-2 to the development of autoimmune inflammatory myopathies.6 Additional mechanisms may also be involved, highlighting an urgent need to better understand the immune processes that underlie viral-induced autoimmunity in COVID-19.

Physicians should carefully evaluate patients who present with progressive elevation of muscle enzymes and be alert to the possible occurrence of autoimmune myopathy triggered by COVID-19. Early diagnosis facilitates timely initiation of adequate treatment, preventing long-term consequences and complications.

Concept or design: A Plavsic, S Arandjelovic, A Peric Popadic, S Raskovic, R Miskovic.
Acquisition of data: A Plavsic, J Bolpacic, R Miskovic.
Analysis or interpretation of data: A Plavsic, A Peric Popadic, S Raskovic, J Bolpacic, R Miskovic.
Drafting of the manuscript: A Plavsic, S Arandjelovic, J Bolpacic, R Miskovic.
Critical revision of the manuscript for important intellectual content: All authors.

All authors had full access to the data, contributed to the study, approved the final version for publication, and take responsibility for its accuracy and integrity.

All authors have disclosed no conflicts of interest.

This study received no specific grant from any funding agency in the public, commercial, or not-for-profit sectors.

Ethics approval was not required as per guidelines for publishing case reports of Ethics Committee of the University Clinical Centre of Serbia. Patient consent has been obtained concerning treatment and procedures, and the patient has given written informed consent to the publication.

1. Beydon M, Chevalier K, Al Tabaa O, et al. Myositis as a manifestation of SARS-CoV-2. Ann Rheum Dis 2021;80:e42. Crossref

2. Gefen AM, Palumbo N, Nathan SK, Singer PS, Castellanos-Reyes LJ, Sethna CB. Pediatric COVID-19–associated rhabdomyolysis: a case report. Pediatr Nephrol 2020;35:1517-20. Crossref

3. Zhang H, Charmchi Z, Seidman RJ, Anziska Y, Velayudhan V, Perk J. COVID-19–associated myositis with severe proximal and bulbar weakness. Muscle Nerve 2020;62:E57-60. Crossref

4. Manzano GS, Woods JK, Amato AA. Covid-19–associated myopathy caused by type I interferonopathy. N Engl J Med 2020;383:2389-90. Crossref

5. Kanduc D. From anti–SARS-CoV-2 immune responses to COVID-19 via molecular mimicry. Antibodies (Basel) 2020;9:33. Crossref

6. Megremis S, Walker TD, He X, et al. Antibodies against immunogenic epitopes with high sequence identity to SARS-CoV-2 in patients with autoimmune dermatomyositis. Ann Rheum Dis 2020;79:1383-6. Crossref

We report the first case of adult-onset Still’s disease (AOSD) following messenger ribonucleic acid (mRNA) coronavirus disease 2019 (COVID-19) vaccination presenting with severe myocarditis with acute heart failure and cardiogenic shock. A 72-year-old Chinese female, with history of subtotal thyroidectomy, hypertension, dyslipidaemia, and osteoporosis, developed gradual onset of fever, dyspnoea, sore throat, generalised arthralgia, malaise, and poor appetite 15 days after receiving the first dose of BNT162b2 mRNA COVID-19 vaccine, and was admitted 7 days after symptom onset in September 2021. Physical examination revealed fever, bilateral ankle oedema, and elevated jugular venous pressure. Polymerase chain reaction test for COVID-19 was negative on admission and throughout hospitalisation. Initial workup found increased C-reactive protein level of 182.3 mg/L (reference range, <7.6), severely elevated cardiac troponin I level of 7789 ng/L (reference range, <40) and N-terminal pro B-type natriuretic peptide level of 26 688 ng/L (reference range, <300), as well as deranged liver function. Chest X-ray showed progressive bilateral pulmonary infiltrates. Electrocardiography revealed fast atrial fibrillation with no other abnormalities including QRS or ST changes. Echocardiography showed severely reduced left ventricular ejection fraction of 20% with normal right ventricular function and no features of cardiomyopathy. Computed tomography of the thorax and upper abdomen did not show any features of malignancy, lymphadenopathy, interstitial lung disease or hepatosplenomegaly. Acute heart failure with reduced ejection fraction was diagnosed. The patient was prescribed empirical intravenous antibiotics and underwent septic workup with unremarkable results.

In view of the severe acute heart failure, the patient was transferred to the cardiac care unit of our hospital for further management on day 26 after vaccination. Significant investigation results are shown in the Table. Extensive viral panel tests (including enterovirus, influenza, and cytomegalovirus) were all negative. Shortly after transfer, the patient developed acute pulmonary oedema requiring 2 L/min oxygen and was treated with amiodarone, apixaban, and furosemide. On day 28 after vaccination, she developed cardiogenic shock requiring intensive care admission and was given noradrenaline and high-flow oxygen. Her atrial fibrillation persisted, and cardioversion was performed with consequent restoration of sinus rhythm.

