instruction stringlengths 34 186 | input stringlengths 2.02k 93.8k | output stringlengths 2 418 | meta_questiontype stringclasses 6 values | meta_inputlicense stringclasses 6 values | meta_pmid stringlengths 8 8 | meta_safetyreportid int64 9.51M 21M | meta_articlepubdate stringlengths 4 10 |
|---|---|---|---|---|---|---|---|
What was the outcome of reaction 'Joint warmth'? | Post-transplant manifestation of ankylosing spondylitis: a case report and review of literature.
Ankylosing spondylitis (AS) is an insidiously progressive and debilitating form of arthritis involving the axial skeleton, characterized by chronic back pain and progressive spinal stiffness, and lessening of pain and stiffness with exercise. Due to subsequent manifestation in different organs, AS causes reduction in life expectancy, so early diagnosis and treatment are of great importance. No AS cases have been reported in solid-organ transplant recipients yet.
A 58-year-old woman with end-stage renal disease due to chronic glomerulonephritis, after allogenic kidney transplantation 25 years earlier, with stable, good graft function, treated with chronic immunosuppressive therapy based on cyclosporine A, mycophenolate mofetil, and prednisone, with no previous history of a connective tissue disease presented fever up to 39 °C accompanied by pain localized in sacroiliac region radiating to the left lower limb. Detailed diagnostic procedures and x-rays of the lumbar spine and of the targeted sacroiliac joints revealed lesions characteristic of AS. Sulphasalazine was added to standard immunosuppression regimen with good clinical results.
We report an adult kidney transplant recipient with a new onset of AS. The risk of relapse or new onset of inflammatory disease in transplant recipients is extremely low due to immunosuppressive therapy following transplantation. However, when it occurs, the clinical presentation is commonly atypical, often leading to delayed diagnosis.
Background
The appearance of inflammatory and autoimmune diseases is quite low in patients after solid organ transplantation [1]. Adequate immunosuppressive therapy usually mitigates the risk of relapse or new onset of an autoimmune disease in this population [2]. The clinical presentation of inflammatory diseases in patients after transplantation is commonly atypical, often leading to delayed diagnosis.
Musculoskeletal pain is a common problem in kidney transplant (KTx) recipients, however, an acute inflammatory arthritis is rare. The differential diagnosis of joint and back pain is broad and includes septic arthritis, systemic infection, crystal arthropathies, autoimmune rheumatologic disorders, and medication-related adverse reactions [3].
Ankylosing spondylitis (AS), previously known as Bechterew’s disease, is a chronic, progressive inflammatory disease with a diverse clinical presentation [3]. AS is characterized by inflammation and new bone formation leading to fusion of the spine and sacroiliac joints. Chronic back pain, progressive spinal stiffness and improvement of pain and stiffness with exercise are the most common features of the disease [4]. Other musculoskeletal manifestations of AS include arthritis, enthesitis and dactylitis [5]. Clinical symptoms most frequently begin in late adolescence or in young adults, with 80% before the age of 30 and with a 3:1 to 2:1 male to female ratio [6, 7].
In addition to spinal inflammation, AS is characterized by a broad clinical spectrum of the extra-articular manifestations like uveitis, psoriasis, inflammatory bowel disease, or aortic insufficiency [8, 9] as well as an increased cardiovascular risk, several pulmonary, renal, and neurological complications or depression [10].
We present a case of late onset of seronegative spondyloarthropaty in KTX patient despite ongoing immunosuppressive treatment. The following description applies to become unusual both in terms of gender, age, comorbidities of the patient, as well as the fact that the patient was constantly treated with triple immunosuppressive regimen.
Case presentation
A 58-year-old woman with end-stage renal disease caused by chronic glomerulonephritis, after allogenic KTx 25 years earlier, with stable, good graft function, treated with chronic immunosuppressive therapy based on cyclosporine A (CsA), mycophenolate mofetil (MMF), and prednisone, with no previous history of a connective tissue disease was admitted to the Nephrology Department with fever up to 39 °C accompanied by pain localized in the sacroiliac region radiating to the left lower limb of 2 weeks duration. Physical examination revealed nothing specific, her vital signs were stable. Initial laboratory data indicated an elevated C-reactive protein (CRP) concentration to 287 mg/l (normal range < 5 mg/l), white blood count (WBC) was 6.4 × 10 3/μl, haemoglobin concentration 10.6 g/dl, serum procalcitonin was negative. Urinalysis showed proteinuria 0.1 g/l, and 15 to 20 leukocytes /higher-power field (HPF), with no erythrocytes in urinary sediment. The graft function was stable (serum creatinine concentration (sCr) 95 μmol/l with estimated glomerular filtration rate (eGFRCKD-EPI) - 57.2 ml/min/1.73m2), serum uric acid was 7.8 mg/dl (normal range 4.2–6.8 mg/dl), alanine and aspartate aminotransferase as well as bilirubin concentration were within normal limits. The blood level of CsA was in the range appropriate to the period after KTx. Hepatitis B, hepatitis C, HIV and CMV DNA tests were negative. Urine and blood culture were negative. Echocardiography was performed, but revealed nothing specific and endocarditis was excluded. The empiric antibiotic therapy with clindamycin was started. Nuclear magnetic resonance (NMR) of the lumbar spine was firstly described as inconclusive, although the patient complained of constant pain aggravation. On the tenth day of hospitalization oedema with a tenderness of the left knee appeared. Due to exudates and excessive warmth of the left knee, arthrocentesis was performed. Sixty millilitres of turbid fluid was withdrawn. The synovial fluid was positive for Streptococcus sp. (saprophytic flora) thus a prolonged, targeted vancomycin therapy was started (the patient was allergic to penicillin). Gout was excluded. Moreover, because of the resistant pain and oedema of the left lower limb, Doppler ultrasound was performed and showed active deep vein thrombosis. Low molecular weight heparin therapy was administered in therapeutic dose. A control ultrasound examination revealed no features of thrombosis or valvular insufficiency. Despite antibiotic treatment further high inflammation parameters were still noted (CRP 149.4 mg/l), thus further diagnosis for atypical infection was performed (the direct examination of synovial fluid for tuberculosis and in vitro QuantiFERON test, anti - Borrelia burgdorferi antibodies in class IgM and IgG – all negative). After failure of treatment and the patient’s continuing complaints, the patient was referred to the Department of Rheumatology.
At the time of admission to the Department of Rheumatology the patient reported left knee pain sustained for more than a month and lumbar spine pain, severity independent of physical exercise, exacerbating during the night and accompanied by morning stiffness. Joint mobility within the normal range, soreness during loading and maximum limbs bent. In addition, Patrick sign was positive on the left side. After more detailed anamnesis the patient confirmed occurrence of typical inflammatory back pain of nearly 20 years. The pain typically worsened with inactivity and improved with exercise and non-steroid anti-inflammatory drugs (NSAIDs) treatment. Morning stiffness was prolonged to nearly all day. Nocturnal pain was not awakening her. The patient’s spine motion was markedly limited in all directions: Otto’s test 2 cm, Schober’s test 1.5 cm, chest expansion 3.5 cm deepening the cervical lordosis. Bath Ankylosing Spondylitis Disease Activity Index (BASDAI) was 6.2 whereas Bath Ankylosing Spondylitis Functional Index (BASFI) 2.5. There was neither edema nor mobility limitations in other peripheral joints. No other significant deviations from the norm in the rest of physical examination were noted. The symptoms were accompanied by high erythrocyte sedimentation rate (ESR) 98 mm/h, CRP 119.8 mg/l following an increase of creatinine concentration up to 144 μmol/l (GFRCKD-EPI 35.7 ml/min/1.73m2).
During hospitalization the antibiotic therapy started in the Department of Nephrology was completed, whilst the anti-coagulant therapy was continued. An x-ray of the lumbar spine and of the targeted sacroiliac joints revealed lesions characteristic of ankylosing spondylitis: vertebral body squaring, diffuse syndesmophyitic ankyloses giving a “bamboo spine” appearance and total ankyloses of sacroiliac joints (Fig. 1). The patient was HLA B27 positive, autoantibodies like the antinuclear antibodies (ANA), anti- cyclic citrullinated peptides antibodies and rheumatoid factor were negative. After the negative result of control culture of the synovial fluid, intrarticular injection of bethametazone and lignocaine mixture was administered. The fluid fulfilled the criteria for the inflammatory fluid type I (Table 1). Uric acid crystals were not detected. The NMR of the lumbar spine done in the Nephrology Unit was assessed once again by a more experienced radiologist in the Rheumatology Unit and was described as typical features of ankylosing spondylitis. A diagnosis of ankylosing spondylitis was posed (Tables 2 and 3) and the patient was started on oral sulphasalazine and NSAIDs. The treatment resulted in a significant decrease of CRP and improvement of the graft function (sCr 92 μmol/l, eGFR 61.4 ml/min/1.73 m2). The diagnosis of chronic kidney disease (CKD) and KTx determined a reduction of sulphasalazine dose to 2x500mg and after a short therapy the NSAIDs administration was reduced. Radiosynovectomy in the left knee joint was performed and after 2 weeks the patient, in good general condition, was discharged home.
Fig. 1 X-ray revealed diffuse syndesmophyitic ankylosis at all levels from Th12 to L1 (also seen above Th12), calcifications of spinal ligaments, features of vertebral body squaring, radiological signs of spondylodiscitis at levels from L1 to L4 with the widening of intervertebral space, blurring the trabecular structure of L5 and L6 narrowing of intervertebral spaces L4-S1. Left site scoliosis
Table 1 Synovial fluid parameters
Synovial fluid parameters
Volume 60 ml
Colour Yellow
Clarity Transparent
Viscosity High
Total protein 50.3 g/l
Glucose level Lower than blood
WBC 800/mm3
PMNs > 50%
Culture Negative
Table 2 Amor diagnostic criteria for spondyloarthropathy
Amor Criteria Our patient
Inflammatory back pain 1 point +
Unilateral buttock pain 1 point –
Alternating buttock pain 2 point –
Enthesitis 2 point +/−
Peripheral arthritis 2 point +
Dactylitis (sausage digit) 2 point –
Acute anterior uveitis 2 point –
HLA-B27
–positive or family history of spondyloarthropathy 2 point +
Good response to NSAIDs 2 point +
Diagnosis of spondyloarthropathy with 6 or more points 7–9 points
Table 3 New York diagnostic criteria for spondyloarthropathy
New York Criteria Our patient
Low back pain with inflammatory characteristics +
Limitation of lumbar spine motion in sagittal and frontal planes +
Decreased chest expansion +
Bilateral sacroiliitis grade 2 or higher +
Unilateral sacroiliitis grade 3 or higher
Definite ankylosing spondylitis when the fourth or fifth criterion mentioned presents with any clinical criteria 4 points
After 6 years of follow up during the routine visits in out-patient Transplantation Department the patient does not present any complaints associated with the left knee (no pain, tenderness, oedema). The graft function is still stable – creatinine concentration 90 μmol/l, GFRCKD-EPI 62 ml/min/1.73m2, she has been treated long-term with her base immunosuppressive therapy (stable dose of CsA 75 mg bid, stable dose of MMF 500 mg bid, and temporarily, increased steroid dose up to 20 mg qd at the moment of AS diagnosis with the subsequent dose reduction to 5 mg qd), with reduced sulphasalazine dose (2 × 500 mg), with no adverse effects of such treatment.
Discussion and conclusion
Joint pain is a frequent problem in individuals with kidney disease and is common both before and after KTx [11]. However, kidney involvement can be one of the complications following rheumatic diseases and can occur as a secondary amyloidosis which is the most common cause of nephrotic syndrome in AS followed by IgA nephropathy, mesangioproliferative glomerulonephritis as well as, rarely, by membranous nephropathy or focal segmental glomerulosclerosis [10]. A study by Hill et al. showed an 18% prevalence of CKD stages 3 to 5 in the rheumatic outpatient group, as compared to 5% reported within the general population [12]. On the other hand, it was shown that rheumatic diseases were the cause of ESRD and KTx in 14% of recipients transplanted in Poland between 1998 and 2015 years [13]. The authors showed that patients and graft survival were distinctly better in nonrheumatic recipients in comparison with rheumatic patients [13].
Differential diagnosis of joint and back pain in patients after successful KTx should take into account common complications of dialysis including crystal deposition disease, β2- microglobulin amyloidosis, secondary hyperparathyroidism, or aluminium overload as well as articular complications followed by hepatitis B and C or a variety of other infections [14]. In KTx recipients some new musculoskeletal and articular disorders, like infection-related arthralgia, polyarticular gout, rheumatoid arthritis flare, or a medication-related adverse reaction, namely steroid induced osteopenia or osteoporosis, may occur [11].
To the best of our knowledge, the present work is the first case report of late onset of seronegative spondyloarthropathy in a transplanted patient despite ongoing immunosuppressive treatment. De novo seropositive erosive rheumatoid arthritis in a patient 7 years after KTx was described by Forslund et al. in 2005 [15].
Immunosuppressive treatment after transplantation on the one hand prevents rejection of the transplanted organ, and on the other hand is an excellent treatment for diseases of the autoimmune and inflammatory background, preventing an exaggerated immune response. However certain injuries may alter this balance leading to dysregulation of the intestinal immune environment promoting the development of chronic inflammatory disease [16]. Immunosuppression heightens susceptibility to infectious agents that may damage the epithelial barrier of the intestinal mucosa resulting in prolonged exposure to luminal antigens followed by chronic immune stimulation [16].
Calcineurin inhibitors including CsA and tacrolimus strongly inhibit production of interleukin-2 (IL-2), which is normally produced by T cells to induce expansion of antigen-specific clones in response to a previously encountered antigen. Deficiency of IL-2 can result in T-cell dysregulation, leading to the development of chronic inflammation [17]. Arthralgia, muscular side effects and osteoarthropathy are some of the described side effects of CsA associated therapy. It was shown that high CsA levels (> 200 ng/ml) are the risk factors of joint pain in KTx recipients [11]. Our patient had the CsA trough level low, appropriate to time passed after KTx.
It has been found that mycophenolate mofetil can be associated with an acute inflammatory response characterized by fever, arthralgia, oligoarthritis and raised inflammatory markers appearing 3 to 5 days after initiation of therapy with MMF. Symptoms rapidly resolve with mycophenolate cessation. The pathogenesis has been associated with paradoxical pro-inflammatory reaction of polymorphonuclear neutrophils [18]. Our patient was treated with MMF for years, thus it is unlikely to have been the cause of symptoms.
The appearance of inflammatory disease regardless of adequate immunosuppressive therapy in transplant recipients is not unusual or impossible, however there is no data available associated with new onset of AS after transplantation. Moreover the most typical risk group of AS are young men, whereas the presented patient is a 58 year old woman. Very rarely does AS begin after the age of 40 resulting in difficulties in making the diagnosis, since standard classification scales are not validated for patients above 45 years old [19, 20].
The diagnosis of arthritis is primarily clinical. The most typical clinical features of arthritis of native joints are acute joint pain, swelling, warmth, erythema, decreased range of motion, fever, and general malaise. AS is characterised by the presence of spinal pain, resulting in limitation of spinal mobility reported also by our patient. These symptoms can be supported by laboratory evidence like leukocytosis or inflammatory markers including CRP, procalcitonin and ESR, which can be useful especially in patients with native joints without underlying haematological or rheumatological conditions. However, all of these laboratory tests have quite low sensitivity and specificity. Laboratory tests are usually followed by X-ray, ultrasound, computer tomography (CT) or magnetic resonance imaging (MRI) of the involved joint. To diagnose joint infection aspiration of the joints can be performed, however mainly in large joints.
As written above the immunosuppressive treatment can be associated with increased risk of infectious diseases. Therefore, the most common cause of monoarticular arthritis in both immunocompetent and immunocompromised patients is septic arthritis [21]. Symptoms of AS (low back pain) were reported by our patient for 20 years, but as low back pain is a common condition and the patient did not present other features of spondyloarthropathy like enthesitis, dactylitis, uveitis, diarrhoea or family clustering, the patient was not referred to a rheumatologist and the complaints were described as non-specific, mechanical low back pain. It cannot be excluded that the symptoms of AS were present earlier but were masked by anti-inflammatory properties of immunosuppressive drugs.
Although most cases of viral and reactive arthritis are connected with infectious background, they are usually not categorized as septic arthritis [21]. Monoarticular arthritis can result from viral infection caused by parvovirus B19, HIV or rubella, as well as from the deposition of immune complexes and complement components in hepatitis B and C infections [19]. In our patient the viral infections were excluded.
Reactive arthritis usually arises from an acute infection of the genitourinary or gastrointestinal tract caused by Shigella spp., Salmonella spp., Campylobacter jejuni, or Yersinia enterocolitica. It may also be one of the manifestations of Lyme disease [21, 22].
In the traditional understanding of septic arthritis the most commonly implicated organisms causing bacteremic septic arthritis are Staphylococcus aureus, Streptococcus pyogenes, Neisseria meningitides, Neisseria gonorrhoeae, Klebsiella pneumonia, Escherichia coli, Proteus spp., Salmonella spp., Morganella morganii, Citrobacter spp., Serratias spp or Pseudomonas aerginosa [22–24]. Septic arthritis can also result from mycobacteria (Mycobacterium tuberculosis), or fungi infections (Histoplasma capsulatum, Blastomyces dermatitidis, Coccidioides immitis) [21].
The most common predisposing factors for septic arthritis include age greater than 80 years, diabetes mellitus, rheumatoid arthritis, prosthetic joint, recent joint surgery, skin infection and skin ulcers, intravenous drug abuse and alcoholism, and previous intra-articular corticosteroid administration [25].
