Melioidosis, also known as Whitmore’s disease, occurs predominantly in tropical climates and can cause pneumonia, soft tissue infection, brain abscess, and septicaemia. Very few cases of melioidosis pericarditis have been reported. The most common cause of constrictive pericarditis in Hong Kong is tuberculosis. We report a patient with melioidosis constrictive pericarditis with presentation mimicking tuberculous pericarditis infection in whom we performed pericardiectomy.

A 61-year-old man who was a chronic smoker and worked on a construction site presented with fever and heart failure symptoms including dyspnoea, orthopnoea, and ankle oedema. Laboratory results showed elevated white blood cell count (21.7 × 10⁹/L) with neutrophils predominant (19 × 10⁹/L) and raised levels of C-reactive protein (303 mg/L) and liver parenchymal enzymes (alanine transaminase level: 153 U/L, alkaline phosphate level: 125 U/L). Repeated blood cultures were negative. Sputum for acid-fast bacilli smear and culture and Mycobacterium tuberculosis polymerase chain reaction were negative. Computed tomography (CT) with contrast showed bilateral multiple small lung nodules (largest 1.3 cm) with mediastinal and right hilar lymphadenopathy. Transthoracic echocardiogram revealed bilateral pleural effusion with pericardial effusion requiring pericardial drain insertion 2 days after admission. Analysis of pericardial fluid showed elevated adenosine deaminase (ADA) level (58 U/L) and culture showed scanty growth of pseudomonal species after 6 days. No Mycobacterium species was isolated after 6 weeks of incubation. The patient was commenced on empiric antituberculosis treatment (isoniazid 300 mg daily, rifampicin 600 mg daily, pyrazinamide 1500 mg daily, ethambutol 900 mg daily, and pyridoxine 20 mg daily) 3 weeks after admission in view of the elevated ADA level, persistent intermittent fever while on intravenous piperacillin/tazobactam and due to the risk of tuberculous pericarditis in Hong Kong. He was discharged and referred to our cardiothoracic centre for elective pericardial biopsy.

While waiting for our outpatient clinic assessment, the patient was admitted as an emergency 1 month after commencing antituberculosis treatment with shortness of breath and frequent episodes of atrial flutter. He was later transferred to our cardiothoracic unit for further management. Echocardiogram and CT scan of the thorax showed a large heterogeneous pericardial collection with adhesions and internal echogenicities of up to 3.5 cm in diameter, located next to the left ventricle with signs of compression and constriction (Fig 1). There were also signs of septal bounce and exaggerated respirophasic changes of tricuspid and mitral inflow. Left and right ventricular systolic function was reduced due to impaired bi-ventricular contractility caused by pericardial adhesions and constriction, confirmed by right heart catheterisation (high right ventricular end-diastolic pressure–to–right ventricular systolic pressure ratio, discordance between left ventricular systolic pressure and right ventricular systolic pressure during respiration).

Pericardiectomy was performed and the excised pericardium sent for sectioning revealed suppurative granulomatous inflammation (Fig 2). The Ziehl–Neelsen stain and Mycobacterium tuberculosis polymerase chain reaction were negative. Pericardial pus aspirate contained Burkholderia pseudomallei species.

Antituberculosis treatment was withheld and melioidosis was treated with intravenous meropenem for 4 weeks and oral co-trimoxazole with doxycycline as maintenance therapy. The patient’s postoperative course was uneventful. Postoperative CT of the thorax at 3 months showed reduced pericardial effusion, decreased lung consolidation, and reduced pleural effusion.

Melioidosis is caused by intracellular Gram-negative saprophytic B pseudomallei. This bacterium was formerly classified in the genus Pseudomonas but is now separated from Pseudomonas and Stenotrophomonas. It is predominantly found in contaminated water and soil and spread to humans through direct contact with contaminated sources. Melioidosis is a multiorgan infectious disease with pneumonia as the most common presentation. A progressive increase in the number of cases has been observed in Hong Kong over the last 20 years, as well as in Asia over the past decade.1 There was no previous reported case of melioidosis pericarditis in Hong Kong.1

Tuberculosis is caused by the acid-fast bacillus M tuberculosis. It is airborne and primarily affects the lungs, and is common in Southeast Asia. The level of ADA, an enzyme in lymphocytes, increases in the presence of inflammatory effusions caused by bacterial infection, granulomatous inflammation, malignancy, and autoimmune disease. It is typically higher in effusions caused by tuberculosis than those caused by other conditions with a level >40 U/L in lymphocyte-predominant effusions having a sensitivity of 87% to 93% and a specificity of 89% to 97% for tuberculosis.2 Nonetheless in neutrophil-predominant effusions, ADA level may lead to false-positive results since ADA is normally elevated.2

Constrictive pericarditis is a disease characterised by pericardial effusion with constrictive pathology. The most common cause is idiopathic, followed by tuberculosis, or post-irradiation and post-pericardiotomy. It is characterised by echocardiography findings of septal bounce, diastolic shift of the interventricular septum, restrictive left ventricular filling pattern, and cardiac catheterisation finding of square root sign.3