The patient’s cardiac function gradually improved as evidenced by recovering left ventricular ejection fraction upon echocardiography. After stabilisation, coronary angiogram with endomyocardial biopsy was performed on day 34 after vaccination. There was no evidence of significant coronary artery disease; histology showed mononuclear infiltrate and viral studies were negative. Nonetheless the patient had persistent quotidian fever of >39°C and arthralgia (bilateral shoulders, wrists, and proximal interphalangeal joints). She also developed a diffuse erythematous maculopapular rash over the trunk and limbs, with skin biopsy revealing interface dermatitis. She was transferred to the rheumatology unit. Blood test results showed neutrophilic leucocytosis (leucocyte count: 20.99×10⁹/L), hyperferritinaemia level of 68 913 pmol/L (reference range, 29-337), deranged liver function, and elevated inflammatory markers (erythrocyte sedimentation rate and C-reactive protein); autoimmune panel was unremarkable except for an antinuclear antibody titre of 1:80 (Table). Extensive septic workup after microbiologist consultation, including viral panel serology, was negative. Cardiac contrast magnetic resonance imaging on day 44 after vaccination showed diffuse myocardial oedema, consistent with myocarditis. Subsequent contrast positron emission tomography–computed tomography showed reactive lymphadenopathy but no features of malignancy.

The diagnosis of AOSD was made based on the Yamaguchi criteria and the Fautrel criteria.1 The patient was treated with oral prednisolone 30 mg daily. Subsequent investigations revealed cytomegalovirus pp65 antigenaemia, hence valganciclovir was prescribed. Treatment was well-tolerated. Her fever gradually subsided, and leucocyte count and C-reactive protein level were normalised although serum ferritin, erythrocyte sedimentation rate and liver enzymes remained elevated. Three months after discharge, the patient was clinically well with prednisolone tapered down to 5 mg daily. Echocardiographic reassessment demonstrated full recovery with left ventricular ejection fraction of 60%.

The pathogenesis of AOSD is hypothesised to be multifactorial and autoinflammatory, contributed by genetic predisposition, environmental triggers, and eventual immune dysregulation.1 Infections can trigger AOSD, as pathogen-associated molecular patterns of pathogenic organisms or damage-associated molecular patterns from damaged host cells activate the innate immune system through pattern recognition receptors such as toll-like receptors on neutrophils and macrophages. In the presence of dysregulation, cytokine storm with overproduction of interleukin (IL)-6, IL-8, IL-17, tumour necrosis factor-alpha, IL-1β, and IL-18 can lead to the hyperinflammatory state of AOSD.1 The mRNA COVID-19 vaccines also stimulate innate immune responses since the mRNA can act as both an immunogen encoding the viral antigen and an adjuvant that directly stimulates pattern recognition receptors, thus mimicking an infection.2 Immune response after vaccination, such as production of cytokines, may trigger AOSD in a similar manner to infections.

To the best of our knowledge, there have not been reports of post–COVID-19 vaccine AOSD presenting with severe myocarditis with acute heart failure and cardiogenic shock. This case highlights the possibility of such an atypical presentation of post–COVID-19 vaccine AOSD, and the importance of monitoring for signs and symptoms of systemic inflammatory diseases in post–COVID-19 vaccine myocarditis patients (especially if the signs and symptoms are persistent). A high index of suspicion should be maintained and, if indicated, extensive workup carried out to establish a diagnosis so that appropriate treatment (such as corticosteroids or other immunosuppressants) can be offered.

Myocarditis is a rarely reported complication of AOSD.1 Nonetheless all reports of post–COVID-19 vaccination AOSD to date, including our case, had some features of myocarditis.3 4 5 Further studies are warranted to determine whether myocarditis is more likely to occur in post–COVID-19 vaccine AOSD, and whether post–COVID-19 vaccine myocarditis and post–COVID-19 vaccine AOSD are part of a spectrum of diseases.

Physicians should be reminded that both mRNA COVID-19 vaccine–related myocarditis and AOSD are exceedingly rare. As illustrated in this report, a comprehensive evaluation to exclude more common causes of heart failure and myocarditis should be performed first. Vaccine-related myocarditis and AOSD should be a diagnosis of exclusion, and all efforts should be made to not miss other possible aetiologies. It is important to emphasise that given the extreme rarity of such adverse reactions, the overall benefits of COVID-19 vaccines still far outweigh the risks for the general population.3 4 5

In conclusion, although exceedingly rare, severe myocarditis with acute heart failure and cardiogenic shock is a possible initial presentation of AOSD after mRNA COVID-19 vaccination. After exclusion of more common aetiologies, it is important to consider AOSD as one of the differential diagnoses in the presence of compatible features following COVID-19 vaccination, such that appropriate and timely workup and treatment can be offered.

Concept or design: All authors.
Acquisition of data: AKC Kan, WWY Yeung.
Analysis or interpretation of data: All authors.
Drafting of the manuscript: AKC Kan.
Critical revision of the manuscript for important intellectual content: All authors.

All authors had full access to the data, contributed to the study, approved the final version for publication, and take responsibility for its accuracy and integrity.

All authors have disclosed no conflicts of interest.

This study received no specific grant from any funding agency in the public, commercial, or not-for-profit sectors.

The patient was treated in accordance with the Declaration of Helsinki and has provided informed consent for all procedures and publication.