Transplant patients are particularly susceptible to develop septic arthritis caused by unusual organisms. These infections are commonly disseminated, involving both the bones and joints [25]. In the first few weeks after transplantation, joint infections are often hematogenous and caused by health-care-associated pathogens such as Staphylococcus aureus (including MRSA) and gram-negative bacilli like Pseudomonas aeruginosa [26]. However, in the months following transplantation, as patients are maintained on immunosuppressive therapy, they are more prone to infections caused by fungi and mycobacteria [26]. In our recipients fungi and mycobacteria were excluded.
Gout etiology was thought unlikely in our patient as no crystals were present on joint aspirate and the patient had no history of gout, with only slight elevated serum uric acid concentration [19] – thus this diagnosis was excluded in our case.
Following the modified New York criteria for AS it has been shown that radiographic sacroilitis is a rather late finding in the disease course of many patients [3]. The most typical radiological evidence for AS are structural changes in the sacroiliac joints and the spine. In our patient the typical features like vertebral body squaring, diffuse syndesmophyitic ankyloses giving a “bamboo spine” appearance and total ankyloses of sacroiliac joints were described on X-ray, whereas MRI revealed nothing specific.
Progression of AS varies among individuals, but some general trends can be observed. Younger age (≤40 years) at disease onset is usually associated with a predominance of axial symptoms, whereas patients with a later disease onset tend to present more peripheral manifestations [9]. Symptoms presented by our patient were associated with the spinal column despite her belonging to an older group.
The main purpose of treating the patient with AS is to improve long-term health-related quality of life by controlling the symptoms of the disease and averting continuous structural damage, thus leading to better joint function followed by improved social participation [3]. The treatment of AS should be personalised according to the present symptoms of the disease, patient’s comorbidities, possible complications resulting from the treatment and psychosocial factors [3].
The first-line drug treatment for patients complaining of pain and stiffness are NSAIDs administered up to the maximum dose, taking into consideration risks and benefits resulting from the treatment [27, 28]. Data from some studies revealed that in young patients failure to administered NSAIDs is associated with an increased mortality [29, 30]. For patients with good response to NSAIDs continuous use is recommended [3]. This first-line treatment should be enhanced by physical therapy including home exercises and by smoking cessation [31]. In patients who are contraindicated to NSAIDs or poorly tolerate this treatment, analgesics such as paracetamol and opioid-(like) drugs should be considered [3].
Lack of efficacy or presence of toxicity with NSAIDs is an indication to consider alternative treatments either with glucocorticoid, sulfasalazine or biological disease-modifying antirheumatic drugs (bDMARDs) [3].
Steroid injections directed to the local site of musculoskeletal inflammation may be recommended in patients with predominant peripheral manifestation as an option to treat arthritis and enthesitis, although direct evidence is lacking. Patients with axial disease should not be treated with systemic glucocorticoids for a long time [3].
Sulfasalazine may be considered in patients with peripheral arthritis, however it does not alleviate axial symptoms [32].
High disease activity defined as BASDAI ≥4 despite conventional treatment, elevated CRP, presence of inflammation on MRI of the SI joints and/or spine or presence of radiographic sacroiliitis is an indication to start bDMARDs and current practice is to start with tumour necrosis factor inhibitor (TNFi) therapy [31].
Our patient due to KTx was put on immunosuppressive therapy including CsA, MMF and steroids. Given the ongoing severity of the patient’s symptoms, no response to maintenance immunosuppressive therapy, contraindication to NSAIDs, a change in management was instituted by the administration of sulfasalazine. Improvement in the patient’s inflammatory markers and arthritis was noticed with subsidence of pain complaints and normalization of CRP within 2 weeks. She has had no further recurrence of acute inflammatory arthritis.
The establishing of proper diagnosis and management of a patient after KTx is difficult. Despite long-term immunosuppressive treatment in solid organ transplant recipients, in the differential diagnosis of joint pain the development of de novo arthritis should be considered, and when conclusive diagnosis is made, the patient may require administration of additional immunosuppressive drugs.
Abbreviations
ANAAntinuclear antibodies
anti-CCPAnti- cyclic citrullinated peptides
ASAnkylosing spondylitis
BASDAIBath Ankylosing Spondylitis Disease Activity Index
BASFIBath Ankylosing Spondylitis Functional Index
bDMARDsBiological disease-modifying antirheumatic drugs
CKDChronic kidney disease
CRPC-reactive protein
CsACyclosporine A
CTComputer tomography
eGFREstimated glomerular filtration rate
ESRErythrocyte sedimentation rate
ESRDEnd-stage renal disease
HPFHigher-power field
KtxKidney transplantation
MMFMycophenolate mofetil
MRIMagnetic resonance imaging
NMRNuclear magnetic resonance
NSAIDsNon-steroid anti-inflammatory drugs
SCrSerum creatinine concentration
TNFiTumour necrosis factor inhibitor
WBCWhite blood count
Publisher’s Note
Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
Acknowledgements
Not applicable.
Authors’ contributions
All authors have read and have approved the submitted version of the manuscript. AZB: designed the case report plan, described the subject medical history and was the primary author for the manuscript; OB: helped design the case report plan, IK helped in writing the manuscript, JM helped in writing the manuscript. All authors have agreed both to be personally accountable for the author’s own contributions and to ensure that questions related to the accuracy or integrity of any part of the work, even ones in which the author was not personally involved, are appropriately investigated, resolved, and the resolution documented in the literature.
Funding
Not applicable.
Availability of data and materials
The patient results used and/or analysed during the current case report are available from the corresponding author on reasonable request.
Ethics approval and consent to participate
Not applicable (case report).
Consent for publication
The patient in written consent agreed to publish the laboratory as well as radiological results.
Competing interests
None of the authors claims a conflict of interest. All authors declare no financial and non-financial competing interests. | Recovered | ReactionOutcome | CC BY | 33517879 | 19,003,793 | 2021-01-31 |
What was the outcome of reaction 'Oedema peripheral'? | Post-transplant manifestation of ankylosing spondylitis: a case report and review of literature.
Ankylosing spondylitis (AS) is an insidiously progressive and debilitating form of arthritis involving the axial skeleton, characterized by chronic back pain and progressive spinal stiffness, and lessening of pain and stiffness with exercise. Due to subsequent manifestation in different organs, AS causes reduction in life expectancy, so early diagnosis and treatment are of great importance. No AS cases have been reported in solid-organ transplant recipients yet.
A 58-year-old woman with end-stage renal disease due to chronic glomerulonephritis, after allogenic kidney transplantation 25 years earlier, with stable, good graft function, treated with chronic immunosuppressive therapy based on cyclosporine A, mycophenolate mofetil, and prednisone, with no previous history of a connective tissue disease presented fever up to 39 °C accompanied by pain localized in sacroiliac region radiating to the left lower limb. Detailed diagnostic procedures and x-rays of the lumbar spine and of the targeted sacroiliac joints revealed lesions characteristic of AS. Sulphasalazine was added to standard immunosuppression regimen with good clinical results.
We report an adult kidney transplant recipient with a new onset of AS. The risk of relapse or new onset of inflammatory disease in transplant recipients is extremely low due to immunosuppressive therapy following transplantation. However, when it occurs, the clinical presentation is commonly atypical, often leading to delayed diagnosis.
Background
The appearance of inflammatory and autoimmune diseases is quite low in patients after solid organ transplantation [1]. Adequate immunosuppressive therapy usually mitigates the risk of relapse or new onset of an autoimmune disease in this population [2]. The clinical presentation of inflammatory diseases in patients after transplantation is commonly atypical, often leading to delayed diagnosis.
Musculoskeletal pain is a common problem in kidney transplant (KTx) recipients, however, an acute inflammatory arthritis is rare. The differential diagnosis of joint and back pain is broad and includes septic arthritis, systemic infection, crystal arthropathies, autoimmune rheumatologic disorders, and medication-related adverse reactions [3].
Ankylosing spondylitis (AS), previously known as Bechterew’s disease, is a chronic, progressive inflammatory disease with a diverse clinical presentation [3]. AS is characterized by inflammation and new bone formation leading to fusion of the spine and sacroiliac joints. Chronic back pain, progressive spinal stiffness and improvement of pain and stiffness with exercise are the most common features of the disease [4]. Other musculoskeletal manifestations of AS include arthritis, enthesitis and dactylitis [5]. Clinical symptoms most frequently begin in late adolescence or in young adults, with 80% before the age of 30 and with a 3:1 to 2:1 male to female ratio [6, 7].
In addition to spinal inflammation, AS is characterized by a broad clinical spectrum of the extra-articular manifestations like uveitis, psoriasis, inflammatory bowel disease, or aortic insufficiency [8, 9] as well as an increased cardiovascular risk, several pulmonary, renal, and neurological complications or depression [10].
We present a case of late onset of seronegative spondyloarthropaty in KTX patient despite ongoing immunosuppressive treatment. The following description applies to become unusual both in terms of gender, age, comorbidities of the patient, as well as the fact that the patient was constantly treated with triple immunosuppressive regimen.
Case presentation
A 58-year-old woman with end-stage renal disease caused by chronic glomerulonephritis, after allogenic KTx 25 years earlier, with stable, good graft function, treated with chronic immunosuppressive therapy based on cyclosporine A (CsA), mycophenolate mofetil (MMF), and prednisone, with no previous history of a connective tissue disease was admitted to the Nephrology Department with fever up to 39 °C accompanied by pain localized in the sacroiliac region radiating to the left lower limb of 2 weeks duration. Physical examination revealed nothing specific, her vital signs were stable. Initial laboratory data indicated an elevated C-reactive protein (CRP) concentration to 287 mg/l (normal range < 5 mg/l), white blood count (WBC) was 6.4 × 10 3/μl, haemoglobin concentration 10.6 g/dl, serum procalcitonin was negative. Urinalysis showed proteinuria 0.1 g/l, and 15 to 20 leukocytes /higher-power field (HPF), with no erythrocytes in urinary sediment. The graft function was stable (serum creatinine concentration (sCr) 95 μmol/l with estimated glomerular filtration rate (eGFRCKD-EPI) - 57.2 ml/min/1.73m2), serum uric acid was 7.8 mg/dl (normal range 4.2–6.8 mg/dl), alanine and aspartate aminotransferase as well as bilirubin concentration were within normal limits. The blood level of CsA was in the range appropriate to the period after KTx. Hepatitis B, hepatitis C, HIV and CMV DNA tests were negative. Urine and blood culture were negative. Echocardiography was performed, but revealed nothing specific and endocarditis was excluded. The empiric antibiotic therapy with clindamycin was started. Nuclear magnetic resonance (NMR) of the lumbar spine was firstly described as inconclusive, although the patient complained of constant pain aggravation. On the tenth day of hospitalization oedema with a tenderness of the left knee appeared. Due to exudates and excessive warmth of the left knee, arthrocentesis was performed. Sixty millilitres of turbid fluid was withdrawn. The synovial fluid was positive for Streptococcus sp. (saprophytic flora) thus a prolonged, targeted vancomycin therapy was started (the patient was allergic to penicillin). Gout was excluded. Moreover, because of the resistant pain and oedema of the left lower limb, Doppler ultrasound was performed and showed active deep vein thrombosis. Low molecular weight heparin therapy was administered in therapeutic dose. A control ultrasound examination revealed no features of thrombosis or valvular insufficiency. Despite antibiotic treatment further high inflammation parameters were still noted (CRP 149.4 mg/l), thus further diagnosis for atypical infection was performed (the direct examination of synovial fluid for tuberculosis and in vitro QuantiFERON test, anti - Borrelia burgdorferi antibodies in class IgM and IgG – all negative). After failure of treatment and the patient’s continuing complaints, the patient was referred to the Department of Rheumatology.
At the time of admission to the Department of Rheumatology the patient reported left knee pain sustained for more than a month and lumbar spine pain, severity independent of physical exercise, exacerbating during the night and accompanied by morning stiffness. Joint mobility within the normal range, soreness during loading and maximum limbs bent. In addition, Patrick sign was positive on the left side. After more detailed anamnesis the patient confirmed occurrence of typical inflammatory back pain of nearly 20 years. The pain typically worsened with inactivity and improved with exercise and non-steroid anti-inflammatory drugs (NSAIDs) treatment. Morning stiffness was prolonged to nearly all day. Nocturnal pain was not awakening her. The patient’s spine motion was markedly limited in all directions: Otto’s test 2 cm, Schober’s test 1.5 cm, chest expansion 3.5 cm deepening the cervical lordosis. Bath Ankylosing Spondylitis Disease Activity Index (BASDAI) was 6.2 whereas Bath Ankylosing Spondylitis Functional Index (BASFI) 2.5. There was neither edema nor mobility limitations in other peripheral joints. No other significant deviations from the norm in the rest of physical examination were noted. The symptoms were accompanied by high erythrocyte sedimentation rate (ESR) 98 mm/h, CRP 119.8 mg/l following an increase of creatinine concentration up to 144 μmol/l (GFRCKD-EPI 35.7 ml/min/1.73m2).
During hospitalization the antibiotic therapy started in the Department of Nephrology was completed, whilst the anti-coagulant therapy was continued. An x-ray of the lumbar spine and of the targeted sacroiliac joints revealed lesions characteristic of ankylosing spondylitis: vertebral body squaring, diffuse syndesmophyitic ankyloses giving a “bamboo spine” appearance and total ankyloses of sacroiliac joints (Fig. 1). The patient was HLA B27 positive, autoantibodies like the antinuclear antibodies (ANA), anti- cyclic citrullinated peptides antibodies and rheumatoid factor were negative. After the negative result of control culture of the synovial fluid, intrarticular injection of bethametazone and lignocaine mixture was administered. The fluid fulfilled the criteria for the inflammatory fluid type I (Table 1). Uric acid crystals were not detected. The NMR of the lumbar spine done in the Nephrology Unit was assessed once again by a more experienced radiologist in the Rheumatology Unit and was described as typical features of ankylosing spondylitis. A diagnosis of ankylosing spondylitis was posed (Tables 2 and 3) and the patient was started on oral sulphasalazine and NSAIDs. The treatment resulted in a significant decrease of CRP and improvement of the graft function (sCr 92 μmol/l, eGFR 61.4 ml/min/1.73 m2). The diagnosis of chronic kidney disease (CKD) and KTx determined a reduction of sulphasalazine dose to 2x500mg and after a short therapy the NSAIDs administration was reduced. Radiosynovectomy in the left knee joint was performed and after 2 weeks the patient, in good general condition, was discharged home.
Fig. 1 X-ray revealed diffuse syndesmophyitic ankylosis at all levels from Th12 to L1 (also seen above Th12), calcifications of spinal ligaments, features of vertebral body squaring, radiological signs of spondylodiscitis at levels from L1 to L4 with the widening of intervertebral space, blurring the trabecular structure of L5 and L6 narrowing of intervertebral spaces L4-S1. Left site scoliosis
Table 1 Synovial fluid parameters
Synovial fluid parameters
Volume 60 ml
Colour Yellow
Clarity Transparent
Viscosity High
Total protein 50.3 g/l
Glucose level Lower than blood
WBC 800/mm3
PMNs > 50%
Culture Negative
Table 2 Amor diagnostic criteria for spondyloarthropathy
Amor Criteria Our patient
Inflammatory back pain 1 point +
Unilateral buttock pain 1 point –
Alternating buttock pain 2 point –
Enthesitis 2 point +/−
Peripheral arthritis 2 point +
Dactylitis (sausage digit) 2 point –
Acute anterior uveitis 2 point –
HLA-B27
–positive or family history of spondyloarthropathy 2 point +
Good response to NSAIDs 2 point +
Diagnosis of spondyloarthropathy with 6 or more points 7–9 points
Table 3 New York diagnostic criteria for spondyloarthropathy
New York Criteria Our patient
Low back pain with inflammatory characteristics +
Limitation of lumbar spine motion in sagittal and frontal planes +
Decreased chest expansion +
Bilateral sacroiliitis grade 2 or higher +
Unilateral sacroiliitis grade 3 or higher
Definite ankylosing spondylitis when the fourth or fifth criterion mentioned presents with any clinical criteria 4 points
After 6 years of follow up during the routine visits in out-patient Transplantation Department the patient does not present any complaints associated with the left knee (no pain, tenderness, oedema). The graft function is still stable – creatinine concentration 90 μmol/l, GFRCKD-EPI 62 ml/min/1.73m2, she has been treated long-term with her base immunosuppressive therapy (stable dose of CsA 75 mg bid, stable dose of MMF 500 mg bid, and temporarily, increased steroid dose up to 20 mg qd at the moment of AS diagnosis with the subsequent dose reduction to 5 mg qd), with reduced sulphasalazine dose (2 × 500 mg), with no adverse effects of such treatment.
Discussion and conclusion
Joint pain is a frequent problem in individuals with kidney disease and is common both before and after KTx [11]. However, kidney involvement can be one of the complications following rheumatic diseases and can occur as a secondary amyloidosis which is the most common cause of nephrotic syndrome in AS followed by IgA nephropathy, mesangioproliferative glomerulonephritis as well as, rarely, by membranous nephropathy or focal segmental glomerulosclerosis [10]. A study by Hill et al. showed an 18% prevalence of CKD stages 3 to 5 in the rheumatic outpatient group, as compared to 5% reported within the general population [12]. On the other hand, it was shown that rheumatic diseases were the cause of ESRD and KTx in 14% of recipients transplanted in Poland between 1998 and 2015 years [13]. The authors showed that patients and graft survival were distinctly better in nonrheumatic recipients in comparison with rheumatic patients [13].
Differential diagnosis of joint and back pain in patients after successful KTx should take into account common complications of dialysis including crystal deposition disease, β2- microglobulin amyloidosis, secondary hyperparathyroidism, or aluminium overload as well as articular complications followed by hepatitis B and C or a variety of other infections [14]. In KTx recipients some new musculoskeletal and articular disorders, like infection-related arthralgia, polyarticular gout, rheumatoid arthritis flare, or a medication-related adverse reaction, namely steroid induced osteopenia or osteoporosis, may occur [11].
