We report the first case of atypical fifth metatarsal fracture in a 69-year-old Chinese woman following long-term treatment for osteoporosis with denosumab. She had been diagnosed with hypertension in 2007 and was managed with amlodipine and losartan. One year previously in 2006, she had been diagnosed with postmenopausal osteoporosis based on low bone mineral density (BMD) revealed at a health screening. Her height and weight were 150 cm and 54 kg, respectively, with a body mass index of 24.0 kg/m². She had no previous history of fracture or parental history of hip fracture.

The patient was initially prescribed raloxifene for 2 years but due to a suboptimal BMD response, she was treated with alendronate for 4 years. Given the prolonged use of alendronate, she was switched to strontium ranelate but this was discontinued a few months later due to intolerance. Dual-energy X-ray absorptiometry at that juncture in 2014 showed the BMD of the L1-L4 level, the left femoral neck, and the left total hip were 0.928 g/cm² (T-score=-2.1), 0.646 g/cm² (T-score=-2.9), and 0.725 g/cm² (T-score=-2.4), respectively. She was started on subcutaneous denosumab 60 mg every 6 months that was continued until October 2021. Her most recent dual-energy X-ray absorptiometry in December 2020 revealed the BMD of the left femoral neck and left total hip were 0.544 g/cm² (T-score=-2.3) and 0.715 g/cm² (T-score=-1.4), respectively, indicating significant improvement. The BMD of the lumbar spine was not reported due to significant degenerative changes.

The patient presented to the primary care physician in November 2021 with a 2-week history of mechanical right lateral foot pain. She reported no preceding injury but physical examination revealed mild tenderness over the base of the right fifth metatarsal. There was no joint effusion or signs of infection and distal neurovascular status was intact. X-ray of the right foot was performed (Fig a) and she was prescribed analgesics for right foot tendinitis. One month later in December 2021, she complained of persistent right foot pain during her scheduled follow-up at the Osteoporosis Centre of The University of Hong Kong. Physical examination revealed intense tenderness over the lateral side of her right foot, near the base of the fifth metatarsal. Review of the X-ray taken in November 2021 identified beaking over the lateral aspect at the base of the right fifth metatarsal, indicating a periosteal reaction, associated with a transverse radiolucency across the cortex. Repeat X-ray of the right foot (Fig b) revealed a more prominent transverse radiolucency across the same site. A diagnosis of denosumab-related atypical metatarsal fracture was reached given the long duration of antiresorptive treatment (likely related to denosumab since fracture occurred after 7 years of denosumab), prodromal symptoms and absence of high-energy trauma, along with characteristic radiological findings. Blood tests showed serum calcium level of 2.44 mmol/L (reference range, 2.24-2.63), phosphate level of 0.98 mmol/L (reference range, 0.88-1.45), creatinine level of 60 μmol/L (reference range, 49-82), parathyroid hormone level of 1.7 pmol/L (reference range, 1.3-6.8), and 25-hydroxyvitamin level of 70 nmol/L (sufficient level: 50-220). Although bone turnover markers were not measured, serum alkaline phosphatase level was on the low side at 48 U/L (reference range, 47-124) that could suggest suppressed bone turnover. An X-ray of the left foot was not available, but the patient had no history of left foot pain. For her atypical right metatarsal fracture, she was given a short leg plaster and completed a course of physiotherapy. The fracture healed completely in 6 months. She was started on teriparatide as anti-osteoporosis treatment, and this was tolerated well.

The American Society for Bone and Mineral Research Task Force published a report in 2014 on the case definition of atypical femoral fracture (AFF),1 which refers to fracture located along the femoral diaphysis just distal to lesser trochanter to just proximal to the supracondylar flare. Major and minor diagnostic criteria were proposed. The pathophysiology is postulated to be related to oversuppression of bone turnover impairing normal bone remodelling in response to physiological stress. Prolonged bisphosphonate use has been associated with rare adverse events of atypical fractures (3.2-50 cases per 100 000 person-years).1 Atypical femoral fractures related to denosumab use have been reported, but they are even rarer (0.8 per 10000 person-years).2 Our patient had been taking alendronate for 4 years and denosumab for 7 years. It was very likely that bone turnover had been severely suppressed. In line with this, her serum alkaline phosphatase level was at the lower end of the reference range.