The presentation, laboratory results and imaging findings are very similar for melioidosis and tuberculous pericarditis. Most patients have a subacute-to-chronic disease course. The protein, sugar and white cell count of pericardial fluid may also be similar in both diseases. Compared with patients with tuberculous pericarditis, those with melioidosis pericarditis more often have a neutrophil-predominant white blood cell count,4 as in our case. Histological findings can show granulomatous inflammation with tuberculosis showing a caseous type.5

It is important to differentiate between B pseudomallei and M tuberculosis and make a correct diagnosis since the treatment for melioidosis pericarditis and tuberculous pericarditis varies markedly. A prolonged course of intravenous ceftazidime followed by a combination of co-trimoxazole and doxycycline is prescribed for melioidosis while a prolonged course of rifampicin, ethambutol, pyrazinamide and isoniazid is prescribed for tuberculosis.3 An incorrect diagnosis not only delayed treatment for melioidosis in our patient with consequent worsening of his clinical condition, but may also have caused more harm by exposing the patient to the side-effects of tuberculosis treatment. It is important to send pericardial fluid for culture and to look meticulously for the two organisms.

The presentation, laboratory results and imaging findings can be very similar for melioidosis and tuberculous pericarditis. It is important to bear this in mind during investigations for chronic pericarditis and obtain pericardial culture. This will ensure prompt diagnosis and timely commencement of appropriate treatment.

All authors contributed to the concept or design, acquisition of data, analysis or interpretation of data, drafting of the manuscript, and critical revision of the manuscript for important intellectual content. 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 provided informed consent for all treatments and procedures, and consent for publication.

1. Lui G, Tam A, Tso YK, et al. Melioidosis in Hong Kong. Trop Med Infect Dis 2018;3:91. Crossref

2. Chau E, Sarkarati M, Spellberg B. Adenosine deaminase diagnostic testing in pericardial fluid. JAMA 2019;322:163-4. Crossref

3. Chow CY, Lun KS. Idiopathic effusive constrictive pericarditis in an adolescent boy: a rare cause of heart failure with diagnostic difficulty. Hong Kong J Paediatr (new series) 2015;20:110-4.

4. Chetchotisakd P, Anunnatsiri S, Kiatchoosakun S, Kularbkaew C. Melioidosis pericarditis mimicking tuberculous pericarditis. Clin Infect Dis 2010;51:e46-9. Crossref

5. Wong KT, Puthucheary SD, Vadivelu J. The histopathology of human melioidosis. Histopathology 1995;26:51-5. Crossref

On 19 June 2022, a 45-year-old man was admitted to intensive care unit with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) pneumonia. His body mass index was 22.3. He had a history of hypertension, diabetes mellitus, hyperlipidaemia, and immunoglobulin A nephropathy. He had been receiving prednisolone and mycophenolate mofetil following a renal transplant. His baseline creatinine level was 203 μmol/L. Three doses of CoronaVac vaccine had failed to induce an antibody response.

The patient was in septic shock and had respiratory failure and acute renal failure. He had myopericarditis with elevated level of serum troponin I, diffuse ST elevation on electrocardiogram, and impaired left ventricular ejection fraction of 40% on echocardiogram. Coronary angiogram on 21 June 2022 was normal and myocardial biopsy revealed increased interstitial macrophages. Urine contained Enterococcus faecalis but no white blood cells on microscopy. Screening for other bacterial, viral or fungal co-infections was negative. He was prescribed intravenous remdesivir 200 mg once followed by 100 mg every 12 hours for four more doses and intravenous hydrocortisone 100 mg every 8 hours, and the nephrologist discontinued his mycophenolate mofetil treatment. He received broad spectrum antibiotics as directed by infectious disease specialists. Enoxaparin 60 mg was administered subcutaneously every 48 hours for prophylaxis of deep vein thrombosis. Infectious disease specialists did not recommend tocilizumab, baricitinib, monoclonal antibodies, or convalescent plasma.