To the best of our knowledge, the present work is the first case report of late onset of seronegative spondyloarthropathy in a transplanted patient despite ongoing immunosuppressive treatment. De novo seropositive erosive rheumatoid arthritis in a patient 7 years after KTx was described by Forslund et al. in 2005 [15].
Immunosuppressive treatment after transplantation on the one hand prevents rejection of the transplanted organ, and on the other hand is an excellent treatment for diseases of the autoimmune and inflammatory background, preventing an exaggerated immune response. However certain injuries may alter this balance leading to dysregulation of the intestinal immune environment promoting the development of chronic inflammatory disease [16]. Immunosuppression heightens susceptibility to infectious agents that may damage the epithelial barrier of the intestinal mucosa resulting in prolonged exposure to luminal antigens followed by chronic immune stimulation [16].
Calcineurin inhibitors including CsA and tacrolimus strongly inhibit production of interleukin-2 (IL-2), which is normally produced by T cells to induce expansion of antigen-specific clones in response to a previously encountered antigen. Deficiency of IL-2 can result in T-cell dysregulation, leading to the development of chronic inflammation [17]. Arthralgia, muscular side effects and osteoarthropathy are some of the described side effects of CsA associated therapy. It was shown that high CsA levels (> 200 ng/ml) are the risk factors of joint pain in KTx recipients [11]. Our patient had the CsA trough level low, appropriate to time passed after KTx.
It has been found that mycophenolate mofetil can be associated with an acute inflammatory response characterized by fever, arthralgia, oligoarthritis and raised inflammatory markers appearing 3 to 5 days after initiation of therapy with MMF. Symptoms rapidly resolve with mycophenolate cessation. The pathogenesis has been associated with paradoxical pro-inflammatory reaction of polymorphonuclear neutrophils [18]. Our patient was treated with MMF for years, thus it is unlikely to have been the cause of symptoms.
The appearance of inflammatory disease regardless of adequate immunosuppressive therapy in transplant recipients is not unusual or impossible, however there is no data available associated with new onset of AS after transplantation. Moreover the most typical risk group of AS are young men, whereas the presented patient is a 58 year old woman. Very rarely does AS begin after the age of 40 resulting in difficulties in making the diagnosis, since standard classification scales are not validated for patients above 45 years old [19, 20].
The diagnosis of arthritis is primarily clinical. The most typical clinical features of arthritis of native joints are acute joint pain, swelling, warmth, erythema, decreased range of motion, fever, and general malaise. AS is characterised by the presence of spinal pain, resulting in limitation of spinal mobility reported also by our patient. These symptoms can be supported by laboratory evidence like leukocytosis or inflammatory markers including CRP, procalcitonin and ESR, which can be useful especially in patients with native joints without underlying haematological or rheumatological conditions. However, all of these laboratory tests have quite low sensitivity and specificity. Laboratory tests are usually followed by X-ray, ultrasound, computer tomography (CT) or magnetic resonance imaging (MRI) of the involved joint. To diagnose joint infection aspiration of the joints can be performed, however mainly in large joints.
As written above the immunosuppressive treatment can be associated with increased risk of infectious diseases. Therefore, the most common cause of monoarticular arthritis in both immunocompetent and immunocompromised patients is septic arthritis [21]. Symptoms of AS (low back pain) were reported by our patient for 20 years, but as low back pain is a common condition and the patient did not present other features of spondyloarthropathy like enthesitis, dactylitis, uveitis, diarrhoea or family clustering, the patient was not referred to a rheumatologist and the complaints were described as non-specific, mechanical low back pain. It cannot be excluded that the symptoms of AS were present earlier but were masked by anti-inflammatory properties of immunosuppressive drugs.
Although most cases of viral and reactive arthritis are connected with infectious background, they are usually not categorized as septic arthritis [21]. Monoarticular arthritis can result from viral infection caused by parvovirus B19, HIV or rubella, as well as from the deposition of immune complexes and complement components in hepatitis B and C infections [19]. In our patient the viral infections were excluded.
Reactive arthritis usually arises from an acute infection of the genitourinary or gastrointestinal tract caused by Shigella spp., Salmonella spp., Campylobacter jejuni, or Yersinia enterocolitica. It may also be one of the manifestations of Lyme disease [21, 22].
In the traditional understanding of septic arthritis the most commonly implicated organisms causing bacteremic septic arthritis are Staphylococcus aureus, Streptococcus pyogenes, Neisseria meningitides, Neisseria gonorrhoeae, Klebsiella pneumonia, Escherichia coli, Proteus spp., Salmonella spp., Morganella morganii, Citrobacter spp., Serratias spp or Pseudomonas aerginosa [22–24]. Septic arthritis can also result from mycobacteria (Mycobacterium tuberculosis), or fungi infections (Histoplasma capsulatum, Blastomyces dermatitidis, Coccidioides immitis) [21].
The most common predisposing factors for septic arthritis include age greater than 80 years, diabetes mellitus, rheumatoid arthritis, prosthetic joint, recent joint surgery, skin infection and skin ulcers, intravenous drug abuse and alcoholism, and previous intra-articular corticosteroid administration [25].
Transplant patients are particularly susceptible to develop septic arthritis caused by unusual organisms. These infections are commonly disseminated, involving both the bones and joints [25]. In the first few weeks after transplantation, joint infections are often hematogenous and caused by health-care-associated pathogens such as Staphylococcus aureus (including MRSA) and gram-negative bacilli like Pseudomonas aeruginosa [26]. However, in the months following transplantation, as patients are maintained on immunosuppressive therapy, they are more prone to infections caused by fungi and mycobacteria [26]. In our recipients fungi and mycobacteria were excluded.
Gout etiology was thought unlikely in our patient as no crystals were present on joint aspirate and the patient had no history of gout, with only slight elevated serum uric acid concentration [19] – thus this diagnosis was excluded in our case.
Following the modified New York criteria for AS it has been shown that radiographic sacroilitis is a rather late finding in the disease course of many patients [3]. The most typical radiological evidence for AS are structural changes in the sacroiliac joints and the spine. In our patient the typical features like vertebral body squaring, diffuse syndesmophyitic ankyloses giving a “bamboo spine” appearance and total ankyloses of sacroiliac joints were described on X-ray, whereas MRI revealed nothing specific.
Progression of AS varies among individuals, but some general trends can be observed. Younger age (≤40 years) at disease onset is usually associated with a predominance of axial symptoms, whereas patients with a later disease onset tend to present more peripheral manifestations [9]. Symptoms presented by our patient were associated with the spinal column despite her belonging to an older group.
The main purpose of treating the patient with AS is to improve long-term health-related quality of life by controlling the symptoms of the disease and averting continuous structural damage, thus leading to better joint function followed by improved social participation [3]. The treatment of AS should be personalised according to the present symptoms of the disease, patient’s comorbidities, possible complications resulting from the treatment and psychosocial factors [3].
The first-line drug treatment for patients complaining of pain and stiffness are NSAIDs administered up to the maximum dose, taking into consideration risks and benefits resulting from the treatment [27, 28]. Data from some studies revealed that in young patients failure to administered NSAIDs is associated with an increased mortality [29, 30]. For patients with good response to NSAIDs continuous use is recommended [3]. This first-line treatment should be enhanced by physical therapy including home exercises and by smoking cessation [31]. In patients who are contraindicated to NSAIDs or poorly tolerate this treatment, analgesics such as paracetamol and opioid-(like) drugs should be considered [3].
Lack of efficacy or presence of toxicity with NSAIDs is an indication to consider alternative treatments either with glucocorticoid, sulfasalazine or biological disease-modifying antirheumatic drugs (bDMARDs) [3].
Steroid injections directed to the local site of musculoskeletal inflammation may be recommended in patients with predominant peripheral manifestation as an option to treat arthritis and enthesitis, although direct evidence is lacking. Patients with axial disease should not be treated with systemic glucocorticoids for a long time [3].
Sulfasalazine may be considered in patients with peripheral arthritis, however it does not alleviate axial symptoms [32].
High disease activity defined as BASDAI ≥4 despite conventional treatment, elevated CRP, presence of inflammation on MRI of the SI joints and/or spine or presence of radiographic sacroiliitis is an indication to start bDMARDs and current practice is to start with tumour necrosis factor inhibitor (TNFi) therapy [31].
Our patient due to KTx was put on immunosuppressive therapy including CsA, MMF and steroids. Given the ongoing severity of the patient’s symptoms, no response to maintenance immunosuppressive therapy, contraindication to NSAIDs, a change in management was instituted by the administration of sulfasalazine. Improvement in the patient’s inflammatory markers and arthritis was noticed with subsidence of pain complaints and normalization of CRP within 2 weeks. She has had no further recurrence of acute inflammatory arthritis.
The establishing of proper diagnosis and management of a patient after KTx is difficult. Despite long-term immunosuppressive treatment in solid organ transplant recipients, in the differential diagnosis of joint pain the development of de novo arthritis should be considered, and when conclusive diagnosis is made, the patient may require administration of additional immunosuppressive drugs.
Abbreviations
ANAAntinuclear antibodies
anti-CCPAnti- cyclic citrullinated peptides
ASAnkylosing spondylitis
BASDAIBath Ankylosing Spondylitis Disease Activity Index
BASFIBath Ankylosing Spondylitis Functional Index
bDMARDsBiological disease-modifying antirheumatic drugs
CKDChronic kidney disease
CRPC-reactive protein
CsACyclosporine A
CTComputer tomography
eGFREstimated glomerular filtration rate
ESRErythrocyte sedimentation rate
ESRDEnd-stage renal disease
HPFHigher-power field
KtxKidney transplantation
MMFMycophenolate mofetil
MRIMagnetic resonance imaging
NMRNuclear magnetic resonance
NSAIDsNon-steroid anti-inflammatory drugs
SCrSerum creatinine concentration
TNFiTumour necrosis factor inhibitor
WBCWhite blood count
Publisher’s Note
Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
Acknowledgements
Not applicable.
Authors’ contributions
All authors have read and have approved the submitted version of the manuscript. AZB: designed the case report plan, described the subject medical history and was the primary author for the manuscript; OB: helped design the case report plan, IK helped in writing the manuscript, JM helped in writing the manuscript. All authors have agreed both to be personally accountable for the author’s own contributions and to ensure that questions related to the accuracy or integrity of any part of the work, even ones in which the author was not personally involved, are appropriately investigated, resolved, and the resolution documented in the literature.
Funding
Not applicable.
Availability of data and materials
The patient results used and/or analysed during the current case report are available from the corresponding author on reasonable request.
Ethics approval and consent to participate
Not applicable (case report).
Consent for publication
The patient in written consent agreed to publish the laboratory as well as radiological results.
Competing interests
None of the authors claims a conflict of interest. All authors declare no financial and non-financial competing interests. | Recovered | ReactionOutcome | CC BY | 33517879 | 19,003,793 | 2021-01-31 |
What was the outcome of reaction 'Pain'? | Post-transplant manifestation of ankylosing spondylitis: a case report and review of literature.
Ankylosing spondylitis (AS) is an insidiously progressive and debilitating form of arthritis involving the axial skeleton, characterized by chronic back pain and progressive spinal stiffness, and lessening of pain and stiffness with exercise. Due to subsequent manifestation in different organs, AS causes reduction in life expectancy, so early diagnosis and treatment are of great importance. No AS cases have been reported in solid-organ transplant recipients yet.
A 58-year-old woman with end-stage renal disease due to chronic glomerulonephritis, after allogenic kidney transplantation 25 years earlier, with stable, good graft function, treated with chronic immunosuppressive therapy based on cyclosporine A, mycophenolate mofetil, and prednisone, with no previous history of a connective tissue disease presented fever up to 39 °C accompanied by pain localized in sacroiliac region radiating to the left lower limb. Detailed diagnostic procedures and x-rays of the lumbar spine and of the targeted sacroiliac joints revealed lesions characteristic of AS. Sulphasalazine was added to standard immunosuppression regimen with good clinical results.
We report an adult kidney transplant recipient with a new onset of AS. The risk of relapse or new onset of inflammatory disease in transplant recipients is extremely low due to immunosuppressive therapy following transplantation. However, when it occurs, the clinical presentation is commonly atypical, often leading to delayed diagnosis.
Background
The appearance of inflammatory and autoimmune diseases is quite low in patients after solid organ transplantation [1]. Adequate immunosuppressive therapy usually mitigates the risk of relapse or new onset of an autoimmune disease in this population [2]. The clinical presentation of inflammatory diseases in patients after transplantation is commonly atypical, often leading to delayed diagnosis.
Musculoskeletal pain is a common problem in kidney transplant (KTx) recipients, however, an acute inflammatory arthritis is rare. The differential diagnosis of joint and back pain is broad and includes septic arthritis, systemic infection, crystal arthropathies, autoimmune rheumatologic disorders, and medication-related adverse reactions [3].
Ankylosing spondylitis (AS), previously known as Bechterew’s disease, is a chronic, progressive inflammatory disease with a diverse clinical presentation [3]. AS is characterized by inflammation and new bone formation leading to fusion of the spine and sacroiliac joints. Chronic back pain, progressive spinal stiffness and improvement of pain and stiffness with exercise are the most common features of the disease [4]. Other musculoskeletal manifestations of AS include arthritis, enthesitis and dactylitis [5]. Clinical symptoms most frequently begin in late adolescence or in young adults, with 80% before the age of 30 and with a 3:1 to 2:1 male to female ratio [6, 7].
In addition to spinal inflammation, AS is characterized by a broad clinical spectrum of the extra-articular manifestations like uveitis, psoriasis, inflammatory bowel disease, or aortic insufficiency [8, 9] as well as an increased cardiovascular risk, several pulmonary, renal, and neurological complications or depression [10].
We present a case of late onset of seronegative spondyloarthropaty in KTX patient despite ongoing immunosuppressive treatment. The following description applies to become unusual both in terms of gender, age, comorbidities of the patient, as well as the fact that the patient was constantly treated with triple immunosuppressive regimen.
Case presentation
A 58-year-old woman with end-stage renal disease caused by chronic glomerulonephritis, after allogenic KTx 25 years earlier, with stable, good graft function, treated with chronic immunosuppressive therapy based on cyclosporine A (CsA), mycophenolate mofetil (MMF), and prednisone, with no previous history of a connective tissue disease was admitted to the Nephrology Department with fever up to 39 °C accompanied by pain localized in the sacroiliac region radiating to the left lower limb of 2 weeks duration. Physical examination revealed nothing specific, her vital signs were stable. Initial laboratory data indicated an elevated C-reactive protein (CRP) concentration to 287 mg/l (normal range < 5 mg/l), white blood count (WBC) was 6.4 × 10 3/μl, haemoglobin concentration 10.6 g/dl, serum procalcitonin was negative. Urinalysis showed proteinuria 0.1 g/l, and 15 to 20 leukocytes /higher-power field (HPF), with no erythrocytes in urinary sediment. The graft function was stable (serum creatinine concentration (sCr) 95 μmol/l with estimated glomerular filtration rate (eGFRCKD-EPI) - 57.2 ml/min/1.73m2), serum uric acid was 7.8 mg/dl (normal range 4.2–6.8 mg/dl), alanine and aspartate aminotransferase as well as bilirubin concentration were within normal limits. The blood level of CsA was in the range appropriate to the period after KTx. Hepatitis B, hepatitis C, HIV and CMV DNA tests were negative. Urine and blood culture were negative. Echocardiography was performed, but revealed nothing specific and endocarditis was excluded. The empiric antibiotic therapy with clindamycin was started. Nuclear magnetic resonance (NMR) of the lumbar spine was firstly described as inconclusive, although the patient complained of constant pain aggravation. On the tenth day of hospitalization oedema with a tenderness of the left knee appeared. Due to exudates and excessive warmth of the left knee, arthrocentesis was performed. Sixty millilitres of turbid fluid was withdrawn. The synovial fluid was positive for Streptococcus sp. (saprophytic flora) thus a prolonged, targeted vancomycin therapy was started (the patient was allergic to penicillin). Gout was excluded. Moreover, because of the resistant pain and oedema of the left lower limb, Doppler ultrasound was performed and showed active deep vein thrombosis. Low molecular weight heparin therapy was administered in therapeutic dose. A control ultrasound examination revealed no features of thrombosis or valvular insufficiency. Despite antibiotic treatment further high inflammation parameters were still noted (CRP 149.4 mg/l), thus further diagnosis for atypical infection was performed (the direct examination of synovial fluid for tuberculosis and in vitro QuantiFERON test, anti - Borrelia burgdorferi antibodies in class IgM and IgG – all negative). After failure of treatment and the patient’s continuing complaints, the patient was referred to the Department of Rheumatology.
At the time of admission to the Department of Rheumatology the patient reported left knee pain sustained for more than a month and lumbar spine pain, severity independent of physical exercise, exacerbating during the night and accompanied by morning stiffness. Joint mobility within the normal range, soreness during loading and maximum limbs bent. In addition, Patrick sign was positive on the left side. After more detailed anamnesis the patient confirmed occurrence of typical inflammatory back pain of nearly 20 years. The pain typically worsened with inactivity and improved with exercise and non-steroid anti-inflammatory drugs (NSAIDs) treatment. Morning stiffness was prolonged to nearly all day. Nocturnal pain was not awakening her. The patient’s spine motion was markedly limited in all directions: Otto’s test 2 cm, Schober’s test 1.5 cm, chest expansion 3.5 cm deepening the cervical lordosis. Bath Ankylosing Spondylitis Disease Activity Index (BASDAI) was 6.2 whereas Bath Ankylosing Spondylitis Functional Index (BASFI) 2.5. There was neither edema nor mobility limitations in other peripheral joints. No other significant deviations from the norm in the rest of physical examination were noted. The symptoms were accompanied by high erythrocyte sedimentation rate (ESR) 98 mm/h, CRP 119.8 mg/l following an increase of creatinine concentration up to 144 μmol/l (GFRCKD-EPI 35.7 ml/min/1.73m2).