Less commonly, atypical fractures involving long bones other than the femur have also been reported among patients prescribed bisphosphonate or denosumab, including the tibia and ulnar.3 Notably, atypical metatarsal fractures associated with bisphosphonate use for osteoporosis have been reported in only three cases.3 4 5 Our case is the first of atypical metatarsal fracture associated with denosumab. Atypical metatarsal fractures associated with antiresorptive agents, as illustrated in our patient and other case reports (Table), share several characteristics and are distinct from typical fifth metatarsal fractures. They were all associated with prodromal pain with no history of high-energy impact. More importantly, the radiological features fulfil some of the criteria of AFF proposed in the American Society for Bone and Mineral Research 2013 consensus,1 including a fracture line originating in the lateral cortex and periosteal reaction. Although the atypical metatarsal fracture in our patient was temporally related to the long duration of denosumab, the possibility that alendronate had caused abnormal microarchitecture that persisted and was perpetuated by denosumab therapy could not be excluded since she had also been prescribed alendronate for 4 years.

When AFF is diagnosed, antiresorptive agents should be stopped. The risk of AFF of the contralateral femur declines after discontinuation of bisphosphonate. Adequate vitamin D, calcium supplementation and teriparatide can promote healing and reunion of atypical femoral fracture. Surgery promotes healing and relieves pain for AFF. Incomplete AFF has been successfully treated with prophylactic intramedullary nailing. Unlike AFF, the treatment for atypical metatarsal fractures is less well defined. The decision about treatment involves a patient-physician discussion, although the presence of a longer transverse radiolucent line across the shaft favours surgical management.

Although bisphosphonate and denosumab are safe and efficacious, rare side-effects of atypical fractures have been reported. Our case highlights the importance of clinician vigilance for atypical fractures when patients on long-term antiresorptive agents complain of pain over the long bones (not limited to the femur) to enable timely management to reduce morbidities and re-evaluate the anti-osteoporosis strategy.

Concept or design: All authors.
Acquisition of data: EKH Leung, AKC Kan, YC Woo, DTW Lui.
Analysis or interpretation of data: EKH Leung, AKC Kan, SCW Cheung, YC Woo, DTW Lui.
Drafting of the manuscript: EKH Leung, AKC Kan, YC Woo, DTW Lui.
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. Informed consent was obtained from the patient for publication of this case report and any accompanying images.

1. Shane E, Burr D, Abrahamsen B, et al. Atypical subtrochanteric and diaphyseal femoral fractures: second report of a task force of the American Society for Bone and Mineral Research. J Bone Miner Res 2014;29:1-23. Crossref

2. Paparodis R, Buehring B, Pelley EM, Binkley N. A case of an unusual subtrochanteric fracture in a patient receiving denosumab. Endocr Pract 2013;19:e64-8. Crossref

3. Min BC, Chung CY, Park MS, Sung KH, Lee KM. A suspicious atypical fracture of 5th metatarsal bone: a case report. J Orthop Sci 2022;27:281-3. Crossref

4. Pradhan P, Saxena V, Yadav A, Mehrotra V. Atypical metatarsal fracture in a patient on long term bisphosphonate therapy. Indian J Orthop 2012;46:589-92. Crossref

5. Valiollahi B, Salehpour M, Bashari H, Majdi Sh, Mohammadpour M. Atypical metatarsal fracture in a patient on long-term bisphosphonate therapy (case report). J Res Orthopedic Sci 2019;6:25-30. Crossref

A young girl aged 9 years 6 months was admitted to hospital in July 2022 with coronavirus disease 2019 infection and found to have refractory hypokalaemia. She reported good past health and denied taking any supplements or medications. Her nonconsanguineous parents and 4-year-old younger brother were healthy and family history was unremarkable.