The patient received intravenous high-dose N-acetylcysteine at a dose appropriate for treatment of paracetamol overdose as treatment of influenza-induced cytokine storm. Animal studies have shown that an oral dose of N-acetylcysteine 1 g/kg/day improved the survival of mice with otherwise lethal influenza infection and was synergistic with oseltamivir with an endpoint survival of 100%.1 Human oral availability of N-acetylcysteine is 6% to 10%. We have reported previously successful treatment of a patient with 2009 H1N1 influenza virus pneumonia with N-acetylcysteine, administered as a 100 mg/kg continuous intravenous infusion daily for 3 days, with consequent suppression of fever and C-reactive protein concentration and corresponding clinical improvement.2 The C-reactive protein of this patient reduced from 183 mg/L to 11.7 mg/L and fraction of inspired oxygen requirement from 1.0 to 0.35. The positive end expiratory pressure reduced from 18 cm H₂O to 10 cm H₂O. Nonetheless the patient experienced a relapse of cytokine storm and pulmonary deterioration following discontinuation of high-dose N-acetylcysteine therapy before viral clearance. The C-reactive protein rebounded to 132 mg/L and fraction of inspired oxygen requirement increased to 0.85 and positive end expiratory pressure requirement to 16 cm H₂O. Results for sepsis workup were negative. The patient responded to reintroduction of N-acetylcysteine therapy and showed no relapse of cytokine storm when it was discontinued after viral clearance.2 The patient, with SARS-CoV-2 pneumonia, received an infusion of N-acetylcysteine 10 g in 500-mL 5% dextrose solution at 21 mL/hour for 2 days from 21 June 2022. C-reactive protein level reduced from 278 mg/L to 72 mg/L and procalcitonin level from >200 ng/mL to 33.33 ng/mL. Fraction of inspired oxygen requirement decreased from 0.6 to 0.35 and positive end expiratory pressure requirement from 10 cm H₂O to 6 cm H₂O over 2 days following high-dose N-acetylcysteine infusion. When the patient showed no signs of viral clearance on 26 June 2022 and antibodies against SARS-CoV-2 remained negative, we commenced maintenance treatment with N-acetylcysteine at 2.5 g in 250 mL 5% dextrose solution infused over 4 hours twice daily (100 mg/kg/day) from 26 June 2022 until viral clearance on 18 July 2022. The patient was weaned off inotropic agents and mechanical ventilation and became dialysis and oxygen supplement independent. He was discharged from the intensive care unit on 29 June 2022 and resumed immunosuppressive therapy on 30 June 2022. He was discharged home on 28 July 2022. The patient failed to develop any antibody response against SARS-CoV-2 throughout the infection (Fig).

The SARS-CoV-2 mutates rapidly and relies on host cell factors and physiological processes for its entry, replication, and egress. These processes result in cytopathic damage, cytokine dysregulation, and death of host cells. These non-mutable key steps inside the host may be novel targets for future therapeutic strategies against these rapidly mutating viruses. The endoplasmic reticulum (ER) stores the majority of calcium ions and governs protein translation. The accumulation of proteins in the ER membrane, namely ER overload, leads to release of calcium ions from the ER and production of reactive oxygen species. This results in the activation of nuclear factor–kappa B (NF-κB) and the release of pro-inflammatory cytokines. The accumulation of coronavirus spike protein in the ER membrane results in an ER-overload response and cytokine storm.3 Open reading frame 3a (ORF3a) protein, ORF7a protein, membrane protein, and nucleocapsid protein of SARS-CoV-2 are also NF-κB activators. Of these four, ORF7a protein is the most potent NF-κB inducer and pro-inflammatory cytokine producer.4 N-acetylcysteine is an antioxidant against reactive oxygen species and is a potent NF-κB inhibitor.5 Oral N-acetylcysteine administered at 600 mg thrice daily has been shown to reduce mortality in hospitalised SARS-CoV-2 patients.6 The clinical course of our patient suggests that high-dose N-acetylcysteine antioxidant therapy was able to control the cytokine storm of SARS-CoV-2 infection.

The SARS-CoV-2 virus mutates rapidly to produce new variants that can evade human antibody response and escape T-cell recognition and clearance. New variants cause challenges to the global effort in developing effective vaccines and medications against SARS-CoV-2. Current therapeutic strategies including vaccination, anti-viral medications, and monoclonal antibodies are directed against the mutable targets of SARS-CoV-2. The SARS-CoV-2 vaccines and monoclonal antibodies that are highly effective against the SARS-CoV-2 wild-type (Wuhan-Hu-1) strain failed to confer adequate protection against the breakthrough infection nor prevent antibody evasion of omicron variants. Nonetheless high-dose N-acetylcysteine therapy acts directly against the reactive oxygen species and NF-κB activation in the ER-overload response of the host, independent of viral mutation. N-acetylcysteine has a complementary or even synergistic role to therapeutic agents that act on the mutable targets of SARS-CoV-2.

This case report illustrates that high-dose N-acetylcysteine can protect against SARS-CoV-2–induced cytokine storm in an immunocompromised host who could not elicit an antibody response. By controlling the cytokine storm, this patient coexisted with SARS-CoV-2 until viral clearance. As of 16 October 2022, only 23.3% of people in low-income countries had received at least one dose of coronavirus disease 2019 vaccine. If the protection afforded by high-dose N-acetylcysteine against severe complications of SARS-CoV-2 infection in patients without antibody response can be confirmed in prospective studies, non-fully vaccinated people and those with suboptimal antibody response to vaccination may benefit. This may include those with malignancies, on chemotherapy or immunosuppressive medications, with inborn errors of immunity, or with autoantibodies against type I interferons who are prone to critical SARS-CoV-2 pneumonia. N-acetylcysteine is safe and a category B drug for pregnancy. It is affordable for countries with limited resources and has the potential to end the coronavirus disease 2019 pandemic.

Concept or design: KY Lai.
Acquisition of data: All authors.
Analysis or interpretation of data: All authors.
Drafting of the manuscript: KY Lai, SY Au.
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 declared 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 provided informed consent for all treatments and procedures, and consent for publication.