During hospitalization the antibiotic therapy started in the Department of Nephrology was completed, whilst the anti-coagulant therapy was continued. An x-ray of the lumbar spine and of the targeted sacroiliac joints revealed lesions characteristic of ankylosing spondylitis: vertebral body squaring, diffuse syndesmophyitic ankyloses giving a “bamboo spine” appearance and total ankyloses of sacroiliac joints (Fig. 1). The patient was HLA B27 positive, autoantibodies like the antinuclear antibodies (ANA), anti- cyclic citrullinated peptides antibodies and rheumatoid factor were negative. After the negative result of control culture of the synovial fluid, intrarticular injection of bethametazone and lignocaine mixture was administered. The fluid fulfilled the criteria for the inflammatory fluid type I (Table 1). Uric acid crystals were not detected. The NMR of the lumbar spine done in the Nephrology Unit was assessed once again by a more experienced radiologist in the Rheumatology Unit and was described as typical features of ankylosing spondylitis. A diagnosis of ankylosing spondylitis was posed (Tables 2 and 3) and the patient was started on oral sulphasalazine and NSAIDs. The treatment resulted in a significant decrease of CRP and improvement of the graft function (sCr 92 μmol/l, eGFR 61.4 ml/min/1.73 m2). The diagnosis of chronic kidney disease (CKD) and KTx determined a reduction of sulphasalazine dose to 2x500mg and after a short therapy the NSAIDs administration was reduced. Radiosynovectomy in the left knee joint was performed and after 2 weeks the patient, in good general condition, was discharged home.
Fig. 1 X-ray revealed diffuse syndesmophyitic ankylosis at all levels from Th12 to L1 (also seen above Th12), calcifications of spinal ligaments, features of vertebral body squaring, radiological signs of spondylodiscitis at levels from L1 to L4 with the widening of intervertebral space, blurring the trabecular structure of L5 and L6 narrowing of intervertebral spaces L4-S1. Left site scoliosis
Table 1 Synovial fluid parameters
Synovial fluid parameters
Volume 60 ml
Colour Yellow
Clarity Transparent
Viscosity High
Total protein 50.3 g/l
Glucose level Lower than blood
WBC 800/mm3
PMNs > 50%
Culture Negative
Table 2 Amor diagnostic criteria for spondyloarthropathy
Amor Criteria Our patient
Inflammatory back pain 1 point +
Unilateral buttock pain 1 point –
Alternating buttock pain 2 point –
Enthesitis 2 point +/−
Peripheral arthritis 2 point +
Dactylitis (sausage digit) 2 point –
Acute anterior uveitis 2 point –
HLA-B27
–positive or family history of spondyloarthropathy 2 point +
Good response to NSAIDs 2 point +
Diagnosis of spondyloarthropathy with 6 or more points 7–9 points
Table 3 New York diagnostic criteria for spondyloarthropathy
New York Criteria Our patient
Low back pain with inflammatory characteristics +
Limitation of lumbar spine motion in sagittal and frontal planes +
Decreased chest expansion +
Bilateral sacroiliitis grade 2 or higher +
Unilateral sacroiliitis grade 3 or higher
Definite ankylosing spondylitis when the fourth or fifth criterion mentioned presents with any clinical criteria 4 points
After 6 years of follow up during the routine visits in out-patient Transplantation Department the patient does not present any complaints associated with the left knee (no pain, tenderness, oedema). The graft function is still stable – creatinine concentration 90 μmol/l, GFRCKD-EPI 62 ml/min/1.73m2, she has been treated long-term with her base immunosuppressive therapy (stable dose of CsA 75 mg bid, stable dose of MMF 500 mg bid, and temporarily, increased steroid dose up to 20 mg qd at the moment of AS diagnosis with the subsequent dose reduction to 5 mg qd), with reduced sulphasalazine dose (2 × 500 mg), with no adverse effects of such treatment.
Discussion and conclusion
Joint pain is a frequent problem in individuals with kidney disease and is common both before and after KTx [11]. However, kidney involvement can be one of the complications following rheumatic diseases and can occur as a secondary amyloidosis which is the most common cause of nephrotic syndrome in AS followed by IgA nephropathy, mesangioproliferative glomerulonephritis as well as, rarely, by membranous nephropathy or focal segmental glomerulosclerosis [10]. A study by Hill et al. showed an 18% prevalence of CKD stages 3 to 5 in the rheumatic outpatient group, as compared to 5% reported within the general population [12]. On the other hand, it was shown that rheumatic diseases were the cause of ESRD and KTx in 14% of recipients transplanted in Poland between 1998 and 2015 years [13]. The authors showed that patients and graft survival were distinctly better in nonrheumatic recipients in comparison with rheumatic patients [13].
Differential diagnosis of joint and back pain in patients after successful KTx should take into account common complications of dialysis including crystal deposition disease, β2- microglobulin amyloidosis, secondary hyperparathyroidism, or aluminium overload as well as articular complications followed by hepatitis B and C or a variety of other infections [14]. In KTx recipients some new musculoskeletal and articular disorders, like infection-related arthralgia, polyarticular gout, rheumatoid arthritis flare, or a medication-related adverse reaction, namely steroid induced osteopenia or osteoporosis, may occur [11].
To the best of our knowledge, the present work is the first case report of late onset of seronegative spondyloarthropathy in a transplanted patient despite ongoing immunosuppressive treatment. De novo seropositive erosive rheumatoid arthritis in a patient 7 years after KTx was described by Forslund et al. in 2005 [15].
Immunosuppressive treatment after transplantation on the one hand prevents rejection of the transplanted organ, and on the other hand is an excellent treatment for diseases of the autoimmune and inflammatory background, preventing an exaggerated immune response. However certain injuries may alter this balance leading to dysregulation of the intestinal immune environment promoting the development of chronic inflammatory disease [16]. Immunosuppression heightens susceptibility to infectious agents that may damage the epithelial barrier of the intestinal mucosa resulting in prolonged exposure to luminal antigens followed by chronic immune stimulation [16].
Calcineurin inhibitors including CsA and tacrolimus strongly inhibit production of interleukin-2 (IL-2), which is normally produced by T cells to induce expansion of antigen-specific clones in response to a previously encountered antigen. Deficiency of IL-2 can result in T-cell dysregulation, leading to the development of chronic inflammation [17]. Arthralgia, muscular side effects and osteoarthropathy are some of the described side effects of CsA associated therapy. It was shown that high CsA levels (> 200 ng/ml) are the risk factors of joint pain in KTx recipients [11]. Our patient had the CsA trough level low, appropriate to time passed after KTx.
It has been found that mycophenolate mofetil can be associated with an acute inflammatory response characterized by fever, arthralgia, oligoarthritis and raised inflammatory markers appearing 3 to 5 days after initiation of therapy with MMF. Symptoms rapidly resolve with mycophenolate cessation. The pathogenesis has been associated with paradoxical pro-inflammatory reaction of polymorphonuclear neutrophils [18]. Our patient was treated with MMF for years, thus it is unlikely to have been the cause of symptoms.
The appearance of inflammatory disease regardless of adequate immunosuppressive therapy in transplant recipients is not unusual or impossible, however there is no data available associated with new onset of AS after transplantation. Moreover the most typical risk group of AS are young men, whereas the presented patient is a 58 year old woman. Very rarely does AS begin after the age of 40 resulting in difficulties in making the diagnosis, since standard classification scales are not validated for patients above 45 years old [19, 20].
The diagnosis of arthritis is primarily clinical. The most typical clinical features of arthritis of native joints are acute joint pain, swelling, warmth, erythema, decreased range of motion, fever, and general malaise. AS is characterised by the presence of spinal pain, resulting in limitation of spinal mobility reported also by our patient. These symptoms can be supported by laboratory evidence like leukocytosis or inflammatory markers including CRP, procalcitonin and ESR, which can be useful especially in patients with native joints without underlying haematological or rheumatological conditions. However, all of these laboratory tests have quite low sensitivity and specificity. Laboratory tests are usually followed by X-ray, ultrasound, computer tomography (CT) or magnetic resonance imaging (MRI) of the involved joint. To diagnose joint infection aspiration of the joints can be performed, however mainly in large joints.
As written above the immunosuppressive treatment can be associated with increased risk of infectious diseases. Therefore, the most common cause of monoarticular arthritis in both immunocompetent and immunocompromised patients is septic arthritis [21]. Symptoms of AS (low back pain) were reported by our patient for 20 years, but as low back pain is a common condition and the patient did not present other features of spondyloarthropathy like enthesitis, dactylitis, uveitis, diarrhoea or family clustering, the patient was not referred to a rheumatologist and the complaints were described as non-specific, mechanical low back pain. It cannot be excluded that the symptoms of AS were present earlier but were masked by anti-inflammatory properties of immunosuppressive drugs.
Although most cases of viral and reactive arthritis are connected with infectious background, they are usually not categorized as septic arthritis [21]. Monoarticular arthritis can result from viral infection caused by parvovirus B19, HIV or rubella, as well as from the deposition of immune complexes and complement components in hepatitis B and C infections [19]. In our patient the viral infections were excluded.
Reactive arthritis usually arises from an acute infection of the genitourinary or gastrointestinal tract caused by Shigella spp., Salmonella spp., Campylobacter jejuni, or Yersinia enterocolitica. It may also be one of the manifestations of Lyme disease [21, 22].
In the traditional understanding of septic arthritis the most commonly implicated organisms causing bacteremic septic arthritis are Staphylococcus aureus, Streptococcus pyogenes, Neisseria meningitides, Neisseria gonorrhoeae, Klebsiella pneumonia, Escherichia coli, Proteus spp., Salmonella spp., Morganella morganii, Citrobacter spp., Serratias spp or Pseudomonas aerginosa [22–24]. Septic arthritis can also result from mycobacteria (Mycobacterium tuberculosis), or fungi infections (Histoplasma capsulatum, Blastomyces dermatitidis, Coccidioides immitis) [21].
The most common predisposing factors for septic arthritis include age greater than 80 years, diabetes mellitus, rheumatoid arthritis, prosthetic joint, recent joint surgery, skin infection and skin ulcers, intravenous drug abuse and alcoholism, and previous intra-articular corticosteroid administration [25].
Transplant patients are particularly susceptible to develop septic arthritis caused by unusual organisms. These infections are commonly disseminated, involving both the bones and joints [25]. In the first few weeks after transplantation, joint infections are often hematogenous and caused by health-care-associated pathogens such as Staphylococcus aureus (including MRSA) and gram-negative bacilli like Pseudomonas aeruginosa [26]. However, in the months following transplantation, as patients are maintained on immunosuppressive therapy, they are more prone to infections caused by fungi and mycobacteria [26]. In our recipients fungi and mycobacteria were excluded.
Gout etiology was thought unlikely in our patient as no crystals were present on joint aspirate and the patient had no history of gout, with only slight elevated serum uric acid concentration [19] – thus this diagnosis was excluded in our case.
Following the modified New York criteria for AS it has been shown that radiographic sacroilitis is a rather late finding in the disease course of many patients [3]. The most typical radiological evidence for AS are structural changes in the sacroiliac joints and the spine. In our patient the typical features like vertebral body squaring, diffuse syndesmophyitic ankyloses giving a “bamboo spine” appearance and total ankyloses of sacroiliac joints were described on X-ray, whereas MRI revealed nothing specific.
Progression of AS varies among individuals, but some general trends can be observed. Younger age (≤40 years) at disease onset is usually associated with a predominance of axial symptoms, whereas patients with a later disease onset tend to present more peripheral manifestations [9]. Symptoms presented by our patient were associated with the spinal column despite her belonging to an older group.
The main purpose of treating the patient with AS is to improve long-term health-related quality of life by controlling the symptoms of the disease and averting continuous structural damage, thus leading to better joint function followed by improved social participation [3]. The treatment of AS should be personalised according to the present symptoms of the disease, patient’s comorbidities, possible complications resulting from the treatment and psychosocial factors [3].
The first-line drug treatment for patients complaining of pain and stiffness are NSAIDs administered up to the maximum dose, taking into consideration risks and benefits resulting from the treatment [27, 28]. Data from some studies revealed that in young patients failure to administered NSAIDs is associated with an increased mortality [29, 30]. For patients with good response to NSAIDs continuous use is recommended [3]. This first-line treatment should be enhanced by physical therapy including home exercises and by smoking cessation [31]. In patients who are contraindicated to NSAIDs or poorly tolerate this treatment, analgesics such as paracetamol and opioid-(like) drugs should be considered [3].
Lack of efficacy or presence of toxicity with NSAIDs is an indication to consider alternative treatments either with glucocorticoid, sulfasalazine or biological disease-modifying antirheumatic drugs (bDMARDs) [3].
Steroid injections directed to the local site of musculoskeletal inflammation may be recommended in patients with predominant peripheral manifestation as an option to treat arthritis and enthesitis, although direct evidence is lacking. Patients with axial disease should not be treated with systemic glucocorticoids for a long time [3].
Sulfasalazine may be considered in patients with peripheral arthritis, however it does not alleviate axial symptoms [32].
High disease activity defined as BASDAI ≥4 despite conventional treatment, elevated CRP, presence of inflammation on MRI of the SI joints and/or spine or presence of radiographic sacroiliitis is an indication to start bDMARDs and current practice is to start with tumour necrosis factor inhibitor (TNFi) therapy [31].
Our patient due to KTx was put on immunosuppressive therapy including CsA, MMF and steroids. Given the ongoing severity of the patient’s symptoms, no response to maintenance immunosuppressive therapy, contraindication to NSAIDs, a change in management was instituted by the administration of sulfasalazine. Improvement in the patient’s inflammatory markers and arthritis was noticed with subsidence of pain complaints and normalization of CRP within 2 weeks. She has had no further recurrence of acute inflammatory arthritis.
The establishing of proper diagnosis and management of a patient after KTx is difficult. Despite long-term immunosuppressive treatment in solid organ transplant recipients, in the differential diagnosis of joint pain the development of de novo arthritis should be considered, and when conclusive diagnosis is made, the patient may require administration of additional immunosuppressive drugs.
Abbreviations
ANAAntinuclear antibodies
anti-CCPAnti- cyclic citrullinated peptides
ASAnkylosing spondylitis
BASDAIBath Ankylosing Spondylitis Disease Activity Index
BASFIBath Ankylosing Spondylitis Functional Index
bDMARDsBiological disease-modifying antirheumatic drugs
CKDChronic kidney disease
CRPC-reactive protein
CsACyclosporine A
CTComputer tomography
eGFREstimated glomerular filtration rate
ESRErythrocyte sedimentation rate
ESRDEnd-stage renal disease
HPFHigher-power field
KtxKidney transplantation
MMFMycophenolate mofetil
MRIMagnetic resonance imaging
NMRNuclear magnetic resonance
NSAIDsNon-steroid anti-inflammatory drugs
SCrSerum creatinine concentration
TNFiTumour necrosis factor inhibitor
WBCWhite blood count
Publisher’s Note
Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
Acknowledgements
Not applicable.
Authors’ contributions
All authors have read and have approved the submitted version of the manuscript. AZB: designed the case report plan, described the subject medical history and was the primary author for the manuscript; OB: helped design the case report plan, IK helped in writing the manuscript, JM helped in writing the manuscript. All authors have agreed both to be personally accountable for the author’s own contributions and to ensure that questions related to the accuracy or integrity of any part of the work, even ones in which the author was not personally involved, are appropriately investigated, resolved, and the resolution documented in the literature.
Funding
Not applicable.
Availability of data and materials
The patient results used and/or analysed during the current case report are available from the corresponding author on reasonable request.
Ethics approval and consent to participate
Not applicable (case report).
Consent for publication
The patient in written consent agreed to publish the laboratory as well as radiological results.
Competing interests
None of the authors claims a conflict of interest. All authors declare no financial and non-financial competing interests. | Recovered | ReactionOutcome | CC BY | 33517879 | 19,003,793 | 2021-01-31 |
What was the outcome of reaction 'Pyrexia'? | Post-transplant manifestation of ankylosing spondylitis: a case report and review of literature.
Ankylosing spondylitis (AS) is an insidiously progressive and debilitating form of arthritis involving the axial skeleton, characterized by chronic back pain and progressive spinal stiffness, and lessening of pain and stiffness with exercise. Due to subsequent manifestation in different organs, AS causes reduction in life expectancy, so early diagnosis and treatment are of great importance. No AS cases have been reported in solid-organ transplant recipients yet.
A 58-year-old woman with end-stage renal disease due to chronic glomerulonephritis, after allogenic kidney transplantation 25 years earlier, with stable, good graft function, treated with chronic immunosuppressive therapy based on cyclosporine A, mycophenolate mofetil, and prednisone, with no previous history of a connective tissue disease presented fever up to 39 °C accompanied by pain localized in sacroiliac region radiating to the left lower limb. Detailed diagnostic procedures and x-rays of the lumbar spine and of the targeted sacroiliac joints revealed lesions characteristic of AS. Sulphasalazine was added to standard immunosuppression regimen with good clinical results.
We report an adult kidney transplant recipient with a new onset of AS. The risk of relapse or new onset of inflammatory disease in transplant recipients is extremely low due to immunosuppressive therapy following transplantation. However, when it occurs, the clinical presentation is commonly atypical, often leading to delayed diagnosis.
Background
The appearance of inflammatory and autoimmune diseases is quite low in patients after solid organ transplantation [1]. Adequate immunosuppressive therapy usually mitigates the risk of relapse or new onset of an autoimmune disease in this population [2]. The clinical presentation of inflammatory diseases in patients after transplantation is commonly atypical, often leading to delayed diagnosis.