Her body weight and height were 35.8 kg at the 75th to 95th percentile and 140 cm at the 75th percentile, respectively. Her body mass index was 18.3 kg/m² at the 75th percentile. Blood pressure was noted to be persistently high up to 152/117 mm Hg (112/73 mm Hg being the 90th percentile for her gender, age and height according to the American Academy of Pediatrics1). Cardiovascular and abdominal examinations were unremarkable. There was no hyperpigmentation or sign of virilisation. She was prepubertal, with normal female external genitalia.

Ambulatory blood pressure monitoring confirmed stage 2 hypertension. Electrolytes and hormone profile are summarised in the Table. Her bone age was 8 years 10 months according to the Greulich and Pyle method of assessment. A standard-dose Synacthen test did not stimulate a rise in 17-hydroxyprogesterone or cortisol level. Ultrasound of the pelvis revealed prepubertal uterus and bilateral ovaries. Her karyotype was 46,XX.

Urine steroid profile showed a characteristic pattern compatible with 17-alpha-hydroxylase/17,20-lyase deficiency (17OHD), with a lack of androgen metabolites and an excess of progesterone, pregnenolone, and corticosterone metabolites (online supplementary Appendix).

Oral hydrocortisone was commenced at 7.6 mg/m²/day. Blood pressure improved to 119/81 mm Hg after 2 weeks. Spironolactone was added for better control.

Genetic analysis revealed compound heterozygous pathogenic variants in the CYP17A1 gene: c.297+2T>C in intron 1 and c.849delC p.(Ser284Glnfs*13) in exon 5, which confirmed the diagnosis of 17OHD. Parental testing confirmed that the two CYP17A1 variants were in trans, and the younger brother was a carrier.

17-alpha-hydroxylase/17,20-lyase deficiency is a rare type of congenital adrenal hyperplasia that accounts for 1% of cases with an estimated incidence of 1 in 50 000 to 100 000.2 17-alpha-hydroxylase and 17,20-lyase enzyme defects result in cortisol and sex hormone deficiency, with compensatory rise in adrenocorticotropic hormone that drives excessive production of 11-deoxycorticosterone and corticosterone (Fig).3

Unlike the pathophysiology of the more common types of congenital adrenal hyperplasia such as 21-hydroxylase deficiency and 11-beta-hydroxylase deficiency, 17OHD does not cause excessive testosterone production with consequent virilisation in affected 46,XX females or precocious puberty in both sexes.3 Instead, due to the lack of sex steroid hormone production, it results in undervirilisation in 46,XY males and sexual infantilism in 46,XX females.3 The excessive accumulation of deoxycorticosterone and corticosterone exerts potent mineralocorticoid effects, resulting in sodium and fluid retention, hence suppression of renin with hypokalaemic hypertension,2 as in our patient. A high concentration of corticosterone provides sufficient glucocorticoid effect to prevent adrenal crisis.3 The classic presentation of 17OHD is a phenotypic female with delayed puberty, primary amenorrhoea, and hypokalaemic hypertension with diagnosis often made in young adulthood.2 4 5 Cases of retained partial enzyme activity resulting in ambiguous genitalia in 46,XY males have been reported.3 4

Delayed diagnosis of 17OHD is not uncommon due to its subtle and late presentation. Hypokalaemic hypertension should prompt a clinician to search for secondary causes of hypertension. Plasma renin activity is an important investigation to differentiate the causes, and would be suppressed in 17OHD by the potent mineralocorticoid activity, and is high in renovascular disease.6 On the contrary, aldosterone level could be suppressed, normal or raised in 17OHD.2 4 5 Low aldosterone level arises as a result of a suppressed renin angiotensin system while high level might be related to more severe enzyme defects resulting in greater production of end product from aldosterone precursors.4 As 17OHD has a characteristic pattern of metabolite excretion and metabolite ratios on urine steroid profiling, this profiling is an important investigation when diagnosing the condition.