1. Ungheri D, Pisani C, Sanson G, et al. Protective effect of N-acetylcysteine in a model of influenza infection in mice. Int J Immunopathol Pharmacol 2000;13:123-8.

2. Lai KY, Ng WY, Chan PK, Wong KF, Cheng F. High-dose N-acetylcysteine therapy for novel H1N1 influenza pneumonia. Ann Intern Med 2010;152:687-8. Crossref

3. Versteeg GA, van de Nes PS, Bredenbeek PJ, Spaan WJ. The coronavirus spike protein induces endoplasmic reticulum stress and upregulation of intracellular chemokine mRNA concentrations. J Virol 2007;81:10981-90. Crossref

4. Su CM, Wang L, Yoo D. Activation of NF-κB and induction of proinflammatory cytokine expressions mediated by ORF7a protein of SARS-CoV-2. Sci Rep 2021;11:13464. Crossref

5. Hariharan A, Hakeem AR, Radhakrishnan S, Reddy MS, Rela M. The role and therapeutic potential of NF-kappa-B pathway in severe COVID-19 patients. Inflammopharmacology 2021;29:91-100. Crossref

6. Izquierdo JL, Soriano JB, González Y, et al. Use of N-acetylcysteine at high doses as an oral treatment for patients hospitalized with COVID-19. Sci Prog 2022;105:368504221074574. Crossref

In February 2020, a 7-year-old girl was brought to our institution. She had been experiencing dysphasia, dysphagia, and weakness in all four limbs for the past 5 days. She had no recent trauma, febrile illness or seizure. She had normal systolic blood pressure but diastolic pressure was persistently low for her age at 35 to 40 mm Hg. She had a Glasgow Coma Scale score of 11 (E4V1M6) with expressive aphasia. Pupils were equal but dilated at 5 mm and cranial nerves were grossly intact. The muscle strength of right lower limb power was the weakest, with a Medical Research Council (MRC) grade of 3, while others were at grade 4. She had brisk jerks over the lower limbs. Her medical history included premature birth at 34 weeks of gestation and surgical repair of a patent ductus arteriosus at 1 month of age. She also had recurrent urinary tract infections with megacystic bladder, managed since early infancy with intermittent bladder catheterisation. Magnetic resonance imaging of the brain was performed at the age of 5 years due to chronic headache and showed a large area of right frontal encephalomalacia that may have been due to a previous unknown insult.

Blood tests including complete blood count, electrolytes, inflammatory markers, lactate, ammonia, dried blood spot test, homocysteine, and plasma amino acids were unremarkable. Clotting profile, protein C, protein S and antithrombin III, and antinuclear antibodies levels were normal. Magnetic resonance imaging of the brain revealed acute ischaemic stroke with diffusion restriction in the left superior frontal, precentral, cingulate cortices, and corona radiata. Magnetic resonance angiography showed the anterior cerebral artery and middle cerebral artery were replaced by pruned cerebral arteries with straightened appearance and multifocal stenosis (Fig 1). Transthoracic echocardiogram showed a dilated aortic root of 23 mm with mild aortic regurgitation. Magnetic resonance aortogram showed comparable measurement with no aortic aneurysm or dissection (Fig 2).

To account for all clinical manifestations of the patient, a rare condition, multisystemic smooth muscle dysfunction syndrome (MSMDS), was suspected. Genetic analysis confirmed the diagnosis with a de novo heterozygous mutation of ACTA2 c.536G>A (Arg179His). No similar mutation was identified in her parents or younger sister.

Our patient was managed conservatively and prescribed oral aspirin. There have been five further episodes of ischaemic stroke or transient ischaemic attack to date. Developmental assessments revealed mild-grade intellectual disability with regression of gross and fine motor skills. During the latest follow-up, she could walk unaided and manage oral feeding. Physical examination showed grossly full proximal power. The right-hand flexors were weak (Medical Research Council grading of 4/5) and right lower limb was spastic. The patient is being followed by a multidisciplinary team comprised of a neurologist, cardiothoracic surgeon, neurosurgeon, and ophthalmologist.

To the best of our best knowledge, this is the first identified case of MSMDS in Hong Kong. The ACTA2 gene encodes the thin filaments alpha-actin of the contractile element of smooth muscle. In 2010, Milewicz et al1 reported the first case series of patients with de novo missense mutation in the ACTA2 gene. Arg179His is the most severe form of this vascular disease spectrum. The three cardinal clinical presentations are congenital mydriasis, patent ductus arteriosus/aortopulmonary window, and white matter lesions with cerebrovascular disease.

