The patient is a 38-year-old man who previously worked as a computer programmer and currently resides in Hong Kong with his parents and his younger brother in a flat of around 500 square feet. At age 22, he was diagnosed with diabetes mellitus subsequently complicated by diabetic nephrosclerosis and non–vision-threatening retinopathy. His comorbidity includes overweight, hypertension, hypothyroidism, and eczema. He developed end-stage kidney disease (ESKD) in late 2015 and commenced peritoneal dialysis (PD) that unfortunately failed after 3 years due to refractory PD-related peritonitis. Thereafter, he commenced in-centre haemodialysis (HD) in 2018.

The patient underwent 4 hours of in-centre HD 3 times per week via his left forearm arteriovenous fistula. He subsequently reported increased lethargy with poor appetite and was mainly sedentary after quitting his job. His daily fluid intake fluctuated widely with interdialytic weight gain up to 4 to 6 kg necessitating an increase in his antihypertensive medications. His appetite remained suboptimal, and his dry body weight gradually decreased from 72 kg (height: 1.72 m, body mass index: 24.3) at the start of in-centre HD in late 2018 to 67 kg (body mass index: 22.6) by late 2020. He also experienced a worsening of uremic pruritus. Cannulation for dialysis became increasingly difficult due to his eczema. His standardised Kt/V value averaged 1.4 only. His medications are shown in Table 1.

In late 2020, our centre started a home haemodialysis (HHD) programme using a novel HD machine (NxStage System One; Fresenius Medical Care, Tijuana, Mexico). The patient was keen to join the programme. The dermatology team was consulted and his eczema improved after treatment. He was taught to self-cannulate his arteriovenous fistula by our dialysis nurses and achieved independent self-cannulation after 10 HD sessions in 3 weeks. A home visit by engineers indicated a need for only minimal home modifications. Haemodialysis could be performed in a room of around 25 square feet, with water source from the washroom basin pipes and drainage to the original ground drain via connecting hoses. He received a further 2 weeks of machine training with the novel HD machine and commenced HD at home in early 2021. He has since adopted a HHD schedule of 3.5 to 4 hours of dialysis per session, 4 times per week since March 2021. We continue to provide 24-hour support for him via telephone and a communication phone application. To date, he has continued treatment with no significant problems reported.

After the commencement of HHD, his need for antihypertensive agents and erythropoiesis-stimulating agent gradually reduced and all were stopped after approximately 3 months. The patient’s appetite greatly improved and his dry weight gradually increased to 72 kg. Nonetheless this was accompanied by frequent pre-HD hyperkalaemia and hyperphosphataemia, hence he was referred for appropriate dietary advice. He achieved an average standardised Kt/V value of 2 to 2.1. A comparison of parameters while he was receiving in-centre HD and 6 months after he commenced HHD is shown in Table 2. It is of note that his hyperphosphataemia is of a lower magnitude after commencing HHD when compared with the level while he was on in-centre HD. He experienced increased energy, started going out more frequently, and resumed exercise that included regular walking and playing badminton. In January 2022, he resumed working as a computer programmer.

When PD fails in patients with ESKD, it is necessary to commence HD, mostly at a conventional in-centre HD unit. A selected number of suitable patients are recruited into the HHD programme.

Conventional in-centre HD has several limitations including a shorter treatment time (about 8-12 hours per week) that may not provide adequate clearance, an inflexible schedule, and additional financial costs associated with travel, all of which could have a negative impact on patients’ employment and social life. In contrast, frequent HHD with longer treatment time may have more benefits such as better fluid and solute removal with consequent improvement in blood pressure control, left ventricular mass index, sleep apnoea, anaemia, quality of life, pregnancy success rates, as well as reduced mortality.1 Nocturnal home haemodialysis (NHHD) service has been provided in Hong Kong since 2006, with a typical regimen of alternate nightly HD for around 8 hours, and benefited numerous patients over the years. Indeed, Hong Kong has been promoting the use of home therapy including HHD and PD in ESKD patients to the global renal community.2