1. Gerfaud-Valentin M, Jamilloux Y, Iwaz J, Sève P. Adult-onset Still’s disease. Autoimmun Rev 2014;13:708-22. Crossref

2. Teijaro JR, Farber DL. COVID-19 vaccines: modes of immune activation and future challenges. Nat Rev Immunol 2021;21:195-7. Crossref

3. Leone F, Cerasuolo PG, Bosello SL, et al. Adult-onset Still’s disease following COVID-19 vaccination. Lancet Rheumatol 2021;3:e678-80. Crossref

4. Sharabi A, Shiber S, Molad Y. Adult-onset Still’s disease following mRNA COVID-19 vaccination. Clin Immunol 2021;233:108878. Crossref

5. Magliulo D, Narayan S, Ue F, Boulougoura A, Badlissi F. Adult-onset Still’s disease after mRNA COVID-19 vaccine. Lancet Rheumatol 2021;3:e680-2. Crossref

Aplastic anaemia is a rare disease in young children that arises from damage to the bone marrow and resident haematopoietic stem cells. Affected patients are susceptible to bacterial and invasive fungal infections due to profound persistent neutropenia.1 Pneumocystis jirovecii pneumonia (PJP) is rarely reported in patients with aplastic anaemia. We review a case of early presentation of PJP associated with very severe aplastic anaemia and the associated literature.

A 31-month previously healthy boy with normal growth and development presented with a 2-month history of profound epistaxis, easy bruising and petechial rash. Apart from a 1-day history of fever prior to admission, he displayed no constitutional symptoms. There was no history suggestive of consumption of herbal or over-the-counter medicine and no family history of haematological disease or malignancy. He was an only child. Complete blood picture revealed pancytopenia (haemoglobin level of 7 g/dL, white blood cell count of 0.3×10⁹/L, platelet count of 3×10⁹/L, reticulocyte count of <0.2%) and after further workup he was diagnosed with very severe aplastic anaemia. Liver function tests were deranged with raised alanine aminotransferase level of 1687 IU/L, alkaline phosphatase level of 347 IU/L, gamma-glutamyl transferase level of 128 IU/L, and total bilirubin level of 11 μmol/L, but the levels of ammonia and lactate were normal. Ultrasound of the liver was suggestive of mild hepatic parenchymal disease such as hepatitis.

Bone marrow trephine showed severe deficiency of all cell lines, markedly hypocellular marrow (overall cellularity <10%) and no abnormal infiltrations. Immunophenotyping of the lymphoid population revealed marked lymphopenia with a reversed CD4:CD8 ratio at 0.3:1. His CD4 count was very low. Within one week of presentation, he developed antibiotic-resistant pneumonia. He was commenced initially on piperacillin/tazobactam but switched to meropenem and micafungin due to fever and progressive chest X-ray changes of bilateral infiltrates (Fig 1). He had increased respiratory distress and required support with high-flow oxygen therapy in the paediatric intensive care unit. Computed tomography scan of the chest revealed bilateral extensive patchy changes, most severe at both anterior segments of the upper lobe and posterior segments of the lower lobes (Fig 2). Prompt bronchoalveolar lavage was performed and Grocott methenamine silver staining revealed the pathogen to be P jirovecii (Fig 3). Bronchoalveolar lavage culture also showed scanty growth of alpha-haemolytic streptococcus (<1000 CFU/mL) with no white cells seen on microscopy. He was treated with a 21-day course of co-trimoxazole (120 mg/kg/day) and oral prednisolone (2 mg/kg/day for 5 days, 1 mg/kg/day for 5 days, then 0.5 mg/kg/day for 11 days). The pneumonia gradually resolved and his liver function tests normalised. Nonetheless he remained pancytopenic.

No test was suggestive of an inherited marrow failure syndrome or recent infection. Bronchoalveolar lavage for viral polymerase chain reaction and culture, Legionella culture, and acid-fast bacillus culture were also negative. No drug history was identified that could account for his aplastic anaemia. Autoimmune screening (immunoglobulin A [IgA], IgG, IgM, complement component 3, complement component 4, antinuclear antibody, and anti-extractable nuclear antigen) was likewise insignificant.

The child was commenced on immunosuppressive therapy with methylprednisolone, cyclosporin A, and lymphocyte immune globulin, antithymocyte globulin after treatment of the PJP. He has been on immunosuppressive therapy for >1 year and is demonstrating a good response to treatment.

Aplastic anaemia is a potentially life-threatening clinical syndrome characterised by pancytopenia with a hypocellular bone marrow in the absence of abnormal infiltration or increased reticulin.2 It is a rare disorder with an incidence of about two cases per million population per year. Nonetheless the incidence is two- to three-fold higher in Asia than in Europe.3 4

Persistent neutropenia is the major risk factor for the development of all types of infection in patients with aplastic anaemia, while bacterial and invasive fungal infections are the major causes of mortality.1 2 Respiratory tract infection is one of the common manifestations of infection in children with aplastic anaemia, and pneumonia in particular can be life-threatening.2 Detection of an infectious agent may be possible in only approximately 12% to 20% of cases, and diagnosis is mainly based on clinical symptoms and radiological investigations.5 6 Previous reviews of respiratory infection in patients with severe aplastic anaemia and very severe aplastic anaemia revealed common causes such as invasive fungal infection (Aspergillus and Zygomycetes) and respiratory viral infections (influenza A and B, respiratory syncytial virus, parainfluenza virus, adenovirus, and cytomegalovirus).2 5 7 Pneumocystis jirovecii pneumonia is rarely reported in patients who have commenced immunosuppressive therapy, and no case of PJP has been reported in three large studies of patients prescribed antithymocyte globulin and cyclosporin A.1 8