Less common mutation loci, including Arg179Cys, Arg179Leu and Arg179Ser, have been reported to cause MSMDS.2

Recurrent ischaemic stroke is the major debilitating manifestation in MSMDS patients. Up to 95% of these patients have periventricular white matter hyperintensities evident on magnetic resonance imaging, signifying ischaemic insult in these watershed areas of blood supply. The vasculopathies were once considered a variant of moyamoya disease. Nonetheless MSMDS has some unique features, namely dilatation from the cavernous to the clinoid segments of the internal carotid arteries, stenosis and occlusive disease of the distal intracranial circulation, and an abnormally straight course of intracranial arteries. Stenosis of major cerebral arteries arises as a result of significant intimal thickening and markedly increased collagen and smooth muscle cells in the medial layers of these vessels.3

Neurosurgical management similar to that applied in moyamoya disease has been extrapolated to patients with MSMDS and includes direct superior temporal artery to anterior cerebral artery revascularisation and indirect revascularisation such as encephaloduroarteriosynangiosis. Nonetheless patients with various ACTA2 mutations respond less well to these operations. Almost half of affected patients who have undergone neurosurgical revascularisation continue to have major stroke episodes.4 After a case conference with neurosurgeons, anaesthesiologists, neurologists and the parents of our patient, we concluded that as surgery carried an exceedingly high risk with doubtful benefit, revascularisation was not considered.

All reported cases of MSMDS have had a patent ductus arteriosus or aortopulmonary window with most requiring surgical ligation. Patent ductus arteriosus with diameter up to 20 mm in a neonate with MSMDS has also been reported.

Regalado et al2 reported that among the various ACTA2 mutations, Arg179His carries the highest risk of serious aortic events. By the age of 25 years, the cumulative risk of either elective aortic aneurysm repair or dissection is 100%.5 The group also suggested that elective surgical repair be considered when the aortic diameter reaches 4.5 cm.5 The benefit of drug therapy such as beta-blockers or angiotensin receptor blockers is unknown. It was not appropriate to prescribe either drug for our patient since further lowering of blood pressure would aggravate cerebral hypoperfusion leading to more stroke episodes.3

Apart from aortopathy, around half of MSMDS patients have peripheral arterial dilation involving the proximal internal carotid artery, common carotid brachiocephalic, subclavian, axillary and external/internal iliac arteries. This might also explain the low diastolic pressure.

All reported cases of MSMDS have had pupillary abnormalities, mostly fixed or nonreactive pupils. Iris hypoplasia or aniridia has also been reported. Pulmonary complications, though not yet evident in our case, are also common. Pulmonary arterial hypertension may present in early infancy and necessitate mechanical ventilation, vasodilator drugs or even lung transplantation. Asthma and chronic lung disease have also been reported.

About half of MSMDS patients have hypotonic bladders. Recurrent urinary tract infections and hydronephrosis, as in our case, have also been frequently identified. One-third of patients have gastrointestinal problems such as gut malrotation, gastroesophageal reflux disease or constipation.2

In conclusion, MSMDS can affect multiple systems with life-threatening complications. Patients with congenital mydriasis, patent ductus arteriosus and recurrent stroke may raise a clinician’s suspicion of this rare condition and prompt early genetic investigations.

Concept or design: CH Ng.
Acquisition of data: CH Ng.
Analysis or interpretation of data: All authors.
Drafting of the manuscript: All authors.
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 provided informed consent for all treatments and procedures, and consent for publication.

1. Milewicz DM, Østergaard JR, Ala-Kokko LM, et al. De novo ACTA2 mutation causes a novel syndrome of multisystemic smooth muscle dysfunction. Am J Med Genet A 2010;152A:2437-43. Crossref

2. Regalado ES, Mellor-Crummey L, De Backer J, et al. Clinical history and management recommendations of the smooth muscle dysfunction syndrome due to ACTA2 arginine 179 alterations. Genet Med 2018;20:1206-15. Crossref

3. Georgescu MM, Pinho M da C, Richardson TE, et al. The defining pathology of the new clinical and histopathologic entity ACTA2-related cerebrovascular disease. Acta Neuropathol Commun 2015;3:81. Crossref

4. Cuoco JA, Busch CM, Klein BJ, et al. ACTA2 cerebral arteriopathy: not just a puff of smoke. Cerebrovasc Dis 2018;46:159-69. Crossref

5. Regalado ES, Guo DC, Prakash S, et al. Aortic disease presentation and outcome associated with ACTA2 mutations. Circ Cardiovasc Genet 2015;8:457-64. Crossref

The use of plasma creatinine as biomarker for renal function is not foolproof. Pre-analytical factors such as dietary intake of cooked meat can significantly influence plasma creatinine level, giving rise to pseudo-renal failure. We report three cases of paediatric oncology patients who presented with spuriously high plasma creatinine level secondary to ingestion of a large amount of cooked meat, domestically prepared in the form of essence. The frequent occurrence of such practice is likely rooted in the traditional Chinese food culture of ingesting meat essence as a tonic.

A drastic increase in plasma creatinine level to 206 μmol/L (reference interval [RI]: 33-59) from normal baseline was noted in a 6-year-old boy with a history of acute lymphocytic leukaemia in remission during a routine pre-clinic blood test taken at 4 pm. Urgent admission was arranged for suspected acute kidney injury (AKI). On admission, his creatinine level measured about 26 hours after the clinic visit had spontaneously normalised in the absence of any treatment. Urgent urinary system ultrasonography and other blood tests were unremarkable. Clinically, the patient was well and asymptomatic. He was discharged uneventfully.