Nonetheless most Hong Kong citizens live in relatively small flats and may have insufficient space for the installation of both the conventional HD machine and the reverse osmosis machine plus other requisite consumables. Those who live in rented accommodation that precludes an ability to make necessary home modifications to meet the specific electricity and water pressure standards required during NHHD treatments may not be suitable for the NHHD programme. The mandatory requirement for NHHD candidates to have a helper who can safeguard them during treatments also excludes those living alone from joining this programme. Furthermore, the relatively longer training time (up to 3 months or more) associated with the use of the more ‘complicated’ conventional machines may pose learning difficulties for many patients.

To expand the HHD service in Hong Kong, a pilot HHD programme using the novel NxStage System One HD machine was introduced in 2019 at the Prince of Wales Hospital. Studies have shown benefits related to frequent HHD using the new system.3 It uses a low–dialysate volume approach aiming to maximise the urea saturation in the dialysate by reducing the dialysate flow rate to a rate slower than the blood flow rate, resulting in very efficient use of the dialysate. Typically, a total of 30 to 60 litres of dialysate is used for a single session with the new system, whereas 120 to 140 litres of dialysate is typically required for the conventional HD machines. Dialysate is generated and stored before starting treatment, therefore the risk of water leakage during treatment is reduced, compared with the ongoing dialysate generation during conventional NHHD. Its simple design and much smaller footprint, on top of the advantage of no requirement for major home plumbing or electrical system modifications, facilitates a shorter machine training time of around 2 weeks.4

Initially the patient’s family had reservations about him performing HD at home alone but were reassured after detailed discussion and understanding the simplicity of machine operation. The patient’s eczema, especially around his arteriovenous fistula site, occasionally gives cause for concern but effective dermatological treatment and the use of the ‘rope ladder’ instead of the ‘buttonhole’ method for cannulation minimises his infection risk. His appetite was much increased after starting HHD and there was concern about his glucose and fluid control as well as rising potassium and phosphate levels. Counselling by our dietitian has improved the situation.

Dialysis adequacy of HD schedules more frequent than thrice weekly is measured by the standardised Kt/V and the current clinical practice guidelines suggest a minimum value of 2.0. Nonetheless studies have shown that standardised Kt/V may not correlate well with clinical outcomes. A more comprehensive evaluation should include other parameters such as self-reported health status and physical measurements of cardiovascular health (such as blood pressure and echocardiogram). Traditional biochemical outcomes and measurements of solute clearance may also be considered.5 Our patient improved clinically as well as socially after commencing HHD with the new system. We believe that this treatment modality has the potential to benefit many more patients with ESKD.

Concept or design: All authors.
Acquisition of data: VWK Kwong, CWY Au.
Analysis or interpretation of data: VWK Kwong, CWY Au, MC Law, PKT Li.
Drafting of the manuscript: VWK Kwong, PKT Li.
Critical revision of the manuscript for important intellectual content: VWK Kwong, CWY Au, MC Law, PKT Li.

The authors have no conflicts of interest to disclose.

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, provided informed consent for the treatment/procedures, and provided consent for publication.

1. Diaz-Buxo JA, White SA, Himmele R. Frequent hemodialysis: a critical review. Semin Dial 2013;26:578-89. Crossref

2. Li PK, Cheung WL, Lui SL, et al. Increasing home based dialysis therapies to tackle dialysis burden around the world: a position statement on dialysis economics from the 2nd Congress of the International Society for Hemodialysis. Nephrology (Carlton) 2011;16:53-6. Crossref

3. Borman N, Ficheux M, Slon MF, et al. SP597 favourable biochemical outcomes of frequent hemodialysis at home using the NxStage® System One™—The European experience. Nephrol Dial Transplant 2016;31(supp_1):i294. Crossref

4. Clark WR, Turk JE Jr. The NxStage System One. Semin Dial 2004;17:167-70. Crossref

5. Rivara MB, Ravel V, Streja E, et al. Weekly standard Kt/Vurea and clinical outcomes in home and in-center hemodialysis. Clin J Am Soc Nephrol 2018;13:445-55. Crossref