The risk of PJP in patients with aplastic anaemia has not been defined in the literature, but the risk should be low since the T cells are not defective.1 T cells (CD4+) are crucial for PJP clearance as they coordinate inflammatory responses in the host by recruiting and activating effector cells.9 Only three cases of PJP in patients with Diamond–Blackfan anaemia and one case in a patient with Fanconi’s anaemia have been reported and all were receiving high-dose corticosteroids.10 11 Our patient is possibly the first reported case of PJP in a patient with aplastic anaemia not yet started on any immunosuppressive therapy. The development of PJP was probably due to the immune deficiency of aplastic anaemia rather than the aetiology, as evidenced by the reversed CD4:CD8 ratio. Patients with aplastic anaemia are usually not considered to be at risk of PJP, hence prophylaxis is not routinely prescribed.12 Nonetheless PJP in aplastic anaemia should not be overlooked as the mortality of PJP in human immunodeficiency virus–seronegative patients is significant (32%-50%).13 14 Our patient developed PJP within a week of diagnosis, before he was started on any immunosuppressive therapy. This raises a broader question of whether PJP prophylaxis (eg, co-trimoxazole, dapsone and pentamidine) should be considered in patients with aplastic anaemia, especially those who fulfil the criteria of very severe aplastic anaemia.

The Red Book 2018 suggests that standard precautions should be taken,15 while the Centers for Disease Control and Prevention in the United States16 and Health Protection Scotland17 both recommend that patients with PJP should not share a hospital room with other immunocompromised patients. Although there have been clusters of PJP cases reported in wards of immunocompromised patients, and a study has also shown that airborne person-to-person transmission of P jirovecii is possible, we believe there is insufficient evidence to warrant mandatory isolation.18 It is more important to identify patients at risk of PJP and commence prophylaxis.19

Pneumocystis jirovecii infection is probably due to immune deficiency in aplastic anaemia, not the aetiology of aplastic anaemia. Clinical and radiological pictures of PJP in a patient with aplastic anaemia are not specific for P jirovecii. All such patients with symptoms of lung infection resistant to antibacterial and antifungal therapy should be examined for PJP. Our patient is possibly the first reported case of PJP in a patient with aplastic anaemia prior to commencement of immunosuppressive therapy. Although standard guidelines do not recommend PJP prophylaxis in patients with aplastic anaemia, further studies should assess whether the benefits of chemoprophylactic agents outweigh the risks in those considered to have very severe aplastic anaemia.

Concept or design: KKY Leung, KL Hon.
Acquisition of data: KKY Leung, KL Hon.
Analysis or interpretation of data: All authors.
Drafting of the manuscript: KKY Leung, KL Hon.
Critical revision of the manuscript for important intellectual content: All authors.

All authors had full access to the data, contributed to the study, approved the final version for publication, and take responsibility for its accuracy and integrity.

As an editor of the journal, KL Hon was not involved in the peer review process. Other authors have disclosed no conflicts of interest.

This study received no specific grant from any funding agency in the public, commercial, or not-for-profit sectors.

The patient was treated in accordance with the Declaration of Helsinki, with informed consent provided for treatment, procedures, and publication.

1. Valdez JM, Scheinberg P, Young NS, Walsh TJ. Infections in patients with aplastic anemia. Semin Hematol 2009;46:269-76. Crossref

2. Dezern AE, Brodsky RA. Clinical management of aplastic anemia. Expert Rev Hematol 2011;4:221-30. Crossref

3. Shimamura A, Nathan DG. Acquired aplastic anemia and pure red cell aplasia. In: Orkin SH, Nathan DG, Ginsburg D, Look AT, Fisher DE, Lux SE, editors. Nathan and Oski’s Hematology of Infancy and Childhood. Philadelphia (PA): Elsevier; 2014: 275-306.

4. Montané E, Ibáñez L, Vidal X, et al. Epidemiology of aplastic anemia: a prospective multicenter study. Haematologica 2008;93:518-23. Crossref

5. Pawelec K, Salamonowicz M, Panasiuk A, Matysiak M, Demkow U. Respiratory and systemic infections in children with severe aplastic anemia on immunosuppressive therapy. Adv Exp Med Biol 2013;788:417-25. Crossref

6. Rudan I, El Arifeen S, Bhutta ZA, et al. Setting research priorities to reduce global mortality from childhood pneumonia by 2015. PLoS Med 2011;8:e1001099. Crossref

7. Quarello P, Saracco P, Giacchino M, et al. Epidemiology of infections in children with acquired aplastic anaemia: a retrospective multicenter study in Italy. Eur J Haematol 2012;88:526-34. Crossref

8. Cordonnier C, Cesaro S, Maschmeyer G, et al. Pneumocystis jirovecii pneumonia: still a concern in patients with haematological malignancies and stem cell transplant recipients. J Antimicrob Chemother 2016;71:2379-85. Crossref

9. Otieno-Odhiambo P, Wasserman S, Hoving JC. The contribution of host cells to pneumocystis immunity: an update. Pathogens 2019;8:52. Crossref