There is no consensus guideline on the management of 17OHD. The mainstay of treatment is glucocorticoid and sex hormone replacement. The use of glucocorticoid would decrease the adrenocorticotropic hormone drive and production of deoxycorticosterone and corticosterone, which would facilitate improved blood pressure control and electrolyte balance.2 Different forms and dosages of glucocorticoid replacement have been described in the literature, ranging from dexamethasone 0.25 mg to 1 mg daily, or equivalent.2 4 5 In some cases, an antihypertensive agent with a mineralocorticoid antagonist effect such as spironolactone or eplerenone may be required for blood pressure control.3 5 Patients may develop end organ damage such as hypertensive retinopathy if blood pressure control is suboptimal.2 Deoxycorticosterone and corticosterone levels might not be normalised despite treatment. Blood pressure control, electrolyte balance, and renin level are more important markers of disease control.4

Our patient was phenotypically female, in line with her genotypic sex. Her hormone blood test revealed hypergonadotropic hypogonadism due to lack of sex hormone production. Oestrogen and progestin replacement should be commenced at an appropriate time during adolescence, or upon diagnosis in adulthood, to induce secondary sexual characteristics and cyclic uterine bleeding.5 Sex steroid replacement therapy may improve bone mineral density in 17OHD patients and prevent osteoporosis. For genotypic males, psychological assessment should determine gender preference prior to initiation of sex hormone replacement, and intraabdominal testes should be removed to prevent malignant change.3 A multidisciplinary team approach involving an endocrinologist, surgeon, psychiatrist, psychologist and social worker is essential and can help in parental counselling, achieving family consensus for gender assignment, and formulation of an individualised plan for each patient.

Genetic test on CYP17A1 is important to make the diagnosis of 17OHD. To date, the Human Gene Mutation Database has reported >100 different types of mutations on the CYP17A1 gene.7 Genetic analysis showed compound heterozygous pathogenic variants in the CYP17A1 gene (reference transcript: NM_000102.4): c.297+2T>C in intron 1 and c.849delC p.(Ser284Glnfs*13) in exon 5. c.297+2T>C is a splice site variant that has been previously described in patients with 17OHD (ClinVar accession No.: VCV0004319808), while c.849delC is a truncating variant that creates a premature termination codon. It is expected to result in an absent or disrupted protein product (ClinVar accession No.: VCV0014174348). This variant has an extremely low minor allele frequency in the general population and has not been reported in patients with CYP17A1-related disease.

17-alpha-hydroxylase/17,20-lyase deficiency is associated with infertility due to premature follicular arrest and poor endometrial development for implantation.9 Women with 17OHD have difficulty conceiving, even with the help of assisted reproductive technology.9 Though not promising, fertility had been possible for patients with partial 17OHD. Patients should be counselled about potential fertility difficulties and referred to an assisted reproductive service when appropriate.

To conclude, 17OHD should be considered in a young hypertensive individual with hypokalaemia. Timely management with glucocorticoid and sex hormone replacement can ameliorate the morbidity of hypertension and hypogonadism. Multidisciplinary collaboration is advised, especially for patients with gender identification or infertility issues.

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. The parents of the patient provided written consent for publication of this case report.

The supplementary material was provided by the authors and some information may not have been peer reviewed. Accepted supplementary material will be published as submitted by the authors, without any editing or formatting. Any opinions or recommendations discussed are solely those of the author(s) and are not endorsed by the Hong Kong Academy of Medicine or the Hong Kong Medical Association. The Hong Kong Academy of Medicine and the Hong Kong Medical Association disclaim all liability and responsibility arising from any reliance placed on the content.