Renal function test requested as part of pre-consolidation chemotherapy assessment for a 14-year-old boy with B-cell acute lymphoblastic leukaemia showed a rise of plasma creatinine level to 125 μmol/L (RI: 45-77) from the normal baseline. Intravenous fluid was started for suspected AKI and the plasma creatinine level normalised the following morning. However, a reassessment after 3 days showed an elevated creatinine level once again. A third reassessment after 5 more days revealed a creatinine level of 110 μmol/L. The patient was admitted for intravenous rehydration with retesting the following morning showing a normal plasma creatinine level. Consolidation was eventually started 9 days later than the initial planned date. The patient remained well and asymptomatic throughout the course.

A sudden increase in creatinine level (154 μmol/L, RI: 33-59) from the normal baseline was noted during a pre-clinic blood test at 1 pm in a 5-year-old girl with B-cell acute lymphoblastic leukaemia on maintenance chemotherapy. Clinically, the patient exhibited no symptoms. Subsequent blood tests at 4 pm and 3 days later showed gradual reduction of creatinine levels to 83 μmol/L and 65 μmol/L, respectively.

In light of this ‘outbreak’ of spuriously high creatinine level in multiple paediatric oncology patients, extensive investigations were performed on the residual samples for suspected interference. Analytical interference was excluded by dilution study, and re-analysis performed on alternative analyser platforms with the same enzymatic method and by other methods, including Jaffe and liquid chromatography–tandem mass spectrometry (Table). A normal and stable plasma cystatin C level was detected in Case 1, indicating that the actual renal function remained stable despite the rise in plasma creatinine level. Unfortunately, the residual samples D and E for Cases 2 and 3, respectively, were insufficient for cystatin C testing. The clinical status and other renal function markers of both cases had remained stable during the episode, despite the spurious transient and abrupt increase in creatinine levels. The levels also returned quickly to normal without active management. Furthermore, the creatinine increase was found to be paired with creatine increase in all three cases, up to 2 to 4 times the upper limit of normal, indicating recent creatine and creatinine loads.

Dietary history was pursued. Initially, all parents denied excessive meat, fish, or egg intake, but later disclosed habitual preparation of cooked meat in the form of essence (燉肉汁) for their child. Intriguingly, the caretakers had been frequently preparing tonic by double-boiling a large amount of pork meat in a slow cooker, a cooking method resembling that of ‘chicken essence’, a popular traditional health remedy in Asia, especially in Chinese.

Renal function can be conveniently estimated by plasma creatinine level but it has its limitations that should not be overlooked. The level can be influenced by multiple patient factors such as age, sex, muscle mass, tubular secretion, and dietary intake of cooked meat.1

Foods rich in creatine include meat, fish, and poultry. Red meat and fish contain 4 to 10 g creatine per kilogram.2 The average daily creatine intake is estimated to be 0.54 to 0.60 g in children and 0.81 to 0.87 g in adults.2 Cooking enhances the in vitro conversion of creatine in meat to creatinine that is readily absorbed in the gastrointestinal tract. Experiments showed that a single cooked meat meal (225 g boiled beef) can lead to a sharp and transient increase in plasma creatinine, with a peak postprandial increase in adults of 52%, followed by a gradual decrease to baseline after 12 to 24 hours.3 4 This phenomenon, also known as ‘goulash effect’, may affect clinical interpretation of plasma creatinine level and the estimated glomerular filtration rate.5 6 7

The three paediatric cases described above demonstrated a transient exaggerated increase in creatinine following consumption of homemade meat essence. The rise in plasma creatinine level was 7.5-fold in Case 1 and mimicked a stage 3 AKI. Clinical features including normal urine output and stable haemodynamics hinted at an inaccurate estimate of renal function by plasma creatinine level. An alternative blood test that is less susceptible to interference such as cystatin C would provide comforting reassurance as illustrated in Case 1. Locally, Lee et al8 reported a case of pseudo-renal failure (creatinine level of 222 μmol/L) in a healthy 14-month-old boy secondary to consumption of domestically prepared concentrated meat broth. Aggarwal et al9 reported a case of fluctuating plasma creatinine level in a transplant recipient who consumed homemade meat soup before blood taking, hindering optimal clinical management. In this series, the caretakers had been preparing meat essence as tonics for their sick child, a healthy remedy favoured among Chinese parents. It is worth noting that this important piece of history might be missed if medical professionals do not question parents about their child’s diet. Pseudo-renal failure secondary to consumption of homemade meat essence resulted in unnecessary hospital admissions, blood taking and imaging studies, as well as a delay in scheduled chemotherapy treatment.

This series highlights domestic preparation of meat essence as a recurring cause of pseudo-renal failure in the local population. Medical professionals should be alert to the influence of cooked meats on plasma creatinine level. Early recognition can prevent excessive or unnecessary treatment and investigations. An alternative blood test for renal function, eg, cystatin C, should be considered in the presence of a spurious rise in plasma creatinine level. Serum cystatin C test is recently available in our laboratory in the Hong Kong Children’s Hospital. Parental advice to avoid excessive cooked meat intake prior to blood taking will also reduce future occurrence.