Musculoskeletal pain is a common problem in kidney transplant (KTx) recipients, however, an acute inflammatory arthritis is rare. The differential diagnosis of joint and back pain is broad and includes septic arthritis, systemic infection, crystal arthropathies, autoimmune rheumatologic disorders, and medication-related adverse reactions [3].
Ankylosing spondylitis (AS), previously known as Bechterew’s disease, is a chronic, progressive inflammatory disease with a diverse clinical presentation [3]. AS is characterized by inflammation and new bone formation leading to fusion of the spine and sacroiliac joints. Chronic back pain, progressive spinal stiffness and improvement of pain and stiffness with exercise are the most common features of the disease [4]. Other musculoskeletal manifestations of AS include arthritis, enthesitis and dactylitis [5]. Clinical symptoms most frequently begin in late adolescence or in young adults, with 80% before the age of 30 and with a 3:1 to 2:1 male to female ratio [6, 7].
In addition to spinal inflammation, AS is characterized by a broad clinical spectrum of the extra-articular manifestations like uveitis, psoriasis, inflammatory bowel disease, or aortic insufficiency [8, 9] as well as an increased cardiovascular risk, several pulmonary, renal, and neurological complications or depression [10].
We present a case of late onset of seronegative spondyloarthropaty in KTX patient despite ongoing immunosuppressive treatment. The following description applies to become unusual both in terms of gender, age, comorbidities of the patient, as well as the fact that the patient was constantly treated with triple immunosuppressive regimen.
Case presentation
A 58-year-old woman with end-stage renal disease caused by chronic glomerulonephritis, after allogenic KTx 25 years earlier, with stable, good graft function, treated with chronic immunosuppressive therapy based on cyclosporine A (CsA), mycophenolate mofetil (MMF), and prednisone, with no previous history of a connective tissue disease was admitted to the Nephrology Department with fever up to 39 °C accompanied by pain localized in the sacroiliac region radiating to the left lower limb of 2 weeks duration. Physical examination revealed nothing specific, her vital signs were stable. Initial laboratory data indicated an elevated C-reactive protein (CRP) concentration to 287 mg/l (normal range < 5 mg/l), white blood count (WBC) was 6.4 × 10 3/μl, haemoglobin concentration 10.6 g/dl, serum procalcitonin was negative. Urinalysis showed proteinuria 0.1 g/l, and 15 to 20 leukocytes /higher-power field (HPF), with no erythrocytes in urinary sediment. The graft function was stable (serum creatinine concentration (sCr) 95 μmol/l with estimated glomerular filtration rate (eGFRCKD-EPI) - 57.2 ml/min/1.73m2), serum uric acid was 7.8 mg/dl (normal range 4.2–6.8 mg/dl), alanine and aspartate aminotransferase as well as bilirubin concentration were within normal limits. The blood level of CsA was in the range appropriate to the period after KTx. Hepatitis B, hepatitis C, HIV and CMV DNA tests were negative. Urine and blood culture were negative. Echocardiography was performed, but revealed nothing specific and endocarditis was excluded. The empiric antibiotic therapy with clindamycin was started. Nuclear magnetic resonance (NMR) of the lumbar spine was firstly described as inconclusive, although the patient complained of constant pain aggravation. On the tenth day of hospitalization oedema with a tenderness of the left knee appeared. Due to exudates and excessive warmth of the left knee, arthrocentesis was performed. Sixty millilitres of turbid fluid was withdrawn. The synovial fluid was positive for Streptococcus sp. (saprophytic flora) thus a prolonged, targeted vancomycin therapy was started (the patient was allergic to penicillin). Gout was excluded. Moreover, because of the resistant pain and oedema of the left lower limb, Doppler ultrasound was performed and showed active deep vein thrombosis. Low molecular weight heparin therapy was administered in therapeutic dose. A control ultrasound examination revealed no features of thrombosis or valvular insufficiency. Despite antibiotic treatment further high inflammation parameters were still noted (CRP 149.4 mg/l), thus further diagnosis for atypical infection was performed (the direct examination of synovial fluid for tuberculosis and in vitro QuantiFERON test, anti - Borrelia burgdorferi antibodies in class IgM and IgG – all negative). After failure of treatment and the patient’s continuing complaints, the patient was referred to the Department of Rheumatology.
At the time of admission to the Department of Rheumatology the patient reported left knee pain sustained for more than a month and lumbar spine pain, severity independent of physical exercise, exacerbating during the night and accompanied by morning stiffness. Joint mobility within the normal range, soreness during loading and maximum limbs bent. In addition, Patrick sign was positive on the left side. After more detailed anamnesis the patient confirmed occurrence of typical inflammatory back pain of nearly 20 years. The pain typically worsened with inactivity and improved with exercise and non-steroid anti-inflammatory drugs (NSAIDs) treatment. Morning stiffness was prolonged to nearly all day. Nocturnal pain was not awakening her. The patient’s spine motion was markedly limited in all directions: Otto’s test 2 cm, Schober’s test 1.5 cm, chest expansion 3.5 cm deepening the cervical lordosis. Bath Ankylosing Spondylitis Disease Activity Index (BASDAI) was 6.2 whereas Bath Ankylosing Spondylitis Functional Index (BASFI) 2.5. There was neither edema nor mobility limitations in other peripheral joints. No other significant deviations from the norm in the rest of physical examination were noted. The symptoms were accompanied by high erythrocyte sedimentation rate (ESR) 98 mm/h, CRP 119.8 mg/l following an increase of creatinine concentration up to 144 μmol/l (GFRCKD-EPI 35.7 ml/min/1.73m2).
During hospitalization the antibiotic therapy started in the Department of Nephrology was completed, whilst the anti-coagulant therapy was continued. An x-ray of the lumbar spine and of the targeted sacroiliac joints revealed lesions characteristic of ankylosing spondylitis: vertebral body squaring, diffuse syndesmophyitic ankyloses giving a “bamboo spine” appearance and total ankyloses of sacroiliac joints (Fig. 1). The patient was HLA B27 positive, autoantibodies like the antinuclear antibodies (ANA), anti- cyclic citrullinated peptides antibodies and rheumatoid factor were negative. After the negative result of control culture of the synovial fluid, intrarticular injection of bethametazone and lignocaine mixture was administered. The fluid fulfilled the criteria for the inflammatory fluid type I (Table 1). Uric acid crystals were not detected. The NMR of the lumbar spine done in the Nephrology Unit was assessed once again by a more experienced radiologist in the Rheumatology Unit and was described as typical features of ankylosing spondylitis. A diagnosis of ankylosing spondylitis was posed (Tables 2 and 3) and the patient was started on oral sulphasalazine and NSAIDs. The treatment resulted in a significant decrease of CRP and improvement of the graft function (sCr 92 μmol/l, eGFR 61.4 ml/min/1.73 m2). The diagnosis of chronic kidney disease (CKD) and KTx determined a reduction of sulphasalazine dose to 2x500mg and after a short therapy the NSAIDs administration was reduced. Radiosynovectomy in the left knee joint was performed and after 2 weeks the patient, in good general condition, was discharged home.
Fig. 1 X-ray revealed diffuse syndesmophyitic ankylosis at all levels from Th12 to L1 (also seen above Th12), calcifications of spinal ligaments, features of vertebral body squaring, radiological signs of spondylodiscitis at levels from L1 to L4 with the widening of intervertebral space, blurring the trabecular structure of L5 and L6 narrowing of intervertebral spaces L4-S1. Left site scoliosis
Table 1 Synovial fluid parameters
Synovial fluid parameters
Volume 60 ml
Colour Yellow
Clarity Transparent
Viscosity High
Total protein 50.3 g/l
Glucose level Lower than blood
WBC 800/mm3
PMNs > 50%
Culture Negative
Table 2 Amor diagnostic criteria for spondyloarthropathy
Amor Criteria Our patient
Inflammatory back pain 1 point +
Unilateral buttock pain 1 point –
Alternating buttock pain 2 point –
Enthesitis 2 point +/−
Peripheral arthritis 2 point +
Dactylitis (sausage digit) 2 point –
Acute anterior uveitis 2 point –
HLA-B27
–positive or family history of spondyloarthropathy 2 point +
Good response to NSAIDs 2 point +
Diagnosis of spondyloarthropathy with 6 or more points 7–9 points
Table 3 New York diagnostic criteria for spondyloarthropathy
New York Criteria Our patient
Low back pain with inflammatory characteristics +
Limitation of lumbar spine motion in sagittal and frontal planes +
Decreased chest expansion +
Bilateral sacroiliitis grade 2 or higher +
Unilateral sacroiliitis grade 3 or higher
Definite ankylosing spondylitis when the fourth or fifth criterion mentioned presents with any clinical criteria 4 points
After 6 years of follow up during the routine visits in out-patient Transplantation Department the patient does not present any complaints associated with the left knee (no pain, tenderness, oedema). The graft function is still stable – creatinine concentration 90 μmol/l, GFRCKD-EPI 62 ml/min/1.73m2, she has been treated long-term with her base immunosuppressive therapy (stable dose of CsA 75 mg bid, stable dose of MMF 500 mg bid, and temporarily, increased steroid dose up to 20 mg qd at the moment of AS diagnosis with the subsequent dose reduction to 5 mg qd), with reduced sulphasalazine dose (2 × 500 mg), with no adverse effects of such treatment.
Discussion and conclusion
Joint pain is a frequent problem in individuals with kidney disease and is common both before and after KTx [11]. However, kidney involvement can be one of the complications following rheumatic diseases and can occur as a secondary amyloidosis which is the most common cause of nephrotic syndrome in AS followed by IgA nephropathy, mesangioproliferative glomerulonephritis as well as, rarely, by membranous nephropathy or focal segmental glomerulosclerosis [10]. A study by Hill et al. showed an 18% prevalence of CKD stages 3 to 5 in the rheumatic outpatient group, as compared to 5% reported within the general population [12]. On the other hand, it was shown that rheumatic diseases were the cause of ESRD and KTx in 14% of recipients transplanted in Poland between 1998 and 2015 years [13]. The authors showed that patients and graft survival were distinctly better in nonrheumatic recipients in comparison with rheumatic patients [13].
Differential diagnosis of joint and back pain in patients after successful KTx should take into account common complications of dialysis including crystal deposition disease, β2- microglobulin amyloidosis, secondary hyperparathyroidism, or aluminium overload as well as articular complications followed by hepatitis B and C or a variety of other infections [14]. In KTx recipients some new musculoskeletal and articular disorders, like infection-related arthralgia, polyarticular gout, rheumatoid arthritis flare, or a medication-related adverse reaction, namely steroid induced osteopenia or osteoporosis, may occur [11].
To the best of our knowledge, the present work is the first case report of late onset of seronegative spondyloarthropathy in a transplanted patient despite ongoing immunosuppressive treatment. De novo seropositive erosive rheumatoid arthritis in a patient 7 years after KTx was described by Forslund et al. in 2005 [15].
Immunosuppressive treatment after transplantation on the one hand prevents rejection of the transplanted organ, and on the other hand is an excellent treatment for diseases of the autoimmune and inflammatory background, preventing an exaggerated immune response. However certain injuries may alter this balance leading to dysregulation of the intestinal immune environment promoting the development of chronic inflammatory disease [16]. Immunosuppression heightens susceptibility to infectious agents that may damage the epithelial barrier of the intestinal mucosa resulting in prolonged exposure to luminal antigens followed by chronic immune stimulation [16].
Calcineurin inhibitors including CsA and tacrolimus strongly inhibit production of interleukin-2 (IL-2), which is normally produced by T cells to induce expansion of antigen-specific clones in response to a previously encountered antigen. Deficiency of IL-2 can result in T-cell dysregulation, leading to the development of chronic inflammation [17]. Arthralgia, muscular side effects and osteoarthropathy are some of the described side effects of CsA associated therapy. It was shown that high CsA levels (> 200 ng/ml) are the risk factors of joint pain in KTx recipients [11]. Our patient had the CsA trough level low, appropriate to time passed after KTx.
It has been found that mycophenolate mofetil can be associated with an acute inflammatory response characterized by fever, arthralgia, oligoarthritis and raised inflammatory markers appearing 3 to 5 days after initiation of therapy with MMF. Symptoms rapidly resolve with mycophenolate cessation. The pathogenesis has been associated with paradoxical pro-inflammatory reaction of polymorphonuclear neutrophils [18]. Our patient was treated with MMF for years, thus it is unlikely to have been the cause of symptoms.
The appearance of inflammatory disease regardless of adequate immunosuppressive therapy in transplant recipients is not unusual or impossible, however there is no data available associated with new onset of AS after transplantation. Moreover the most typical risk group of AS are young men, whereas the presented patient is a 58 year old woman. Very rarely does AS begin after the age of 40 resulting in difficulties in making the diagnosis, since standard classification scales are not validated for patients above 45 years old [19, 20].
The diagnosis of arthritis is primarily clinical. The most typical clinical features of arthritis of native joints are acute joint pain, swelling, warmth, erythema, decreased range of motion, fever, and general malaise. AS is characterised by the presence of spinal pain, resulting in limitation of spinal mobility reported also by our patient. These symptoms can be supported by laboratory evidence like leukocytosis or inflammatory markers including CRP, procalcitonin and ESR, which can be useful especially in patients with native joints without underlying haematological or rheumatological conditions. However, all of these laboratory tests have quite low sensitivity and specificity. Laboratory tests are usually followed by X-ray, ultrasound, computer tomography (CT) or magnetic resonance imaging (MRI) of the involved joint. To diagnose joint infection aspiration of the joints can be performed, however mainly in large joints.
As written above the immunosuppressive treatment can be associated with increased risk of infectious diseases. Therefore, the most common cause of monoarticular arthritis in both immunocompetent and immunocompromised patients is septic arthritis [21]. Symptoms of AS (low back pain) were reported by our patient for 20 years, but as low back pain is a common condition and the patient did not present other features of spondyloarthropathy like enthesitis, dactylitis, uveitis, diarrhoea or family clustering, the patient was not referred to a rheumatologist and the complaints were described as non-specific, mechanical low back pain. It cannot be excluded that the symptoms of AS were present earlier but were masked by anti-inflammatory properties of immunosuppressive drugs.
Although most cases of viral and reactive arthritis are connected with infectious background, they are usually not categorized as septic arthritis [21]. Monoarticular arthritis can result from viral infection caused by parvovirus B19, HIV or rubella, as well as from the deposition of immune complexes and complement components in hepatitis B and C infections [19]. In our patient the viral infections were excluded.
Reactive arthritis usually arises from an acute infection of the genitourinary or gastrointestinal tract caused by Shigella spp., Salmonella spp., Campylobacter jejuni, or Yersinia enterocolitica. It may also be one of the manifestations of Lyme disease [21, 22].
In the traditional understanding of septic arthritis the most commonly implicated organisms causing bacteremic septic arthritis are Staphylococcus aureus, Streptococcus pyogenes, Neisseria meningitides, Neisseria gonorrhoeae, Klebsiella pneumonia, Escherichia coli, Proteus spp., Salmonella spp., Morganella morganii, Citrobacter spp., Serratias spp or Pseudomonas aerginosa [22–24]. Septic arthritis can also result from mycobacteria (Mycobacterium tuberculosis), or fungi infections (Histoplasma capsulatum, Blastomyces dermatitidis, Coccidioides immitis) [21].
The most common predisposing factors for septic arthritis include age greater than 80 years, diabetes mellitus, rheumatoid arthritis, prosthetic joint, recent joint surgery, skin infection and skin ulcers, intravenous drug abuse and alcoholism, and previous intra-articular corticosteroid administration [25].
Transplant patients are particularly susceptible to develop septic arthritis caused by unusual organisms. These infections are commonly disseminated, involving both the bones and joints [25]. In the first few weeks after transplantation, joint infections are often hematogenous and caused by health-care-associated pathogens such as Staphylococcus aureus (including MRSA) and gram-negative bacilli like Pseudomonas aeruginosa [26]. However, in the months following transplantation, as patients are maintained on immunosuppressive therapy, they are more prone to infections caused by fungi and mycobacteria [26]. In our recipients fungi and mycobacteria were excluded.
Gout etiology was thought unlikely in our patient as no crystals were present on joint aspirate and the patient had no history of gout, with only slight elevated serum uric acid concentration [19] – thus this diagnosis was excluded in our case.
Following the modified New York criteria for AS it has been shown that radiographic sacroilitis is a rather late finding in the disease course of many patients [3]. The most typical radiological evidence for AS are structural changes in the sacroiliac joints and the spine. In our patient the typical features like vertebral body squaring, diffuse syndesmophyitic ankyloses giving a “bamboo spine” appearance and total ankyloses of sacroiliac joints were described on X-ray, whereas MRI revealed nothing specific.
Progression of AS varies among individuals, but some general trends can be observed. Younger age (≤40 years) at disease onset is usually associated with a predominance of axial symptoms, whereas patients with a later disease onset tend to present more peripheral manifestations [9]. Symptoms presented by our patient were associated with the spinal column despite her belonging to an older group.
The main purpose of treating the patient with AS is to improve long-term health-related quality of life by controlling the symptoms of the disease and averting continuous structural damage, thus leading to better joint function followed by improved social participation [3]. The treatment of AS should be personalised according to the present symptoms of the disease, patient’s comorbidities, possible complications resulting from the treatment and psychosocial factors [3].
The first-line drug treatment for patients complaining of pain and stiffness are NSAIDs administered up to the maximum dose, taking into consideration risks and benefits resulting from the treatment [27, 28]. Data from some studies revealed that in young patients failure to administered NSAIDs is associated with an increased mortality [29, 30]. For patients with good response to NSAIDs continuous use is recommended [3]. This first-line treatment should be enhanced by physical therapy including home exercises and by smoking cessation [31]. In patients who are contraindicated to NSAIDs or poorly tolerate this treatment, analgesics such as paracetamol and opioid-(like) drugs should be considered [3].