A 20-year-old male presented with a history of dysuria after taking a hot bath 13 days prior to visiting a urology clinic. A urinary tract infection was diagnosed. He reported difficulty urinating about 3 minutes after taking a hot bath, accompanied by a distended and painful bladder. The symptoms gradually resolved after about 30 minutes but dysuria worsened over time, especially when he took a hot bath (about 40°C, a shower or bath). Eventually his symptoms began to persist even 12 hours after bathing and a urinary catheter was inserted after 5 days. In the meantime, he developed numbness in his back and limb weakness and was transferred to the neurology department. The patient’s medical, family and medication history were otherwise unremarkable.

The patient’s temperature (36.6°C), blood pressure (108/72 mmHg), and pulse (76 beats/min) were normal as was respiratory, cardiovascular, and abdominal examination. Neurological examination revealed bilateral knee and ankle reflexes (notedly hyperactive), limb muscle strength (slightly decreased), and sensory system examination was normal. His pupils were isochoric and the papillary light reflex was present. No sensitive focal signs were detected and Babinski sign was negative.

His laboratory test results (complete blood count, blood sugar, lipid, hepatic, renal function, antinuclear antibodies, antiphospholipid antibodies, antineutrophil cytoplasmic antibodies, and rheumatoid factor) were normal. Routine urinalysis revealed a red blood cell count of 16/μL and white blood cell count of 16/μL. Examination of a cerebrospinal fluid sample showed a white blood cell level of 16 × 10⁶ L. The oligoclonal bands in cerebrospinal fluid and serum were negative, and anti–aquaporin-4 antibodies in the serum were positive.

Cerebral magnetic resonance imaging (MRI) revealed abnormal signals in the right brachium pontis, brainstem, and left parietal lobe, with no contrast enhancement. The whole spinal MRI scan displayed abnormal signals from C6 to T1 (Fig). The patient was diagnosed with neuromyelitis optica spectrum disorder (NMOSD). Treatment included intravenous immunoglobulin (0.4 g/kg/d) and glucocorticoids (1000 mg intravenous methylprednisolone for 5 days, then changed to oral methylprednisolone 60 mg for 1 week). He recovered gradually; 5 days later, the catheter was removed and he could urinate freely. The numbness in his back and limb weakness resolved gradually. Five months later, the abnormal signals on the MRI scan were no longer present, and there was no recurrence at 1-year follow-up.

German professor Wilhelm Uhthoff described the phenomenon of transitory visual disturbance in 1890 in patients with multiple sclerosis (MS) occurring after physical exercise and an increase in body temperature. In 1961, G Ricklefs named this phenomenon Uhthoff’s phenomenon (UP),1 as Uhthoff observed the appearance of reversible optic symptoms induced by an increase in body temperature in four of 100 patients with MS and described it as the ‘prominent deterioration of visual acuity during physical exercise and exhausting activity’.2 Subsequent observations revealed that the physiological mechanism of visual dysfunction during heat exposure was the same as that of various other neurological symptoms experienced by MS patients. When Uhthoff researched the phenomenon, he considered exercise to be the only aetiology and ignored the importance of elevated body temperature. In 1950, the hot bath test was developed based on this phenomenon and was used to diagnose MS. Nonetheless because of the non-specific nature and potential complications of the hot bath test, it was replaced in 1980 by other diagnostic tests such as cerebrospinal fluid analysis and MRI. The transient worsening of neurological function due to heat exposure affects the cognitive and physical functions of MS patients and affects their daily life and functional capacity. As this worsening differs to a real relapse or exacerbation of MS, it is necessary to understand this phenomenon and its pathophysiology so that suitable treatment can be administered.