10. Huh WW, Gill J, Sheth S, Buchanan GR. Pneumocystis carinii pneumonia in patients with Diamond–Blackfan anemia receiving high-dose corticosteroids. J Pediatr Hematol Oncol 2002;24:410-2. Crossref

11. Pedersen FK, Hertz H, Lundsteen C, Platz P, Thomsen M. Indication of primary immune deficiency in Fanconi’s anemia. Acta Paediatr Scand 1977;66:745-51. Crossref

12. Killick SB, Bown N, Cavenagh J, et al. Guidelines for the diagnosis and management of adult aplastic anaemia. Br J Haematol 2016;172:187-207.Crossref

13. Gerrard JG. Pneumocystis carinii pneumonia in HIV-negative immunocompromised adults. Med J Aust 1995;162:233-5. Crossref

14. Kovacs JA, Hiemenz JW, Macher AM, et al. Pneumocystis carinii pneumonia: a comparison between patients with the acquired immunodeficiency syndrome and patients with other immunodeficiencies. Ann Intern Med 1984;100:663-71. Crossref

15. American Academy of Pediatrics. Committee on Infectious Diseases. Red Book (2018): Report of the Committee on Infectious Diseases. 31st edition. Kimberlin DW, Brady MT, Jackson MA, editors. Elk Grove Village (IL): American Academy of Pediatrics; 2018: 651-6.

16. Centers for Disease Control and Prevention, Infectious Diseases Society of America. Guidelines for the prevention and treatment of opportunistic infections in adults and adolescents with HIV. 2009. Available from: https://www.idsociety.org/practice-guideline/prevention-and-treatment-of-opportunistic-infections-among-adults-and-adolescents/. Accessed 18 Oct 2020.

17. Health Protection Scotland. Information for staff on Pneumocystis Pneumonia (PcP). 2020. Available from: https://hpspubsrepo.blob.core.windows.net/hps-website/nss/2117/documents/1_pcp-staff-information-2020-01.pdf. Accessed 18 Oct 2020.

18. Vargas SL, Ponce CA, Gigliotti F, et al. Transmission of Pneumocystis carinii DNA from a patient with P. carinii pneumonia to immunocompetent contact health care workers. J Clin Microbiol 2000;38:1536-8. Crossref

19. Cooley L, Dendle C, Wolf J, et al. Consensus guidelines for diagnosis, prophylaxis and management of Pneumocystis jirovecii pneumonia in patients with haematological and solid malignancies, 2014. Intern Med J 2014;44:1350-63. Crossref

A 40-year-old nulliparous woman carried the index dichorionic diamniotic (DCDA) twin pregnancy, conceived in 2014 by in vitro fertilisation due to unexplained infertility. Antenatal investigations were all unremarkable.

At 26 weeks and 1 day of gestation she presented to our local delivery suite with signs of preterm labour. Examination revealed the cervix to be fully dilated. Maternal corticosteroids for foetal lung maturation, prophylactic antibiotics and magnesium sulphate infusion for neuroprotection were administered. Twin 1 (T1) was delivered vaginally 4 hours after admission. The baby weighed 800 g, with Apgar scores (AS) of 6 at 1 minute and 8 at 5 minutes. The first blood gas showed a pH of 7.37.

Soon after, uterine contractions subsided spontaneously and the cervix quickly closed. Twin 2 (T2) membranes remained intact. After counselling, the couple opted for delayed interval delivery (DID), aiming to enhance the lung maturity of T2. The cord of T1 was ligated and placed in the vagina. Oral nifedipine was added to maintain uterine quiescence. Twelve hours later, the patient developed regular uterine contractions with fever of 37.8°C. Vaginal examination revealed a fully dilated cervix with bulging membranes and shoulder presentation of T2, converted manually to cephalic presentation following uterine relaxation with the tocolytic atosiban. Twin 2 was born vaginally with a twin-to-twin delivery interval of 14 hours and weighing 780 g with AS of 4 at 1 minute, 5 at 5 minutes and 7 at 10 minutes and arterial cord gas of pH 6.94. A placental swab grew Escherichia coli and a high vaginal swab grew Pseudomonas aeruginosa. The placenta showed acute chorioamnionitis.

Twin 1 had acute respiratory distress syndrome and was intubated up to day 27 of life. The baby was discharged at 4 months of age with severe bronchopulmonary dysplasia. Mild speech delay at 3 years of age required additional therapy. Twin 2 benefited from antenatal corticosteroid and was weaned off mechanical ventilation on day 17 of life and discharged home at 3 months of age. Both twins have normal growth and development at the age of 6 years.

A 39-year-old woman carried the index monochorionic diamniotic twin pregnancy, conceived naturally in late 2019. Antenatal investigations and ultrasound scans every 2 weeks were unremarkable until 24 weeks and 5 days of gestation when she was admitted with preterm prelabour rupture of membranes. Maternal corticosteroids for foetal lung maturation and prophylactic antibiotics were administered. Maternal leukocytosis of 15.5 × 10⁹/L and raised C-reactive protein of 16.3 g/L were noted, but high vaginal swab and mid-stream urine cultures were negative. Three days later, she went into spontaneous labour. Magnesium sulphate infusion was commenced for neuroprotection. Twin 1 was delivered vaginally and weighed 670 g. Apgar scores were 6 at 1 minute and 8 at 5 minutes, and arterial cord gas pH was 7.349.