Lack of efficacy or presence of toxicity with NSAIDs is an indication to consider alternative treatments either with glucocorticoid, sulfasalazine or biological disease-modifying antirheumatic drugs (bDMARDs) [3].
Steroid injections directed to the local site of musculoskeletal inflammation may be recommended in patients with predominant peripheral manifestation as an option to treat arthritis and enthesitis, although direct evidence is lacking. Patients with axial disease should not be treated with systemic glucocorticoids for a long time [3].
Sulfasalazine may be considered in patients with peripheral arthritis, however it does not alleviate axial symptoms [32].
High disease activity defined as BASDAI ≥4 despite conventional treatment, elevated CRP, presence of inflammation on MRI of the SI joints and/or spine or presence of radiographic sacroiliitis is an indication to start bDMARDs and current practice is to start with tumour necrosis factor inhibitor (TNFi) therapy [31].
Our patient due to KTx was put on immunosuppressive therapy including CsA, MMF and steroids. Given the ongoing severity of the patient’s symptoms, no response to maintenance immunosuppressive therapy, contraindication to NSAIDs, a change in management was instituted by the administration of sulfasalazine. Improvement in the patient’s inflammatory markers and arthritis was noticed with subsidence of pain complaints and normalization of CRP within 2 weeks. She has had no further recurrence of acute inflammatory arthritis.
The establishing of proper diagnosis and management of a patient after KTx is difficult. Despite long-term immunosuppressive treatment in solid organ transplant recipients, in the differential diagnosis of joint pain the development of de novo arthritis should be considered, and when conclusive diagnosis is made, the patient may require administration of additional immunosuppressive drugs.
Abbreviations
ANAAntinuclear antibodies
anti-CCPAnti- cyclic citrullinated peptides
ASAnkylosing spondylitis
BASDAIBath Ankylosing Spondylitis Disease Activity Index
BASFIBath Ankylosing Spondylitis Functional Index
bDMARDsBiological disease-modifying antirheumatic drugs
CKDChronic kidney disease
CRPC-reactive protein
CsACyclosporine A
CTComputer tomography
eGFREstimated glomerular filtration rate
ESRErythrocyte sedimentation rate
ESRDEnd-stage renal disease
HPFHigher-power field
KtxKidney transplantation
MMFMycophenolate mofetil
MRIMagnetic resonance imaging
NMRNuclear magnetic resonance
NSAIDsNon-steroid anti-inflammatory drugs
SCrSerum creatinine concentration
TNFiTumour necrosis factor inhibitor
WBCWhite blood count
Publisher’s Note
Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
Acknowledgements
Not applicable.
Authors’ contributions
All authors have read and have approved the submitted version of the manuscript. AZB: designed the case report plan, described the subject medical history and was the primary author for the manuscript; OB: helped design the case report plan, IK helped in writing the manuscript, JM helped in writing the manuscript. All authors have agreed both to be personally accountable for the author’s own contributions and to ensure that questions related to the accuracy or integrity of any part of the work, even ones in which the author was not personally involved, are appropriately investigated, resolved, and the resolution documented in the literature.
Funding
Not applicable.
Availability of data and materials
The patient results used and/or analysed during the current case report are available from the corresponding author on reasonable request.
Ethics approval and consent to participate
Not applicable (case report).
Consent for publication
The patient in written consent agreed to publish the laboratory as well as radiological results.
Competing interests
None of the authors claims a conflict of interest. All authors declare no financial and non-financial competing interests. | Recovered | ReactionOutcome | CC BY | 33517879 | 19,003,793 | 2021-01-31 |
What was the outcome of reaction 'Septic arthritis streptococcal'? | Post-transplant manifestation of ankylosing spondylitis: a case report and review of literature.
Ankylosing spondylitis (AS) is an insidiously progressive and debilitating form of arthritis involving the axial skeleton, characterized by chronic back pain and progressive spinal stiffness, and lessening of pain and stiffness with exercise. Due to subsequent manifestation in different organs, AS causes reduction in life expectancy, so early diagnosis and treatment are of great importance. No AS cases have been reported in solid-organ transplant recipients yet.
A 58-year-old woman with end-stage renal disease due to chronic glomerulonephritis, after allogenic kidney transplantation 25 years earlier, with stable, good graft function, treated with chronic immunosuppressive therapy based on cyclosporine A, mycophenolate mofetil, and prednisone, with no previous history of a connective tissue disease presented fever up to 39 °C accompanied by pain localized in sacroiliac region radiating to the left lower limb. Detailed diagnostic procedures and x-rays of the lumbar spine and of the targeted sacroiliac joints revealed lesions characteristic of AS. Sulphasalazine was added to standard immunosuppression regimen with good clinical results.
We report an adult kidney transplant recipient with a new onset of AS. The risk of relapse or new onset of inflammatory disease in transplant recipients is extremely low due to immunosuppressive therapy following transplantation. However, when it occurs, the clinical presentation is commonly atypical, often leading to delayed diagnosis.
Background
The appearance of inflammatory and autoimmune diseases is quite low in patients after solid organ transplantation [1]. Adequate immunosuppressive therapy usually mitigates the risk of relapse or new onset of an autoimmune disease in this population [2]. The clinical presentation of inflammatory diseases in patients after transplantation is commonly atypical, often leading to delayed diagnosis.
Musculoskeletal pain is a common problem in kidney transplant (KTx) recipients, however, an acute inflammatory arthritis is rare. The differential diagnosis of joint and back pain is broad and includes septic arthritis, systemic infection, crystal arthropathies, autoimmune rheumatologic disorders, and medication-related adverse reactions [3].
Ankylosing spondylitis (AS), previously known as Bechterew’s disease, is a chronic, progressive inflammatory disease with a diverse clinical presentation [3]. AS is characterized by inflammation and new bone formation leading to fusion of the spine and sacroiliac joints. Chronic back pain, progressive spinal stiffness and improvement of pain and stiffness with exercise are the most common features of the disease [4]. Other musculoskeletal manifestations of AS include arthritis, enthesitis and dactylitis [5]. Clinical symptoms most frequently begin in late adolescence or in young adults, with 80% before the age of 30 and with a 3:1 to 2:1 male to female ratio [6, 7].
In addition to spinal inflammation, AS is characterized by a broad clinical spectrum of the extra-articular manifestations like uveitis, psoriasis, inflammatory bowel disease, or aortic insufficiency [8, 9] as well as an increased cardiovascular risk, several pulmonary, renal, and neurological complications or depression [10].
We present a case of late onset of seronegative spondyloarthropaty in KTX patient despite ongoing immunosuppressive treatment. The following description applies to become unusual both in terms of gender, age, comorbidities of the patient, as well as the fact that the patient was constantly treated with triple immunosuppressive regimen.
Case presentation
A 58-year-old woman with end-stage renal disease caused by chronic glomerulonephritis, after allogenic KTx 25 years earlier, with stable, good graft function, treated with chronic immunosuppressive therapy based on cyclosporine A (CsA), mycophenolate mofetil (MMF), and prednisone, with no previous history of a connective tissue disease was admitted to the Nephrology Department with fever up to 39 °C accompanied by pain localized in the sacroiliac region radiating to the left lower limb of 2 weeks duration. Physical examination revealed nothing specific, her vital signs were stable. Initial laboratory data indicated an elevated C-reactive protein (CRP) concentration to 287 mg/l (normal range < 5 mg/l), white blood count (WBC) was 6.4 × 10 3/μl, haemoglobin concentration 10.6 g/dl, serum procalcitonin was negative. Urinalysis showed proteinuria 0.1 g/l, and 15 to 20 leukocytes /higher-power field (HPF), with no erythrocytes in urinary sediment. The graft function was stable (serum creatinine concentration (sCr) 95 μmol/l with estimated glomerular filtration rate (eGFRCKD-EPI) - 57.2 ml/min/1.73m2), serum uric acid was 7.8 mg/dl (normal range 4.2–6.8 mg/dl), alanine and aspartate aminotransferase as well as bilirubin concentration were within normal limits. The blood level of CsA was in the range appropriate to the period after KTx. Hepatitis B, hepatitis C, HIV and CMV DNA tests were negative. Urine and blood culture were negative. Echocardiography was performed, but revealed nothing specific and endocarditis was excluded. The empiric antibiotic therapy with clindamycin was started. Nuclear magnetic resonance (NMR) of the lumbar spine was firstly described as inconclusive, although the patient complained of constant pain aggravation. On the tenth day of hospitalization oedema with a tenderness of the left knee appeared. Due to exudates and excessive warmth of the left knee, arthrocentesis was performed. Sixty millilitres of turbid fluid was withdrawn. The synovial fluid was positive for Streptococcus sp. (saprophytic flora) thus a prolonged, targeted vancomycin therapy was started (the patient was allergic to penicillin). Gout was excluded. Moreover, because of the resistant pain and oedema of the left lower limb, Doppler ultrasound was performed and showed active deep vein thrombosis. Low molecular weight heparin therapy was administered in therapeutic dose. A control ultrasound examination revealed no features of thrombosis or valvular insufficiency. Despite antibiotic treatment further high inflammation parameters were still noted (CRP 149.4 mg/l), thus further diagnosis for atypical infection was performed (the direct examination of synovial fluid for tuberculosis and in vitro QuantiFERON test, anti - Borrelia burgdorferi antibodies in class IgM and IgG – all negative). After failure of treatment and the patient’s continuing complaints, the patient was referred to the Department of Rheumatology.
At the time of admission to the Department of Rheumatology the patient reported left knee pain sustained for more than a month and lumbar spine pain, severity independent of physical exercise, exacerbating during the night and accompanied by morning stiffness. Joint mobility within the normal range, soreness during loading and maximum limbs bent. In addition, Patrick sign was positive on the left side. After more detailed anamnesis the patient confirmed occurrence of typical inflammatory back pain of nearly 20 years. The pain typically worsened with inactivity and improved with exercise and non-steroid anti-inflammatory drugs (NSAIDs) treatment. Morning stiffness was prolonged to nearly all day. Nocturnal pain was not awakening her. The patient’s spine motion was markedly limited in all directions: Otto’s test 2 cm, Schober’s test 1.5 cm, chest expansion 3.5 cm deepening the cervical lordosis. Bath Ankylosing Spondylitis Disease Activity Index (BASDAI) was 6.2 whereas Bath Ankylosing Spondylitis Functional Index (BASFI) 2.5. There was neither edema nor mobility limitations in other peripheral joints. No other significant deviations from the norm in the rest of physical examination were noted. The symptoms were accompanied by high erythrocyte sedimentation rate (ESR) 98 mm/h, CRP 119.8 mg/l following an increase of creatinine concentration up to 144 μmol/l (GFRCKD-EPI 35.7 ml/min/1.73m2).
During hospitalization the antibiotic therapy started in the Department of Nephrology was completed, whilst the anti-coagulant therapy was continued. An x-ray of the lumbar spine and of the targeted sacroiliac joints revealed lesions characteristic of ankylosing spondylitis: vertebral body squaring, diffuse syndesmophyitic ankyloses giving a “bamboo spine” appearance and total ankyloses of sacroiliac joints (Fig. 1). The patient was HLA B27 positive, autoantibodies like the antinuclear antibodies (ANA), anti- cyclic citrullinated peptides antibodies and rheumatoid factor were negative. After the negative result of control culture of the synovial fluid, intrarticular injection of bethametazone and lignocaine mixture was administered. The fluid fulfilled the criteria for the inflammatory fluid type I (Table 1). Uric acid crystals were not detected. The NMR of the lumbar spine done in the Nephrology Unit was assessed once again by a more experienced radiologist in the Rheumatology Unit and was described as typical features of ankylosing spondylitis. A diagnosis of ankylosing spondylitis was posed (Tables 2 and 3) and the patient was started on oral sulphasalazine and NSAIDs. The treatment resulted in a significant decrease of CRP and improvement of the graft function (sCr 92 μmol/l, eGFR 61.4 ml/min/1.73 m2). The diagnosis of chronic kidney disease (CKD) and KTx determined a reduction of sulphasalazine dose to 2x500mg and after a short therapy the NSAIDs administration was reduced. Radiosynovectomy in the left knee joint was performed and after 2 weeks the patient, in good general condition, was discharged home.
Fig. 1 X-ray revealed diffuse syndesmophyitic ankylosis at all levels from Th12 to L1 (also seen above Th12), calcifications of spinal ligaments, features of vertebral body squaring, radiological signs of spondylodiscitis at levels from L1 to L4 with the widening of intervertebral space, blurring the trabecular structure of L5 and L6 narrowing of intervertebral spaces L4-S1. Left site scoliosis
Table 1 Synovial fluid parameters
Synovial fluid parameters
Volume 60 ml
Colour Yellow
Clarity Transparent
Viscosity High
Total protein 50.3 g/l
Glucose level Lower than blood
WBC 800/mm3
PMNs > 50%
Culture Negative
Table 2 Amor diagnostic criteria for spondyloarthropathy
Amor Criteria Our patient
Inflammatory back pain 1 point +
Unilateral buttock pain 1 point –
Alternating buttock pain 2 point –
Enthesitis 2 point +/−
Peripheral arthritis 2 point +
Dactylitis (sausage digit) 2 point –
Acute anterior uveitis 2 point –
HLA-B27
–positive or family history of spondyloarthropathy 2 point +
Good response to NSAIDs 2 point +
Diagnosis of spondyloarthropathy with 6 or more points 7–9 points
Table 3 New York diagnostic criteria for spondyloarthropathy
New York Criteria Our patient
Low back pain with inflammatory characteristics +
Limitation of lumbar spine motion in sagittal and frontal planes +
Decreased chest expansion +
Bilateral sacroiliitis grade 2 or higher +
Unilateral sacroiliitis grade 3 or higher
Definite ankylosing spondylitis when the fourth or fifth criterion mentioned presents with any clinical criteria 4 points
After 6 years of follow up during the routine visits in out-patient Transplantation Department the patient does not present any complaints associated with the left knee (no pain, tenderness, oedema). The graft function is still stable – creatinine concentration 90 μmol/l, GFRCKD-EPI 62 ml/min/1.73m2, she has been treated long-term with her base immunosuppressive therapy (stable dose of CsA 75 mg bid, stable dose of MMF 500 mg bid, and temporarily, increased steroid dose up to 20 mg qd at the moment of AS diagnosis with the subsequent dose reduction to 5 mg qd), with reduced sulphasalazine dose (2 × 500 mg), with no adverse effects of such treatment.
Discussion and conclusion
Joint pain is a frequent problem in individuals with kidney disease and is common both before and after KTx [11]. However, kidney involvement can be one of the complications following rheumatic diseases and can occur as a secondary amyloidosis which is the most common cause of nephrotic syndrome in AS followed by IgA nephropathy, mesangioproliferative glomerulonephritis as well as, rarely, by membranous nephropathy or focal segmental glomerulosclerosis [10]. A study by Hill et al. showed an 18% prevalence of CKD stages 3 to 5 in the rheumatic outpatient group, as compared to 5% reported within the general population [12]. On the other hand, it was shown that rheumatic diseases were the cause of ESRD and KTx in 14% of recipients transplanted in Poland between 1998 and 2015 years [13]. The authors showed that patients and graft survival were distinctly better in nonrheumatic recipients in comparison with rheumatic patients [13].
Differential diagnosis of joint and back pain in patients after successful KTx should take into account common complications of dialysis including crystal deposition disease, β2- microglobulin amyloidosis, secondary hyperparathyroidism, or aluminium overload as well as articular complications followed by hepatitis B and C or a variety of other infections [14]. In KTx recipients some new musculoskeletal and articular disorders, like infection-related arthralgia, polyarticular gout, rheumatoid arthritis flare, or a medication-related adverse reaction, namely steroid induced osteopenia or osteoporosis, may occur [11].
To the best of our knowledge, the present work is the first case report of late onset of seronegative spondyloarthropathy in a transplanted patient despite ongoing immunosuppressive treatment. De novo seropositive erosive rheumatoid arthritis in a patient 7 years after KTx was described by Forslund et al. in 2005 [15].
Immunosuppressive treatment after transplantation on the one hand prevents rejection of the transplanted organ, and on the other hand is an excellent treatment for diseases of the autoimmune and inflammatory background, preventing an exaggerated immune response. However certain injuries may alter this balance leading to dysregulation of the intestinal immune environment promoting the development of chronic inflammatory disease [16]. Immunosuppression heightens susceptibility to infectious agents that may damage the epithelial barrier of the intestinal mucosa resulting in prolonged exposure to luminal antigens followed by chronic immune stimulation [16].
Calcineurin inhibitors including CsA and tacrolimus strongly inhibit production of interleukin-2 (IL-2), which is normally produced by T cells to induce expansion of antigen-specific clones in response to a previously encountered antigen. Deficiency of IL-2 can result in T-cell dysregulation, leading to the development of chronic inflammation [17]. Arthralgia, muscular side effects and osteoarthropathy are some of the described side effects of CsA associated therapy. It was shown that high CsA levels (> 200 ng/ml) are the risk factors of joint pain in KTx recipients [11]. Our patient had the CsA trough level low, appropriate to time passed after KTx.
It has been found that mycophenolate mofetil can be associated with an acute inflammatory response characterized by fever, arthralgia, oligoarthritis and raised inflammatory markers appearing 3 to 5 days after initiation of therapy with MMF. Symptoms rapidly resolve with mycophenolate cessation. The pathogenesis has been associated with paradoxical pro-inflammatory reaction of polymorphonuclear neutrophils [18]. Our patient was treated with MMF for years, thus it is unlikely to have been the cause of symptoms.