Uhthoff’s phenomenon is most commonly observed in individuals with MS but can also occur in those with NMOSDs.3 To date, the exact mechanisms of UP have remained unclear; however they likely involve a combination of structural and physiological changes within the demyelinated axons in the central nervous system that occur in the presence of a raised core body temperature.4 Factors including exercise, taking a hot bath or shower, fever, exposure to sun, menstrual cycle, psychological stress, and hot meals may worsen the symptoms in MS or NMOSD.5

A study reported UP as the first manifestation of MS in an adult male who presented with blurred vision after performing intense exercise in the fitness room.6 Another study reported three episodes of oscillopsia that occurred while a 17-year-old man participated in intense sports in summer (which was interpreted as recurrent UP); the man was finally diagnosed with radiologically isolated syndrome.7 To date, no studies have reported UP as the initial symptom in individuals with NMOSDs.

The longitudinally extensive spinal cord lesions and anti–aquaporin-4 antibodies in the serum of our patient supported the diagnosis of NMOSD. Our patient first presented with dysuria after taking a hot bath and was considered a case of UP. Loss of the myelin sheath is the primary cause of UP: an elevation in the core body temperature in the context of axonal demyelination results in pore closure of voltage-gated sodium channels, thus compromising action potential depolarisation. There are a variety of heat stressors (fever, hot bath, premenstrual period, physical exercise) and clinical manifestations of UP depending on where demyelinating plaques are located.8 In our patient, the rise in core body temperature during the hot bath could have aggravated the spinal lesion that impaired the micturition centre and led to dysuria.

The patient initially visited the urology clinic and was misdiagnosed with urinary infection; due to the development of additional symptoms, he was suspected of having spinal cord lesions. Overall, urologists as well as neurologists should be aware of the phenomenon to avoid misdiagnosing diseases related to UP.

Concept or design: H Liang, C Xu.
Acquisition of data: H Liang, C Xu.
Analysis or interpretation of data: J Xu.
Drafting of the manuscript: H Liang, C Xu.
Critical revision of the manuscript for important intellectual content: J Xu.

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.

The authors declare no conflict of interest.

This study was supported by Natural Science Foundation Fund of Hainan Province (Ref No.: 823QN343) and Hainan General Hospital Qingnian Fund (Ref No.: QN202002). The funders had no role in study design, data collection/analysis/interpretation or manuscript preparation.

Written informed consent was obtained from the patient for the publication of this case report and any accompanying images.

1. Fraser CL, Davagnanam I, Radon M, Plant GT. The time course and phenotype of Uhthoff phenomenon following optic neuritis. Mult Scler 2012;18:1042-4. Crossref

2. Pearce JM. Early observations on optic neuritis and Uhthoff’s sign. Eur Neurol 2010;63:243-7. Crossref

3. Park K, Tanaka K, Tanaka M. Uhthoff’s phenomenon in multiple sclerosis and neuromyelitis optica. Eur Neurol 2014;72:153-6. Crossref

4. Jacquerye P, Poma JF, Dupuis M. Uhthoff’s phenomenon as the presenting symptom of multiple sclerosis (MS). Acta Neurol Belg 2017;117:953-4. Crossref

5. Panginikkod S, Rayi A, Rocha Cabrero F, Rukmangadachar LA. Uhthoff Phenomenon. Treasure Island (FL): StatPearls Publishing; 2019.

6. Santos-Bueso E, Viera-Peláez D, Asorey-García A, Porta-Etessam J, Vinuesa-Silva JM, García-Sánchez J. Uhthoff’s phenomenon as the first manifestation of multiple sclerosis in an adult male. J Fr Ophtalmol 2016;39:e123-4. Crossref

7. Baroncini D, Zaffaroni M, Minonzio G, et al. Uhthoff’s phenomena and brain MRI suggesting demyelinating lesions: RIS or CIS? A case report. J Neurol Sci 2014;345:262-4. Crossref

8. Frohman TC, Davis SL, Beh S, Greenberg BM, Remington G, Frohman EM. Uhthoff’s phenomena in MS—clinical features and pathophysiology. Nat Rev Neurol 2013;9:535-40. Crossref

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.

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