Uterine contractions subsided afterwards and the cervix closed. In view of extreme prematurity, the couple opted for DID. High ligation of the cord was performed (Fig). The patient continued to receive intravenous ampicillin, metronidazole and oral erythromycin with monitoring of vital signs. There were no signs of sepsis, and serial blood tests revealed that white cell count and C-reactive protein had normalised after delivery of T1. Serial cardiotocography of T2 showed normal foetal heart rate pattern and ultrasound confirmed normal middle cerebral artery peak systolic velocity. Nine days later, at 26 weeks and 4 days gestation, preterm prelabour rupture of membranes of T2 occurred. Labour was induced by syntocinon infusion but fresh per vaginal bleeding was noted 5 hours later. Cardiotocography showed a non-reassuring pattern but the cervix was only 3 cm dilated. Emergency lower segment caesarean section was performed for suspected foetal distress. Twin 2 was delivered weighing 860 g with AS of 6 at both 1 and 5 minutes, and arterial cord gas pH of 7.4.

Apart from severe respiratory distress syndrome, T1 had E coli septicaemia, a large left subdural haematoma and right intraventricular haemorrhage, disseminated intravascular coagulopathy, and seizures. Despite intensive treatment, T1 deteriorated and died on day 17 of life. Twin 2 remained stable and was extubated to non-invasive ventilation on day 9. Cranial ultrasounds were normal. Twin 2 was discharged home at 3 months of age and remains well at 1 year of age at the time of writing.

To the best of our knowledge these two cases are the first reported DID in Hong Kong. Twin pregnancies are at higher risk of preterm delivery and DID has been proposed to improve survival of the second twin. In a recent systematic review of 492 multifetal pregnancies managed with DID, the reported twin-to-twin delivery interval ranged from 1 to 153 days with a median of 29 days. Delayed interval delivery was associated with significantly improved perinatal survival of the remaining foetus compared with the co-twin (odds ratio=5.22, 95% confidence interval=2.95-9.25).1 A delay as short as one day may be sufficient for steroid treatment to enhance foetal lung maturation, as illustrated by Case 1: T1 had respiratory distress syndrome and required a longer duration of intubation and hospitalisation than T2. Although T2 had acute foetal distress secondary to in-utero infection and shoulder presentation, T2 recovered rapidly from the acute event with no long-term sequelae.

The beneficial effect of DID is more often described in DCDA twins (odds ratio=14.89, 95% confidence interval=6.19-35.84).1 Data on monochorionic diamniotic twins are sparse since monochorionicity is often regarded as a contra-indication for DID due to the potential risk associated with vascular anastomoses between the twins.2 Nonetheless with complete occlusion of the first twin’s umbilical vessels on delivery, the risk of vascular instability for T2 should be minimised, as illustrated in our Case 2.3 4 Interestingly in Case 2, only T1 had in-utero infection with consequent E coli septicaemia. It is possible that the inter-twin membrane acted as a barrier and prevented or delayed spread of infection to the second twin.

There are several elements to consider when deciding to opt for DID. First, the underlying cause of preterm labour is often unknown at the time of presentation. If there is subclinical infection or placental abruption, leaving the second twin in utero may be detrimental. Second, a secondary ascending infection may occur following delivery of the first twin. Obstetricians should carefully consider the risks and benefits of DID versus those of delivery at periviable or extreme preterm gestation. Extra precautions should be taken before and after opting for DID, including a high ligature of the first twin’s cord, antibiotic cover, and close surveillance of maternal and foetal well-being.5

Concept or design: All authors.
Acquisition of data: All authors.
Analysis or interpretation of data: All authors.
Drafting of the manuscript: ASY Hui, TY Leung.
Critical revision of the manuscript for important intellectual content: All authors.

All authors had full access to the data, contributed to the study, approved the final version for publication, and take responsibility for its accuracy and integrity.

All authors have disclosed no conflicts of interest.

This study received no specific grant from any funding agency in the public, commercial, or not-for-profit sectors.

This study was approved by the Joint Chinese University of Hong Kong–New Territories East Cluster Clinical Research Ethics Committee (Ref No.: 2021.159). Both patients provided informed consent for the publication of non-identifiable information.

1. Cheung KW, Seto MT, Wang W, Lai CW, Kilby MD, Ng EH. Effect of delayed interval delivery of remaining fetus(es) in multiple pregnancies on survival: a systematic review and meta-analysis. Am J Obstet Gynecol 2020;222:306-19.e18. Crossref

2. Minakami H, Honma Y, Izumi A, Sayama M, Sato I. Emergency cervical cerclage after the first delivery in a twin pregnancy with dichorionic placenta. Am J Obstet Gynecol 1995;173:345-6. Crossref

3. Ting YH, Poon LC, Tse WT, et al. Outcome of radiofrequency ablation for selective fetal reduction before vs at or after 16 gestational weeks in complicated monochorionic pregnancy. Ultrasound Obstet Gynecol 2021;58:214-20. Crossref

4. Lu J, Ting YH, Law KM, Lau TK, Leung TY. Radiofrequency ablation for selective reduction in complicated monochorionic multiple pregnancies. Fetal Diagn Ther 2013;34:211-6. Crossref

5. Porreco RP, Farkouh LJ. Multifetal gestation: role of delayed-interval delivery. Available from: https://www.uptodate.com/contents/multifetal-gestation-role-of-delayed-interval-delivery. Accessed 4 Oct 2021.