All authors contributed to the concept or design, acquisition of data, analysis or interpretation of data, drafting of the manuscript, and critical revision of the manuscript for important intellectual content. 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 study was approved by the Hong Kong Children’s Hospital Research Ethics Committee (Ref No.: HKCH-REC-2021-059). The requirement for patient consent was waived by the Committee due to the retrospective nature of the study and the use of anonymised data.

1. Samra M, Abcar AC. False estimates of elevated creatinine. Perm J 2012;16:51-2. Crossref

2. Korovljev D, Todorovic N, Stajer V, Ostojic SM. Temporal trends in dietary creatine intake from 1999 to 2018: an ecological study with 89,161 participants. J Int Soc Sports Nutr 2021;18:53. Crossref

3. Mayersohn M, Conrad KA, Achari R. The influence of a cooked meat meal on creatinine plasma concentration and creatinine clearance. Br J Clin Pharmacol 1983;15:227-30. Crossref

4. Jacobsen FK, Christensen CK, Mogensen CE, Andreasen F, Heilskov NS. Pronounced increase in serum creatinine concentration after eating cooked meat. Br Med J 1979;1:1049-50. Crossref

5. Nair S, O’Brien SV, Hayden K, et al. Effect of a cooked meat meal on serum creatinine and estimated glomerular filtration rate in diabetes-related kidney disease. Diabetes Care 2014;37:483-7. Crossref

6. Pimenta E, Jensen M, Jung D, Schaumann F, Boxnick S, Truebel H. Effect of diet on serum creatinine in healthy subjects during a phase I study. J Clin Med Res 2016;8:836-9. Crossref

7. Cottrell A. Renal function. In: Probert JL, editor. Urology: an atlas of investigation and diagnosis. Oxford: Clinical Publishing; 2009.

8. Lee HC, Mak MC, Tong RC, et al. Congee: a cause of gross but transient elevation in plasma creatinine concentration. Br J Biomed Sci 2011;68:47-8. Crossref

9. Aggarwal S, Sukkar L, Wynter L, Richards K, Cheung J, Chadban SJ. Dangers of broth after transplantation. Nephrology (Carlton) 2015;20:297-9. Crossref

A 63-year-old lady presented to our emergency department with a 6-month history of chronic cough and progressive shortness of breath on exertion with New York Heart Association class III heart failure. She also reported episodic non-exertional chest pain and bilateral ankle swelling. On examination, she was afebrile, with blood pressure 121/77 mm Hg, heart rate 97 beats/min and respiratory rate 16 breaths/min. Cardiac examination revealed an elevated jugular venous pressure at 4 cm above the sternal notch with a right parasternal heave. A loud pulmonary second heart sound and a diastolic murmur were detected. The murmur was variable with posture and was best heard at the apex in the right lateral position on end expiration. Respiratory examination showed clear lung fields, and mild pitting ankle oedema was noted. Chest X-ray revealed enlarged bilateral pulmonary trunks. Electrocardiogram showed sinus rhythm of 94 beats/min, right axis deviation and tall right precordial R waves. Inflammatory markers were within normal range. However, levels of highly sensitive troponin I and N-terminal prohormone of brain natriuretic peptide were elevated (85 ng/L and 1786 ng/L, respectively). Bedside transthoracic echocardiography screening in the emergency department revealed a large left atrial mass. The clinical impression was pulmonary hypertension secondary to a left-sided cardiac tumour.

The patient had a history of left parotid pleomorphic adenoma for which she had undergone partial excision 15 years ago. She had no history of cardiopulmonary disease and no family history of cardiac tumours.

The top differential diagnosis of primary cardiac tumour was cardiac myxoma but other primary malignant tumours such as sarcoma and secondary cardiac tumours were possible. Given the clinical history, absence of fever and normal inflammatory markers, an infective process was deemed unlikely.

A detailed transthoracic echocardiography examination demonstrated a double-barrel–shaped left atrial mass with central echolucent space of 5.8 cm × 2.7 cm in size (Fig 1a). The mass was seen attached to a thick echogenic base at the interatrial septum and was prolapsing through the mitral valve into the left ventricle during each diastolic phase, causing a mild degree of mitral regurgitation and significant mitral inflow obstruction. The average mean gradient across the mitral valve was 15 mm Hg (Fig 1b). Bi-atrial enlargement was seen. The right ventricle was dilated with preserved systolic function. There was a significant degree of pulmonary hypertension and right ventricular systolic pressure was 87 mm Hg. Left ventricular size and systolic function were normal. A contrast echocardiographic study was performed by intravenous administration of SonoVue (Bracco Diagnostics Inc, Milan, Italy) and revealed an initial contrast enhancement at the base of the stalk (Fig 1c), followed by delayed contrast enhancement of the central echolucent space (Fig 1d and 1e) and subsequent early contrast washout prior to the cardiac chambers (Fig 1f).