1. Flynn JT, Kaelber DC, Baker-Smith CM, et al. Clinical practice guideline for screening and management of high blood pressure in children and adolescents. Pediatrics 2017;140:e20171904. Crossref

2. Kim SM, Rhee JH. A case of 17 alpha-hydroxylase deficiency. Clin Exp Reprod Med 2015;42:72-6. Crossref

3. Auchus RJ. Steroid 17-hydroxylase and 17,20-lyase deficiencies, genetic and pharmacologic. J Steroid Biochem Mol Biol 2017;165(Pt A):71-8. Crossref

4. Peter M, Sippell WG, Wernze H. Diagnosis and treatment of 17-hydroxylase deficiency. J Steroid Biochem Mol Biol 1993;45:107-16. Crossref

5. Han LH, Wang L, Wu XY. 17 alpha-hydroxylase deficiency: a case report of young Chinese woman with a rare gene mutation. Clin Case Rep 2022;10:e6109. Crossref

6. Choi KB. Hypertensive hypokalemic disorders. Electrolytes Blood Press 2007;5:34-41. Crossref

7. Institute of Medical Genetics in Cardiff. Human Gene Mutation Database. Available from: https://www.hgmd.cf.ac.uk/ac/index.php. Accessed 24 May 2024.

8. National Center for Biotechnology Information, National Library of Medicine. ClinVar. Available from: https://www.ncbi.nlm.nih.gov/clinvar/". Accessed 24 May 2024.

9. Marsh CA, Auchus RJ. Fertility in patients with genetic deficiencies of cytochrome P450c17 (CYP17A1): combined 17-hydroxylase/17,20-lyase deficiency and isolated 17,20-lyase deficiency. Fertil Steril 2014;101:317-22.Crossref

A 60-year-old woman presented to United Christian Hospital in 2019 with a 2-month history of progressive generalised ascending weakness and numbness affecting all four limbs. On clinical examination, she had significant oedema involving her hands and feet. Proximal limb power was full while distal limb power was rated grade 3 on the Medical Research Council scale. Sensory modalities involving pinprick, light touch and proprioception were all diminished distally. She had generalised areflexia. Nerve conduction study revealed markedly reduced motor conduction velocity at 18 to 28 m/s (normal range, >50) in the upper limbs, consistent with demyelination. There was evidence of secondary axonal injury. Limited by significant oedema, lower limb nerve compound muscle action potential and sensory nerve action potential were unrecordable. Cerebrospinal fluid study showed elevated protein level at 899 mg/L with normal white blood cell count. The patient was managed as presumed chronic inflammatory demyelinating polyneuropathy (CIDP). Evaluation of monoclonal gammopathy with serum protein electrophoresis (SPE), urine Bence Jones protein and serum immunoglobulin pattern was unrevealing. Systemic steroid was commenced followed by intravenous immunoglobulin due to disease progression but the patient deteriorated further with distal power grade 0 and became wheelchair bound.

Repeated SPE and urine Bence Jones protein test failed to detect any monoclonal gammopathy. Serum free light chain assay of the patient showed persistently raised lambda light chain but normal kappa/lambda ratio. Serum immunofixation was negative. Six months after her initial presentation, positron emission tomography–computed tomography (PET-CT) scan revealed multiple hypermetabolic bony lesions in the skeleton. The dominant lesions were mixed lytic-sclerotic lesions at the left sacrum (maximum standardised uptake value=22.4) and left L5 vertebra (maximum standardised uptake value=16.3). Mild inactive bilateral pleural effusion, pericardial effusion as well as diffuse subcutaneous oedema were also noted. Random trephine bone marrow examination performed at the right iliac crest was unremarkable.

At this juncture, the patient developed skin changes with plethora, white nails, flushing, and hypertrichosis of the trunk and limbs (Fig). She was oedematous with orthopnoea and paroxysmal nocturnal dyspnoea. A diagnosis of POEMS syndrome (polyneuropathy, organomegaly, endocrinopathy, monoclonal plasma cell disorder, and skin changes) was strongly suspected in view of her polyneuropathy, skin changes, lytic-sclerotic bone lesion, and extracellular volume overload. Plasma vascular endothelial growth factor was checked and was markedly elevated at 370 pg/mL (reference range, <96.2).