A 67-year-old man with kappa light chain multiple myeloma (MM) had a baseline negative skeletal survey and had undergone dual-tracer positron emission tomography–computed tomography (CT) with fluorine-18 fluorodeoxyglucose and carbon-11 acetate. An initial biochemical response to combined chemotherapy with bortezomib, thalidomide and dexamethasone later plateaued; therefore, he was switched to second-line chemotherapy with ixazomib, lenalidomide and dexamethasone. He then developed progressively deranged liver function and new-onset pancytopenia with fever during the first cycle. Ultrasound revealed multiple bi-lobar hepatic hypoechoic lesions, some with a central echogenic focus surrounded by hypoechoic rim (target appearance), suggesting possible hepatic candidiasis. Nonetheless there was progressive worsening of liver function and recurrent fever despite intravenous antifungal therapy. Urgent multiphasic CT revealed a small arterial enhancing nodule in hepatic segment V with washout. A newly developed lytic sacral lesion was suspected to be myeloma involvement. The liver CT 3 weeks later showed an interval increase in size and number of these liver lesions with similar enhancement pattern. Multifocal hepatocellular carcinoma (HCC) was one of the prime differential diagnoses (Fig 1). Hepatitis B and C tests were negative. Tumour markers including alpha-fetoprotein were normal. Due to the rapid interval lesion enlargement, absence of risk factor for HCC, and the need to exclude possible opportunistic fungal infection, ultrasound-guided liver biopsy was performed and confirmed myeloma involvement.

A 51-year-old woman with lambda light chain MM diagnosed in 2011 was in remission following treatment with bortezomib, thalidomide and dexamethasone. Autologous peripheral blood stem cell transplantation was performed but she developed disease relapse 18 months later, salvaged by combined bortezomib-melphalan-prednisone. She presented within a year with a second relapse and a 1-week history of fever, increasing diffuse bone pain and abdominal distention. Mild hepatosplenomegaly was noted on physical examination. Pancytopenia was evident (haemoglobin 7.6 g/dL, platelet count 17×10⁹/L, white blood cell count 1.7×10⁹/L). Blood culture and hepatitis markers were negative. Ultrasound revealed a hypoechoic lesion at the right hepatic lobe, bi-lobar hepatic hyperechoic lesions with hypoechoic rim and mild ascites. In the presence of her high swinging fever, liver abscesses were suspected. Hepatosplenomegaly was confirmed on CT performed 1 day later. In addition, multiple hypodense liver lesions, most of which were subcapsular, were observed. They showed arterial contrast enhancement and became hypo-enhancing in the portovenous phase. No rim-enhancing lesions were present to suggest abscess formation. There were innumerable lytic lesions in bone, including partial collapse of T11 and L1 and a lytic lesion at the right transverse process of T10 with enhancing soft tissue mass (Fig 2). Overall features suggested progressive disease with presumably myelomatous involvement of liver and bone. She was prescribed two cycles of lenalidomide, bortezomib, and dexamethasone followed by four more cycles of lenalidomide and dexamethasone. Follow-up CT showed interval resolution of the previous noted bi-lobar liver lesions and sub-centimetre hypo-enhancing focus representing post-treatment change or residual disease, supporting the presumption of liver extraosseous myeloma (EM). Repeat bone marrow examination revealed hypercellular marrow with residual plasma cell myeloma. She then underwent hematopoietic stem cell transplantation.

Extraosseous myeloma is an uncommon form of MM associated with poorer prognosis and survival.1 2 It is caused by migration of malignant plasma cells from the bone marrow microenvironment. The presence of extraosseous involvement of MM is not uncommon; it has been previously reported in more than 63% of patients in an autopsy series, with 28 to 30% having liver involvement.1 The reticuloendothelial system (liver, spleen and lymph nodes) is the most commonly affected extraosseous site.2 Although well documented in the pathology literature, this clinical entity remains under-recognised and underreported in radiology.

We report two cases of multifocal EM of the liver in two Chinese patients from a tertiary hospital in Hong Kong, mimicking multifocal HCC on multiphasic CT. To the best of our knowledge, this pattern has not been reported previously. First, we aim to increase radiologist awareness of the hypervascular multinodular pattern of liver EM. Second, HCC is common in Southeast Asia including Hong Kong and remains an imaging diagnosis with no histological confirmation required prior to treatment. There are overlapping imaging features of both extraosseous MM in liver and HCC. Hence, biopsy is needed for differentiation.