Urgent in-house cardiothoracic surgical consultation was obtained and immediate open-heart excision of the cardiac tumour was performed. Intraoperative findings showed a large left atrial cystic mass with an internal solid component and wide-based stalk attaching to the interatrial septum. The mitral valve appeared normal. The left atrial mass, along with the stalk and part of the involved interatrial septum, was resected en bloc. No significant mitral regurgitation was detected with saline testing and there was no interatrial flow detected on intraoperative transoesophageal echocardiography following resection. The patient was successfully decannulated and the sternum was closed uneventfully.

Gross examination of the specimen showed a solid cystic tumour measuring 5.5 cm × 4.5 cm × 2.5 cm with a base measuring 2.5 cm × 1.5 cm (Fig 2a). The tumour was carefully cut open to reveal multilocular surfaces with small gelatinous semitranslucent areas. Serially sectioned specimens showed prominent cystic change with solid myxoid areas adjacent to the base (Fig 2b). Microscopic examination showed thick-walled blood vessels at the stalk of the mass (Fig 2c). The tumour cells exhibited a classic concentric arrangement around capillary and a halo of matrix around cellular clusters (Fig 2d). Sampling from the cystic area revealed morphology similar to the rest of the tumour. Immunostaining for calretinin showed positive nuclear staining in tumour cells (Fig 2e). Overall histopathological features were compatible with cardiac myxoma.

The patient made an uneventful postoperative recovery and pre-discharge echocardiogram showed no residual mass, significant mitral regurgitation or pericardial effusion. She did not report any chest pain or shortness of breath. She was discharged uneventfully on postoperative day 7.

The patient was followed up in the outpatient clinic 2 months after discharge. Her exercise tolerance had improved and ankle swelling resolved. She did not complain of any chest pain or shortness of breath. Her chronic cough had subsided.

Cystic degeneration of cardiac myxoma is rare. It is caused by foci of myxoma stromal liquefaction resulting in a cyst-like structure with clear fluid content. The stalk of cardiac myxoma is typically dominated by the presence of large, thick-walled and occasionally dysplastic arteries giving rise to the described ‘tumour blush’ occasionally observed at coronary angiography.1 Previous histopathological studies of cardiac myxomas have shown that these tumours produce vascular endothelial growth factor that likely induces angiogenesis for tumour growth.2 3 On microscopic tissue examination of our patient, we also found these thick-walled blood vessels at the stalk of cardiac myxoma (Fig 2c). Vascular communication between the stalk and the fluid content of cardiac myxoma with cystic degeneration has not been described before.

The use of contrast agent in echocardiography is particularly helpful in assessing vascular communications, vascularity of cardiac masses and to differentiate masses from intracardiac thrombi.4 Compared with contrast computed tomography, contrast echocardiography offers the advantage of capturing the extended real-time contrast enhancement sequence. To the best of our knowledge, only one case report has discussed the feature of cystic degeneration of cardiac myxoma on contrast echocardiography.5 We have described a novel feature on contrast echocardiography of cystic degeneration of myxoma: initial enhancement of the base of stalk (Fig 1c), followed by delayed contrast enhancement of the central echolucent space (Fig 1d and 1e) and early contrast washout prior to the cardiac chambers (Fig 1f). This suggested the presence of some degree of vascularity at the contrast-enhanced base of stalk with vascular communication between the stalk and the echolucent cystic space of the mass.

Left atrial tumour is a rare cause of pulmonary hypertension. Variable diastolic murmur may be detected on physical examination. Cystic degeneration of cardiac myxoma is rare with specific features on contrast echocardiography. Histopathological examination of the cardiac mass provided a histological basis for the unique contrast enhancement pattern on echocardiography.

Concept or design: DPH Lee.
Acquisition of data: All authors.
Analysis or interpretation of data: DPH Lee.
Drafting of the manuscript: DPH Lee.
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 consent for all procedures and publication.

1. Tazelaar HD, Maleszewski JJ. Tumors of the heart and pericardium. In: Fletcher CD, author. Diagnostic histopathology of tumors. 5th ed. Philadelphia (PA): Elsevier; 2021: 13.

2. Kono T, Koide N, Hama Y, et al. Expression of vascular endothelial growth factor and angiogenesis in cardiac myxoma: a study of fifteen patients. J Thorac Cardiovasc Surg 2000;119:101-7. Crossref

3. Sakamoto H, Sakamaki T, Kanda T, et al. Vascular endothelial growth factor is an autocrine growth factor for cardiac myxoma cells. Circ J 2004;68:488-93. Crossref

4. Lanzoni L, Bonapace S, Dugo C, et al. Cardiac masses and contrast echocardiography. Eur Heart J Cardiovasc Imaging 2022;23 (Suppl 1):jeab289.296. Crossref

5. Yousaf H, Patel M, Khandheria BK, et al. Myxoma blush with contrast echocardiography. Int J Cardiol 2013;166:e1-2. Crossref