The appearance of inflammatory disease regardless of adequate immunosuppressive therapy in transplant recipients is not unusual or impossible, however there is no data available associated with new onset of AS after transplantation. Moreover the most typical risk group of AS are young men, whereas the presented patient is a 58 year old woman. Very rarely does AS begin after the age of 40 resulting in difficulties in making the diagnosis, since standard classification scales are not validated for patients above 45 years old [19, 20].
The diagnosis of arthritis is primarily clinical. The most typical clinical features of arthritis of native joints are acute joint pain, swelling, warmth, erythema, decreased range of motion, fever, and general malaise. AS is characterised by the presence of spinal pain, resulting in limitation of spinal mobility reported also by our patient. These symptoms can be supported by laboratory evidence like leukocytosis or inflammatory markers including CRP, procalcitonin and ESR, which can be useful especially in patients with native joints without underlying haematological or rheumatological conditions. However, all of these laboratory tests have quite low sensitivity and specificity. Laboratory tests are usually followed by X-ray, ultrasound, computer tomography (CT) or magnetic resonance imaging (MRI) of the involved joint. To diagnose joint infection aspiration of the joints can be performed, however mainly in large joints.
As written above the immunosuppressive treatment can be associated with increased risk of infectious diseases. Therefore, the most common cause of monoarticular arthritis in both immunocompetent and immunocompromised patients is septic arthritis [21]. Symptoms of AS (low back pain) were reported by our patient for 20 years, but as low back pain is a common condition and the patient did not present other features of spondyloarthropathy like enthesitis, dactylitis, uveitis, diarrhoea or family clustering, the patient was not referred to a rheumatologist and the complaints were described as non-specific, mechanical low back pain. It cannot be excluded that the symptoms of AS were present earlier but were masked by anti-inflammatory properties of immunosuppressive drugs.
Although most cases of viral and reactive arthritis are connected with infectious background, they are usually not categorized as septic arthritis [21]. Monoarticular arthritis can result from viral infection caused by parvovirus B19, HIV or rubella, as well as from the deposition of immune complexes and complement components in hepatitis B and C infections [19]. In our patient the viral infections were excluded.
Reactive arthritis usually arises from an acute infection of the genitourinary or gastrointestinal tract caused by Shigella spp., Salmonella spp., Campylobacter jejuni, or Yersinia enterocolitica. It may also be one of the manifestations of Lyme disease [21, 22].
In the traditional understanding of septic arthritis the most commonly implicated organisms causing bacteremic septic arthritis are Staphylococcus aureus, Streptococcus pyogenes, Neisseria meningitides, Neisseria gonorrhoeae, Klebsiella pneumonia, Escherichia coli, Proteus spp., Salmonella spp., Morganella morganii, Citrobacter spp., Serratias spp or Pseudomonas aerginosa [22–24]. Septic arthritis can also result from mycobacteria (Mycobacterium tuberculosis), or fungi infections (Histoplasma capsulatum, Blastomyces dermatitidis, Coccidioides immitis) [21].
The most common predisposing factors for septic arthritis include age greater than 80 years, diabetes mellitus, rheumatoid arthritis, prosthetic joint, recent joint surgery, skin infection and skin ulcers, intravenous drug abuse and alcoholism, and previous intra-articular corticosteroid administration [25].
Transplant patients are particularly susceptible to develop septic arthritis caused by unusual organisms. These infections are commonly disseminated, involving both the bones and joints [25]. In the first few weeks after transplantation, joint infections are often hematogenous and caused by health-care-associated pathogens such as Staphylococcus aureus (including MRSA) and gram-negative bacilli like Pseudomonas aeruginosa [26]. However, in the months following transplantation, as patients are maintained on immunosuppressive therapy, they are more prone to infections caused by fungi and mycobacteria [26]. In our recipients fungi and mycobacteria were excluded.
Gout etiology was thought unlikely in our patient as no crystals were present on joint aspirate and the patient had no history of gout, with only slight elevated serum uric acid concentration [19] – thus this diagnosis was excluded in our case.
Following the modified New York criteria for AS it has been shown that radiographic sacroilitis is a rather late finding in the disease course of many patients [3]. The most typical radiological evidence for AS are structural changes in the sacroiliac joints and the spine. In our patient the typical features like vertebral body squaring, diffuse syndesmophyitic ankyloses giving a “bamboo spine” appearance and total ankyloses of sacroiliac joints were described on X-ray, whereas MRI revealed nothing specific.
Progression of AS varies among individuals, but some general trends can be observed. Younger age (≤40 years) at disease onset is usually associated with a predominance of axial symptoms, whereas patients with a later disease onset tend to present more peripheral manifestations [9]. Symptoms presented by our patient were associated with the spinal column despite her belonging to an older group.
The main purpose of treating the patient with AS is to improve long-term health-related quality of life by controlling the symptoms of the disease and averting continuous structural damage, thus leading to better joint function followed by improved social participation [3]. The treatment of AS should be personalised according to the present symptoms of the disease, patient’s comorbidities, possible complications resulting from the treatment and psychosocial factors [3].
The first-line drug treatment for patients complaining of pain and stiffness are NSAIDs administered up to the maximum dose, taking into consideration risks and benefits resulting from the treatment [27, 28]. Data from some studies revealed that in young patients failure to administered NSAIDs is associated with an increased mortality [29, 30]. For patients with good response to NSAIDs continuous use is recommended [3]. This first-line treatment should be enhanced by physical therapy including home exercises and by smoking cessation [31]. In patients who are contraindicated to NSAIDs or poorly tolerate this treatment, analgesics such as paracetamol and opioid-(like) drugs should be considered [3].
Lack of efficacy or presence of toxicity with NSAIDs is an indication to consider alternative treatments either with glucocorticoid, sulfasalazine or biological disease-modifying antirheumatic drugs (bDMARDs) [3].
Steroid injections directed to the local site of musculoskeletal inflammation may be recommended in patients with predominant peripheral manifestation as an option to treat arthritis and enthesitis, although direct evidence is lacking. Patients with axial disease should not be treated with systemic glucocorticoids for a long time [3].
Sulfasalazine may be considered in patients with peripheral arthritis, however it does not alleviate axial symptoms [32].
High disease activity defined as BASDAI ≥4 despite conventional treatment, elevated CRP, presence of inflammation on MRI of the SI joints and/or spine or presence of radiographic sacroiliitis is an indication to start bDMARDs and current practice is to start with tumour necrosis factor inhibitor (TNFi) therapy [31].
Our patient due to KTx was put on immunosuppressive therapy including CsA, MMF and steroids. Given the ongoing severity of the patient’s symptoms, no response to maintenance immunosuppressive therapy, contraindication to NSAIDs, a change in management was instituted by the administration of sulfasalazine. Improvement in the patient’s inflammatory markers and arthritis was noticed with subsidence of pain complaints and normalization of CRP within 2 weeks. She has had no further recurrence of acute inflammatory arthritis.
The establishing of proper diagnosis and management of a patient after KTx is difficult. Despite long-term immunosuppressive treatment in solid organ transplant recipients, in the differential diagnosis of joint pain the development of de novo arthritis should be considered, and when conclusive diagnosis is made, the patient may require administration of additional immunosuppressive drugs.
Abbreviations
ANAAntinuclear antibodies
anti-CCPAnti- cyclic citrullinated peptides
ASAnkylosing spondylitis
BASDAIBath Ankylosing Spondylitis Disease Activity Index
BASFIBath Ankylosing Spondylitis Functional Index
bDMARDsBiological disease-modifying antirheumatic drugs
CKDChronic kidney disease
CRPC-reactive protein
CsACyclosporine A
CTComputer tomography
eGFREstimated glomerular filtration rate
ESRErythrocyte sedimentation rate
ESRDEnd-stage renal disease
HPFHigher-power field
KtxKidney transplantation
MMFMycophenolate mofetil
MRIMagnetic resonance imaging
NMRNuclear magnetic resonance
NSAIDsNon-steroid anti-inflammatory drugs
SCrSerum creatinine concentration
TNFiTumour necrosis factor inhibitor
WBCWhite blood count
Publisher’s Note
Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
Acknowledgements
Not applicable.
Authors’ contributions
All authors have read and have approved the submitted version of the manuscript. AZB: designed the case report plan, described the subject medical history and was the primary author for the manuscript; OB: helped design the case report plan, IK helped in writing the manuscript, JM helped in writing the manuscript. All authors have agreed both to be personally accountable for the author’s own contributions and to ensure that questions related to the accuracy or integrity of any part of the work, even ones in which the author was not personally involved, are appropriately investigated, resolved, and the resolution documented in the literature.
Funding
Not applicable.
Availability of data and materials
The patient results used and/or analysed during the current case report are available from the corresponding author on reasonable request.
Ethics approval and consent to participate
Not applicable (case report).
Consent for publication
The patient in written consent agreed to publish the laboratory as well as radiological results.
Competing interests
None of the authors claims a conflict of interest. All authors declare no financial and non-financial competing interests. | Recovered | ReactionOutcome | CC BY | 33517879 | 19,794,934 | 2021-01-31 |
What was the outcome of reaction 'Streptococcal infection'? | Post-transplant manifestation of ankylosing spondylitis: a case report and review of literature.
Ankylosing spondylitis (AS) is an insidiously progressive and debilitating form of arthritis involving the axial skeleton, characterized by chronic back pain and progressive spinal stiffness, and lessening of pain and stiffness with exercise. Due to subsequent manifestation in different organs, AS causes reduction in life expectancy, so early diagnosis and treatment are of great importance. No AS cases have been reported in solid-organ transplant recipients yet.
A 58-year-old woman with end-stage renal disease due to chronic glomerulonephritis, after allogenic kidney transplantation 25 years earlier, with stable, good graft function, treated with chronic immunosuppressive therapy based on cyclosporine A, mycophenolate mofetil, and prednisone, with no previous history of a connective tissue disease presented fever up to 39 °C accompanied by pain localized in sacroiliac region radiating to the left lower limb. Detailed diagnostic procedures and x-rays of the lumbar spine and of the targeted sacroiliac joints revealed lesions characteristic of AS. Sulphasalazine was added to standard immunosuppression regimen with good clinical results.
We report an adult kidney transplant recipient with a new onset of AS. The risk of relapse or new onset of inflammatory disease in transplant recipients is extremely low due to immunosuppressive therapy following transplantation. However, when it occurs, the clinical presentation is commonly atypical, often leading to delayed diagnosis.
Background
The appearance of inflammatory and autoimmune diseases is quite low in patients after solid organ transplantation [1]. Adequate immunosuppressive therapy usually mitigates the risk of relapse or new onset of an autoimmune disease in this population [2]. The clinical presentation of inflammatory diseases in patients after transplantation is commonly atypical, often leading to delayed diagnosis.
Musculoskeletal pain is a common problem in kidney transplant (KTx) recipients, however, an acute inflammatory arthritis is rare. The differential diagnosis of joint and back pain is broad and includes septic arthritis, systemic infection, crystal arthropathies, autoimmune rheumatologic disorders, and medication-related adverse reactions [3].
Ankylosing spondylitis (AS), previously known as Bechterew’s disease, is a chronic, progressive inflammatory disease with a diverse clinical presentation [3]. AS is characterized by inflammation and new bone formation leading to fusion of the spine and sacroiliac joints. Chronic back pain, progressive spinal stiffness and improvement of pain and stiffness with exercise are the most common features of the disease [4]. Other musculoskeletal manifestations of AS include arthritis, enthesitis and dactylitis [5]. Clinical symptoms most frequently begin in late adolescence or in young adults, with 80% before the age of 30 and with a 3:1 to 2:1 male to female ratio [6, 7].
In addition to spinal inflammation, AS is characterized by a broad clinical spectrum of the extra-articular manifestations like uveitis, psoriasis, inflammatory bowel disease, or aortic insufficiency [8, 9] as well as an increased cardiovascular risk, several pulmonary, renal, and neurological complications or depression [10].
We present a case of late onset of seronegative spondyloarthropaty in KTX patient despite ongoing immunosuppressive treatment. The following description applies to become unusual both in terms of gender, age, comorbidities of the patient, as well as the fact that the patient was constantly treated with triple immunosuppressive regimen.
Case presentation
A 58-year-old woman with end-stage renal disease caused by chronic glomerulonephritis, after allogenic KTx 25 years earlier, with stable, good graft function, treated with chronic immunosuppressive therapy based on cyclosporine A (CsA), mycophenolate mofetil (MMF), and prednisone, with no previous history of a connective tissue disease was admitted to the Nephrology Department with fever up to 39 °C accompanied by pain localized in the sacroiliac region radiating to the left lower limb of 2 weeks duration. Physical examination revealed nothing specific, her vital signs were stable. Initial laboratory data indicated an elevated C-reactive protein (CRP) concentration to 287 mg/l (normal range < 5 mg/l), white blood count (WBC) was 6.4 × 10 3/μl, haemoglobin concentration 10.6 g/dl, serum procalcitonin was negative. Urinalysis showed proteinuria 0.1 g/l, and 15 to 20 leukocytes /higher-power field (HPF), with no erythrocytes in urinary sediment. The graft function was stable (serum creatinine concentration (sCr) 95 μmol/l with estimated glomerular filtration rate (eGFRCKD-EPI) - 57.2 ml/min/1.73m2), serum uric acid was 7.8 mg/dl (normal range 4.2–6.8 mg/dl), alanine and aspartate aminotransferase as well as bilirubin concentration were within normal limits. The blood level of CsA was in the range appropriate to the period after KTx. Hepatitis B, hepatitis C, HIV and CMV DNA tests were negative. Urine and blood culture were negative. Echocardiography was performed, but revealed nothing specific and endocarditis was excluded. The empiric antibiotic therapy with clindamycin was started. Nuclear magnetic resonance (NMR) of the lumbar spine was firstly described as inconclusive, although the patient complained of constant pain aggravation. On the tenth day of hospitalization oedema with a tenderness of the left knee appeared. Due to exudates and excessive warmth of the left knee, arthrocentesis was performed. Sixty millilitres of turbid fluid was withdrawn. The synovial fluid was positive for Streptococcus sp. (saprophytic flora) thus a prolonged, targeted vancomycin therapy was started (the patient was allergic to penicillin). Gout was excluded. Moreover, because of the resistant pain and oedema of the left lower limb, Doppler ultrasound was performed and showed active deep vein thrombosis. Low molecular weight heparin therapy was administered in therapeutic dose. A control ultrasound examination revealed no features of thrombosis or valvular insufficiency. Despite antibiotic treatment further high inflammation parameters were still noted (CRP 149.4 mg/l), thus further diagnosis for atypical infection was performed (the direct examination of synovial fluid for tuberculosis and in vitro QuantiFERON test, anti - Borrelia burgdorferi antibodies in class IgM and IgG – all negative). After failure of treatment and the patient’s continuing complaints, the patient was referred to the Department of Rheumatology.
At the time of admission to the Department of Rheumatology the patient reported left knee pain sustained for more than a month and lumbar spine pain, severity independent of physical exercise, exacerbating during the night and accompanied by morning stiffness. Joint mobility within the normal range, soreness during loading and maximum limbs bent. In addition, Patrick sign was positive on the left side. After more detailed anamnesis the patient confirmed occurrence of typical inflammatory back pain of nearly 20 years. The pain typically worsened with inactivity and improved with exercise and non-steroid anti-inflammatory drugs (NSAIDs) treatment. Morning stiffness was prolonged to nearly all day. Nocturnal pain was not awakening her. The patient’s spine motion was markedly limited in all directions: Otto’s test 2 cm, Schober’s test 1.5 cm, chest expansion 3.5 cm deepening the cervical lordosis. Bath Ankylosing Spondylitis Disease Activity Index (BASDAI) was 6.2 whereas Bath Ankylosing Spondylitis Functional Index (BASFI) 2.5. There was neither edema nor mobility limitations in other peripheral joints. No other significant deviations from the norm in the rest of physical examination were noted. The symptoms were accompanied by high erythrocyte sedimentation rate (ESR) 98 mm/h, CRP 119.8 mg/l following an increase of creatinine concentration up to 144 μmol/l (GFRCKD-EPI 35.7 ml/min/1.73m2).
During hospitalization the antibiotic therapy started in the Department of Nephrology was completed, whilst the anti-coagulant therapy was continued. An x-ray of the lumbar spine and of the targeted sacroiliac joints revealed lesions characteristic of ankylosing spondylitis: vertebral body squaring, diffuse syndesmophyitic ankyloses giving a “bamboo spine” appearance and total ankyloses of sacroiliac joints (Fig. 1). The patient was HLA B27 positive, autoantibodies like the antinuclear antibodies (ANA), anti- cyclic citrullinated peptides antibodies and rheumatoid factor were negative. After the negative result of control culture of the synovial fluid, intrarticular injection of bethametazone and lignocaine mixture was administered. The fluid fulfilled the criteria for the inflammatory fluid type I (Table 1). Uric acid crystals were not detected. The NMR of the lumbar spine done in the Nephrology Unit was assessed once again by a more experienced radiologist in the Rheumatology Unit and was described as typical features of ankylosing spondylitis. A diagnosis of ankylosing spondylitis was posed (Tables 2 and 3) and the patient was started on oral sulphasalazine and NSAIDs. The treatment resulted in a significant decrease of CRP and improvement of the graft function (sCr 92 μmol/l, eGFR 61.4 ml/min/1.73 m2). The diagnosis of chronic kidney disease (CKD) and KTx determined a reduction of sulphasalazine dose to 2x500mg and after a short therapy the NSAIDs administration was reduced. Radiosynovectomy in the left knee joint was performed and after 2 weeks the patient, in good general condition, was discharged home.