The patient’s fluid overload symptoms deteriorated with respiratory distress. She was oxygen dependent and diuretic therapy was only partially helpful. Therapeutic thoracentesis of the left chest drained 700 mL of transudative fluid. She subsequently underwent CT-guided bone biopsy (Fig). Her sacrum bone biopsy revealed plasmacytoma with lambda light chain restriction. A diagnosis of POEMS was confirmed.

Around the same time, DNA from the previous random bone marrow blood was extracted from the patient for immunoglobulin heavy chain and kappa light chain B-cell clonality assay (BIOMED-2 polymerase chain reaction assay). Results revealed clonal gene rearrangement (targeting Vk-Jk segments of immunoglobulin kappa gene) consistent with the presence of a clonal B-cell population.

The patient was prescribed a combination of bortezomib, cyclophosphamide and corticosteroid. Oedema resolved first with subsequent improved limb power and dexterity. Her follow-up PET-CT scan after 10 months showed similar bony lesions with reduced metabolic activity.

A 40-year-old man presented to Queen Elizabeth Hospital in 2013 with progressive generalised oedema. He had had repeated admissions for bilateral lower limb oedema, dyspnoea and orthopnoea. Diuretics were partially helpful. Echocardiogram showed normal left ventricular ejection fraction but evidence of pulmonary hypertension. Serum and urine albumin level was normal. Computed tomography of the thorax and abdomen revealed bilateral pleural effusion, pericardial effusion and ascites. He subsequently developed severe distal limb weakness and became wheelchair bound. Nerve conduction study showed demyelinating sensorimotor polyneuropathy in his upper limbs. Lower limb nerves were unable to be assessed due to severe oedema. The patient developed other features of POEMS with hepatosplenomegaly, papilledema, skin changes with hypertrichosis and acrocyanosis. A PET-CT scan revealed sclerotic bony lesions over the left ilium and multiple thoracic and lumbar vertebral bodies.

Similar to Case 1, the patient’s serum and urine were negative for paraprotein. Serum free light chain assay revealed an unremarkable kappa/lambda ratio. Random bone marrow aspiration and trephine biopsy revealed active marrow with mild plasmacytosis. Targeted left iliac bone biopsy showed plasmacytic infiltrates with reversed kappa/lambda ratio. Although plasmacytoma was a concern, there were no definitive histological criteria. Nonetheless based on the highly compatible clinical features of POEMS, he was managed accordingly with cyclophosphamide and corticosteroid. His oedema resolved and he was subsequently able to mobilise with a stick.

The POEMS is a rare paraneoplastic syndrome caused by plasma cell disorder. Presentation may mimic that of demyelinating polyneuropathy. The diagnostic criteria of POEMS include two mandatory criteria, namely, presence of monoclonal plasma cell disorder of lambda origin and demyelinating polyneuropathy. Major criteria include sclerotic bone lesions, elevated vascular endothelial growth factor, and Castleman disease; minor criteria include skin changes, organomegaly, endocrinopathy, extravascular volume overload, papilledema, thrombocytosis, and polycythemia.1 The diagnosis of POEMS is often delayed. The median time for diagnosis has been reported to be 15 months in a longitudinal cohort of 100 patients, by which time 35% patients had become bed or wheelchair bound.2

The above two cases illustrate the difficulty in establishing monoclonal gammopathy even though neurologists and haematologists were alert to the possibility of POEMS. Repeated SPE test, Bence Jones protein test and random bone biopsy were all negative. Plasmacytoma can be demonstrated only on targeted bone biopsy. As a mandatory diagnostic criterion, failure to detect monoclonal gammopathy delays the subsequent management of POEMS. In a large retrospective series, positive monoclonal protein detection on SPE was only 24% to 54%.1