Imaging findings of EM are highly variable and non-specific. The two most common presentations are the more common diffuse form with hepatomegaly in the absence of a focal lesion due to diffuse liver parenchymal infiltration and the focal nodular form with hypodense non-calcified nodule and minimal enhancement. On ultrasound, focal patterns of involvement can be hypoechoic, hyperechoic, mixed or target (isoechoic nodule with hypoechoic rim). On CT, focal lesions are generally described as hypoattenuating with minimal enhancement and no calcification. On magnetic resonance imaging, focal lesions may be hyper- or hypo-intense on T1-weighted images and hyperintense on T2-weighted images with minimal gadolinium enhancement.2 3 Scarce literature has documented hypervascular enhancement patterns with washout on multiphasic CT or magnetic resonance imaging, and only few case reports have reported only a solitary focal mass.4 5 6 The multinodular form with hypervascular enhancement pattern has not been reported before. Currently there remains a lack of knowledge about distinction of EM of liver from other hypervascular liver tumours due to its rarity. Arterial phase imaging is vital for lesion detection since some of the lesions may be too small and too vaguely hypo-enhancing to be detected during portovenous or delayed phases. The differential diagnoses with multiple hypervascular liver masses commonly include multifocal HCC and hypervascular metastases. Its significance is underestimated, especially in areas where HCC is endemic, such as Southeast Asia. Clinicians and even radiologists may misdiagnose these lesions as HCC, which is an imaging diagnosis, and specific oncological treatment will be given without histological confirmation of the lesion leading to mismanagement. It is important to bear in mind the possibility of myeloma of liver in patients with known myeloma who present with hypervascular mass on CT. We advocate a diagnostic approach with emphasis on the use of multiphasic cross-sectional studies including CT for detection, and risk stratification (by alpha-foetal protein, and hepatitis status). If these appear atypical of HCC or EM involvement of liver, a timely biopsy to confirm the diagnosis is recommended to avoid misdiagnosis and subsequent mismanagement.

There are other points in the diagnostic challenge posed by EM of the liver that influence clinical management.

First, the variable sonographic appearance of multinodular hepatic lesions, including target appearance mimicking hepatic candidiasis, and hypoechoic lesions raising a suspicion of pyogenic abscesses, may lead to unnecessary antifungal or antibacterial treatment.

Second, only one single large lesion was initially seen in our first case on multiphasic CT. This was in concordance with multiple previous studies that reported cases of EM of liver where lesions are more conspicuous on ultrasound than on CT.3 Regarding the hepatic lesions on CT from our cases, they were most conspicuous on the arterial phase, while the smaller ones may be isoattenuating or minimally hypo-enhancing on portovenous or delayed phases. In addition, most lesions had a subcapsular location in the liver, an important area to review. Knowing that this entity may be underdiagnosed, further studies are needed to determine the most sensitive initial staging modality to look for liver involvement. Based on our cases, both ultrasound and multiphasic CT (including arterial, portovenous, and 5-minute delayed) phases play an important role in initial screening, subsequent characterisation, and in guiding biopsy.

Extraosseous myeloma of the liver is a rare and under-recognised entity associated with poorer prognosis and survival. Imaging features are non-specific but can mimic multifocal HCC on multiphase CT. We advocate the use of multiphasic CT (including arterial phase) for detection. The presence of hypervascular liver masses in patients with known MM should alert radiologists to this diagnosis. Definitive diagnosis should be by tissue biopsy if there is a mismatch between clinical risk factors and imaging, especially in areas endemic for HCC.

Concept or design: HM Kwok, ES Lo.
Acquisition of data: HM Kwok, ES Lo.
Analysis or interpretation of data: All authors.
Drafting of the manuscript: HM Kwok, ES Lo.
Critical revision of the manuscript for important intellectual content: HM Kwok, ES Lo.

All authors had full access to the data, contributed to the study, approved the final version for publication, and take responsibility for its accuracy and integrity.

All authors have disclosed no conflicts of interest.

We would like to express our gratitude to the haematology and oncology physicians of Princess Margaret Hospital, Hong Kong, for their professional patient care and invaluable contribution to the understanding of a novel disease.

Case 1 of the study was accepted as oral presentation in the 19th Asian Oceanian Congress of Radiology 2021, Malaysia.

This study received no specific grant from any funding agency in the public, commercial, or not-for-profit sectors.

This study was approved by the Kowloon West Cluster Research Ethics Committee [Ref No.: KW/EX-21-054 (157-19)]. Patients were treated in accordance with the Declaration of Helsinki, with informed consent provided for treatment, procedures, and publication.

1. Oshima K, Kanda Y, Nannya Y, et al. Clinical and pathologic findings in 52 consecutively autopsied cases with multiple myeloma. Am J Hematol 2001;67:1-5. Crossref

2. Moulopoulos LA, Granfield CA, Dimopoulos MA, Kim EE, Alexanian R, Libshitz HI. Extraosseous multiple myeloma: imaging features. AJR Am J Roentgenol 1993;161:1083-7. Crossref

3. Philips S, Menias C, Vikram R, Sunnapwar A, Prasad SR. Abdominal manifestations of extraosseous myeloma: cross-sectional imaging spectrum. J Comput Assist Tomogr 2012;36:207-12. Crossref

4. Cho R, Myers DT, Onwubiko IN, Williams TR. Extraosseous multiple myeloma: imaging spectrum in the abdomen and pelvis. Abdom Radiol (NY) 2021;46:1194-209. Crossref

5. Marcon M, Cereser L, Girometti R, Cataldi P, Volpetti S, Bazzocchi M. Liver involvement by multiple myeloma presenting as hypervascular focal lesions in a patient with chronic hepatitis B infection. BJR Case Rep 2016;2:20150013. Crossref

6. Tan CH, Wang M, Fu WJ, Vikram R. Nodular extramedullary multiple myeloma: hepatic involvement presenting as hypervascular lesions on CT. Ann Acad Med Singap 2011;40:329-31. Crossref