Thorough investigations with serum, urine and histological samples are essential. These consist of performing serum protein electrophoresis, immunofixation, serum free light chain assay as well as urine equivalents. Failure to perform immunofixation and serum free light chain analysis may result in missing 30% of POEMS cases.3 Haematological advice and laboratory communication is of utmost importance to exhaust diagnostic means. For Case 1, immunofixation was performed after liaison with the laboratory. A similar situation arises in the United Kingdom where it is a common practice for laboratories to perform immunofixation only if a paraprotein is present in SPE, despite having superior sensitivity.4

Non-targeted bone marrow examination carries a high chance of missing the pathology, reflected by a prior case series of six patients in whom three had their pathology missed.5 Image guidance, eg, PET-CT, should be considered in the diagnostic workflow of POEMS. It plays a significant role not only in detecting abnormal bone lesions, but also in increasing diagnostic yield for plasmacytoma in biopsy.

Case 1 also illustrates the diagnostic delay of POEMS syndrome partly due to a trial of CIDP treatment, a not uncommon phenomenon. This issue was addressed in a cost-effective analysis of POEMS patients in the United Kingdom.4 The study introduced a diagnostic algorithm incorporating early mandatory vascular endothelial growth factor testing in acquired demyelinating neuropathy patients and helped avoid misdiagnosis and associated healthcare costs.4

The two cases are also similar in terms of the debilitation from significant oedema. One should be alert of POEMS when a CIDP patient presents with unexplained oedema. Extravascular volume overload is a common feature of POEMS and can occur in 90% patients, presumably due to a capillary leak phenomenon.1 This includes leg oedema, pleural effusion, pericardial effusion, ascites, papilledema, and asymptomatic pachymeningeal thickening from fluid collection. Presence of oedema in POEMS should not be overlooked as it is a helpful diagnostic clue to differentiate POEMS from CIDP. It also causes significant patient morbidity. Patients may require repeated paracentesis if the oedema remains refractory to diuretics.

These two cases illustrate the challenge of establishing monoclonal gammopathy in POEMS. Negative serum and urine paraprotein, immunofixation, serum free light chain assay, or a normal random bone marrow examination do not exclude POEMS and warrant further investigations. We should be aware of the limitation of test methods. Comprehensive clinical assessment, thorough investigations and multidisciplinary communication are essential for early diagnosis and management.

Concept or design: YN Mew, WC Fong.
Acquisition of data: All authors.
Analysis or interpretation of data: All authors.
Drafting of the manuscript: YN Mew.
Critical revision of the manuscript for important intellectual content: WC Fong, KF Hui.

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.

The authors thank Dr Kwan-hung Leung, haematologist at United Christian Hospital, for contributing to patient management.

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

The patients were managed in accordance with the Declaration of Helsinki and provided informed consent for publication.

1. Dispenzieri A. POEMS syndrome: 2019 update on diagnosis, risk-stratification, and management. Am J Hematol 2019;94:812-27. Crossref

2. Keddie S, Foldes D, Caimari F, et al. Clinical characteristics, risk factors, and outcomes of POEMS syndrome: a longitudinal cohort study. Neurology 2020;95:e268-79. Crossref

3. Keddie S, D’Sa S, Foldes D, Carr AS, Reilly MM, Lunn MP. POEMS neuropathy: optimising diagnosis and management. Pract Neurol 2018;18:278-90. Crossref

4. Marsh ES, Keddie S, Terris-Prestholt F, D’Sa S, Lunn MP. Early VEGF testing in inflammatory neuropathy avoids POEMS syndrome misdiagnosis and associated costs. J Neurol Neurosurg Psychiatry 2021;92:172-6. Crossref

5. Li Y, Valent J, Soltanzadeh P, Thakore N, Katirji B. Diagnostic challenges in POEMS syndrome presenting with polyneuropathy: a case series. J Neurol Sci 2017;378:170-4. Crossref

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