Fig. 1 X-ray revealed diffuse syndesmophyitic ankylosis at all levels from Th12 to L1 (also seen above Th12), calcifications of spinal ligaments, features of vertebral body squaring, radiological signs of spondylodiscitis at levels from L1 to L4 with the widening of intervertebral space, blurring the trabecular structure of L5 and L6 narrowing of intervertebral spaces L4-S1. Left site scoliosis
Table 1 Synovial fluid parameters
Synovial fluid parameters
Volume 60 ml
Colour Yellow
Clarity Transparent
Viscosity High
Total protein 50.3 g/l
Glucose level Lower than blood
WBC 800/mm3
PMNs > 50%
Culture Negative
Table 2 Amor diagnostic criteria for spondyloarthropathy
Amor Criteria Our patient
Inflammatory back pain 1 point +
Unilateral buttock pain 1 point –
Alternating buttock pain 2 point –
Enthesitis 2 point +/−
Peripheral arthritis 2 point +
Dactylitis (sausage digit) 2 point –
Acute anterior uveitis 2 point –
HLA-B27
–positive or family history of spondyloarthropathy 2 point +
Good response to NSAIDs 2 point +
Diagnosis of spondyloarthropathy with 6 or more points 7–9 points
Table 3 New York diagnostic criteria for spondyloarthropathy
New York Criteria Our patient
Low back pain with inflammatory characteristics +
Limitation of lumbar spine motion in sagittal and frontal planes +
Decreased chest expansion +
Bilateral sacroiliitis grade 2 or higher +
Unilateral sacroiliitis grade 3 or higher
Definite ankylosing spondylitis when the fourth or fifth criterion mentioned presents with any clinical criteria 4 points
After 6 years of follow up during the routine visits in out-patient Transplantation Department the patient does not present any complaints associated with the left knee (no pain, tenderness, oedema). The graft function is still stable – creatinine concentration 90 μmol/l, GFRCKD-EPI 62 ml/min/1.73m2, she has been treated long-term with her base immunosuppressive therapy (stable dose of CsA 75 mg bid, stable dose of MMF 500 mg bid, and temporarily, increased steroid dose up to 20 mg qd at the moment of AS diagnosis with the subsequent dose reduction to 5 mg qd), with reduced sulphasalazine dose (2 × 500 mg), with no adverse effects of such treatment.
Discussion and conclusion
Joint pain is a frequent problem in individuals with kidney disease and is common both before and after KTx [11]. However, kidney involvement can be one of the complications following rheumatic diseases and can occur as a secondary amyloidosis which is the most common cause of nephrotic syndrome in AS followed by IgA nephropathy, mesangioproliferative glomerulonephritis as well as, rarely, by membranous nephropathy or focal segmental glomerulosclerosis [10]. A study by Hill et al. showed an 18% prevalence of CKD stages 3 to 5 in the rheumatic outpatient group, as compared to 5% reported within the general population [12]. On the other hand, it was shown that rheumatic diseases were the cause of ESRD and KTx in 14% of recipients transplanted in Poland between 1998 and 2015 years [13]. The authors showed that patients and graft survival were distinctly better in nonrheumatic recipients in comparison with rheumatic patients [13].
Differential diagnosis of joint and back pain in patients after successful KTx should take into account common complications of dialysis including crystal deposition disease, β2- microglobulin amyloidosis, secondary hyperparathyroidism, or aluminium overload as well as articular complications followed by hepatitis B and C or a variety of other infections [14]. In KTx recipients some new musculoskeletal and articular disorders, like infection-related arthralgia, polyarticular gout, rheumatoid arthritis flare, or a medication-related adverse reaction, namely steroid induced osteopenia or osteoporosis, may occur [11].
To the best of our knowledge, the present work is the first case report of late onset of seronegative spondyloarthropathy in a transplanted patient despite ongoing immunosuppressive treatment. De novo seropositive erosive rheumatoid arthritis in a patient 7 years after KTx was described by Forslund et al. in 2005 [15].
Immunosuppressive treatment after transplantation on the one hand prevents rejection of the transplanted organ, and on the other hand is an excellent treatment for diseases of the autoimmune and inflammatory background, preventing an exaggerated immune response. However certain injuries may alter this balance leading to dysregulation of the intestinal immune environment promoting the development of chronic inflammatory disease [16]. Immunosuppression heightens susceptibility to infectious agents that may damage the epithelial barrier of the intestinal mucosa resulting in prolonged exposure to luminal antigens followed by chronic immune stimulation [16].
Calcineurin inhibitors including CsA and tacrolimus strongly inhibit production of interleukin-2 (IL-2), which is normally produced by T cells to induce expansion of antigen-specific clones in response to a previously encountered antigen. Deficiency of IL-2 can result in T-cell dysregulation, leading to the development of chronic inflammation [17]. Arthralgia, muscular side effects and osteoarthropathy are some of the described side effects of CsA associated therapy. It was shown that high CsA levels (> 200 ng/ml) are the risk factors of joint pain in KTx recipients [11]. Our patient had the CsA trough level low, appropriate to time passed after KTx.
It has been found that mycophenolate mofetil can be associated with an acute inflammatory response characterized by fever, arthralgia, oligoarthritis and raised inflammatory markers appearing 3 to 5 days after initiation of therapy with MMF. Symptoms rapidly resolve with mycophenolate cessation. The pathogenesis has been associated with paradoxical pro-inflammatory reaction of polymorphonuclear neutrophils [18]. Our patient was treated with MMF for years, thus it is unlikely to have been the cause of symptoms.
The appearance of inflammatory disease regardless of adequate immunosuppressive therapy in transplant recipients is not unusual or impossible, however there is no data available associated with new onset of AS after transplantation. Moreover the most typical risk group of AS are young men, whereas the presented patient is a 58 year old woman. Very rarely does AS begin after the age of 40 resulting in difficulties in making the diagnosis, since standard classification scales are not validated for patients above 45 years old [19, 20].
The diagnosis of arthritis is primarily clinical. The most typical clinical features of arthritis of native joints are acute joint pain, swelling, warmth, erythema, decreased range of motion, fever, and general malaise. AS is characterised by the presence of spinal pain, resulting in limitation of spinal mobility reported also by our patient. These symptoms can be supported by laboratory evidence like leukocytosis or inflammatory markers including CRP, procalcitonin and ESR, which can be useful especially in patients with native joints without underlying haematological or rheumatological conditions. However, all of these laboratory tests have quite low sensitivity and specificity. Laboratory tests are usually followed by X-ray, ultrasound, computer tomography (CT) or magnetic resonance imaging (MRI) of the involved joint. To diagnose joint infection aspiration of the joints can be performed, however mainly in large joints.
As written above the immunosuppressive treatment can be associated with increased risk of infectious diseases. Therefore, the most common cause of monoarticular arthritis in both immunocompetent and immunocompromised patients is septic arthritis [21]. Symptoms of AS (low back pain) were reported by our patient for 20 years, but as low back pain is a common condition and the patient did not present other features of spondyloarthropathy like enthesitis, dactylitis, uveitis, diarrhoea or family clustering, the patient was not referred to a rheumatologist and the complaints were described as non-specific, mechanical low back pain. It cannot be excluded that the symptoms of AS were present earlier but were masked by anti-inflammatory properties of immunosuppressive drugs.
Although most cases of viral and reactive arthritis are connected with infectious background, they are usually not categorized as septic arthritis [21]. Monoarticular arthritis can result from viral infection caused by parvovirus B19, HIV or rubella, as well as from the deposition of immune complexes and complement components in hepatitis B and C infections [19]. In our patient the viral infections were excluded.
Reactive arthritis usually arises from an acute infection of the genitourinary or gastrointestinal tract caused by Shigella spp., Salmonella spp., Campylobacter jejuni, or Yersinia enterocolitica. It may also be one of the manifestations of Lyme disease [21, 22].
In the traditional understanding of septic arthritis the most commonly implicated organisms causing bacteremic septic arthritis are Staphylococcus aureus, Streptococcus pyogenes, Neisseria meningitides, Neisseria gonorrhoeae, Klebsiella pneumonia, Escherichia coli, Proteus spp., Salmonella spp., Morganella morganii, Citrobacter spp., Serratias spp or Pseudomonas aerginosa [22–24]. Septic arthritis can also result from mycobacteria (Mycobacterium tuberculosis), or fungi infections (Histoplasma capsulatum, Blastomyces dermatitidis, Coccidioides immitis) [21].
The most common predisposing factors for septic arthritis include age greater than 80 years, diabetes mellitus, rheumatoid arthritis, prosthetic joint, recent joint surgery, skin infection and skin ulcers, intravenous drug abuse and alcoholism, and previous intra-articular corticosteroid administration [25].
Transplant patients are particularly susceptible to develop septic arthritis caused by unusual organisms. These infections are commonly disseminated, involving both the bones and joints [25]. In the first few weeks after transplantation, joint infections are often hematogenous and caused by health-care-associated pathogens such as Staphylococcus aureus (including MRSA) and gram-negative bacilli like Pseudomonas aeruginosa [26]. However, in the months following transplantation, as patients are maintained on immunosuppressive therapy, they are more prone to infections caused by fungi and mycobacteria [26]. In our recipients fungi and mycobacteria were excluded.
Gout etiology was thought unlikely in our patient as no crystals were present on joint aspirate and the patient had no history of gout, with only slight elevated serum uric acid concentration [19] – thus this diagnosis was excluded in our case.
Following the modified New York criteria for AS it has been shown that radiographic sacroilitis is a rather late finding in the disease course of many patients [3]. The most typical radiological evidence for AS are structural changes in the sacroiliac joints and the spine. In our patient the typical features like vertebral body squaring, diffuse syndesmophyitic ankyloses giving a “bamboo spine” appearance and total ankyloses of sacroiliac joints were described on X-ray, whereas MRI revealed nothing specific.
Progression of AS varies among individuals, but some general trends can be observed. Younger age (≤40 years) at disease onset is usually associated with a predominance of axial symptoms, whereas patients with a later disease onset tend to present more peripheral manifestations [9]. Symptoms presented by our patient were associated with the spinal column despite her belonging to an older group.
The main purpose of treating the patient with AS is to improve long-term health-related quality of life by controlling the symptoms of the disease and averting continuous structural damage, thus leading to better joint function followed by improved social participation [3]. The treatment of AS should be personalised according to the present symptoms of the disease, patient’s comorbidities, possible complications resulting from the treatment and psychosocial factors [3].
The first-line drug treatment for patients complaining of pain and stiffness are NSAIDs administered up to the maximum dose, taking into consideration risks and benefits resulting from the treatment [27, 28]. Data from some studies revealed that in young patients failure to administered NSAIDs is associated with an increased mortality [29, 30]. For patients with good response to NSAIDs continuous use is recommended [3]. This first-line treatment should be enhanced by physical therapy including home exercises and by smoking cessation [31]. In patients who are contraindicated to NSAIDs or poorly tolerate this treatment, analgesics such as paracetamol and opioid-(like) drugs should be considered [3].
Lack of efficacy or presence of toxicity with NSAIDs is an indication to consider alternative treatments either with glucocorticoid, sulfasalazine or biological disease-modifying antirheumatic drugs (bDMARDs) [3].
Steroid injections directed to the local site of musculoskeletal inflammation may be recommended in patients with predominant peripheral manifestation as an option to treat arthritis and enthesitis, although direct evidence is lacking. Patients with axial disease should not be treated with systemic glucocorticoids for a long time [3].
Sulfasalazine may be considered in patients with peripheral arthritis, however it does not alleviate axial symptoms [32].
High disease activity defined as BASDAI ≥4 despite conventional treatment, elevated CRP, presence of inflammation on MRI of the SI joints and/or spine or presence of radiographic sacroiliitis is an indication to start bDMARDs and current practice is to start with tumour necrosis factor inhibitor (TNFi) therapy [31].
Our patient due to KTx was put on immunosuppressive therapy including CsA, MMF and steroids. Given the ongoing severity of the patient’s symptoms, no response to maintenance immunosuppressive therapy, contraindication to NSAIDs, a change in management was instituted by the administration of sulfasalazine. Improvement in the patient’s inflammatory markers and arthritis was noticed with subsidence of pain complaints and normalization of CRP within 2 weeks. She has had no further recurrence of acute inflammatory arthritis.
The establishing of proper diagnosis and management of a patient after KTx is difficult. Despite long-term immunosuppressive treatment in solid organ transplant recipients, in the differential diagnosis of joint pain the development of de novo arthritis should be considered, and when conclusive diagnosis is made, the patient may require administration of additional immunosuppressive drugs.
Abbreviations
ANAAntinuclear antibodies
anti-CCPAnti- cyclic citrullinated peptides
ASAnkylosing spondylitis
BASDAIBath Ankylosing Spondylitis Disease Activity Index
BASFIBath Ankylosing Spondylitis Functional Index
bDMARDsBiological disease-modifying antirheumatic drugs
CKDChronic kidney disease
CRPC-reactive protein
CsACyclosporine A
CTComputer tomography
eGFREstimated glomerular filtration rate
ESRErythrocyte sedimentation rate
ESRDEnd-stage renal disease
HPFHigher-power field
KtxKidney transplantation
MMFMycophenolate mofetil
MRIMagnetic resonance imaging
NMRNuclear magnetic resonance
NSAIDsNon-steroid anti-inflammatory drugs
SCrSerum creatinine concentration
TNFiTumour necrosis factor inhibitor
WBCWhite blood count
Publisher’s Note
Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
Acknowledgements
Not applicable.
Authors’ contributions
All authors have read and have approved the submitted version of the manuscript. AZB: designed the case report plan, described the subject medical history and was the primary author for the manuscript; OB: helped design the case report plan, IK helped in writing the manuscript, JM helped in writing the manuscript. All authors have agreed both to be personally accountable for the author’s own contributions and to ensure that questions related to the accuracy or integrity of any part of the work, even ones in which the author was not personally involved, are appropriately investigated, resolved, and the resolution documented in the literature.
Funding
Not applicable.
Availability of data and materials
The patient results used and/or analysed during the current case report are available from the corresponding author on reasonable request.
Ethics approval and consent to participate
Not applicable (case report).
Consent for publication
The patient in written consent agreed to publish the laboratory as well as radiological results.
Competing interests
None of the authors claims a conflict of interest. All authors declare no financial and non-financial competing interests. | Recovered | ReactionOutcome | CC BY | 33517879 | 19,794,934 | 2021-01-31 |
What was the outcome of reaction 'Tenderness'? | Post-transplant manifestation of ankylosing spondylitis: a case report and review of literature.
Ankylosing spondylitis (AS) is an insidiously progressive and debilitating form of arthritis involving the axial skeleton, characterized by chronic back pain and progressive spinal stiffness, and lessening of pain and stiffness with exercise. Due to subsequent manifestation in different organs, AS causes reduction in life expectancy, so early diagnosis and treatment are of great importance. No AS cases have been reported in solid-organ transplant recipients yet.
A 58-year-old woman with end-stage renal disease due to chronic glomerulonephritis, after allogenic kidney transplantation 25 years earlier, with stable, good graft function, treated with chronic immunosuppressive therapy based on cyclosporine A, mycophenolate mofetil, and prednisone, with no previous history of a connective tissue disease presented fever up to 39 °C accompanied by pain localized in sacroiliac region radiating to the left lower limb. Detailed diagnostic procedures and x-rays of the lumbar spine and of the targeted sacroiliac joints revealed lesions characteristic of AS. Sulphasalazine was added to standard immunosuppression regimen with good clinical results.
We report an adult kidney transplant recipient with a new onset of AS. The risk of relapse or new onset of inflammatory disease in transplant recipients is extremely low due to immunosuppressive therapy following transplantation. However, when it occurs, the clinical presentation is commonly atypical, often leading to delayed diagnosis.
Background
The appearance of inflammatory and autoimmune diseases is quite low in patients after solid organ transplantation [1]. Adequate immunosuppressive therapy usually mitigates the risk of relapse or new onset of an autoimmune disease in this population [2]. The clinical presentation of inflammatory diseases in patients after transplantation is commonly atypical, often leading to delayed diagnosis.
Musculoskeletal pain is a common problem in kidney transplant (KTx) recipients, however, an acute inflammatory arthritis is rare. The differential diagnosis of joint and back pain is broad and includes septic arthritis, systemic infection, crystal arthropathies, autoimmune rheumatologic disorders, and medication-related adverse reactions [3].
Ankylosing spondylitis (AS), previously known as Bechterew’s disease, is a chronic, progressive inflammatory disease with a diverse clinical presentation [3]. AS is characterized by inflammation and new bone formation leading to fusion of the spine and sacroiliac joints. Chronic back pain, progressive spinal stiffness and improvement of pain and stiffness with exercise are the most common features of the disease [4]. Other musculoskeletal manifestations of AS include arthritis, enthesitis and dactylitis [5]. Clinical symptoms most frequently begin in late adolescence or in young adults, with 80% before the age of 30 and with a 3:1 to 2:1 male to female ratio [6, 7].
In addition to spinal inflammation, AS is characterized by a broad clinical spectrum of the extra-articular manifestations like uveitis, psoriasis, inflammatory bowel disease, or aortic insufficiency [8, 9] as well as an increased cardiovascular risk, several pulmonary, renal, and neurological complications or depression [10].
We present a case of late onset of seronegative spondyloarthropaty in KTX patient despite ongoing immunosuppressive treatment. The following description applies to become unusual both in terms of gender, age, comorbidities of the patient, as well as the fact that the patient was constantly treated with triple immunosuppressive regimen.
Case presentation
A 58-year-old woman with end-stage renal disease caused by chronic glomerulonephritis, after allogenic KTx 25 years earlier, with stable, good graft function, treated with chronic immunosuppressive therapy based on cyclosporine A (CsA), mycophenolate mofetil (MMF), and prednisone, with no previous history of a connective tissue disease was admitted to the Nephrology Department with fever up to 39 °C accompanied by pain localized in the sacroiliac region radiating to the left lower limb of 2 weeks duration. Physical examination revealed nothing specific, her vital signs were stable. Initial laboratory data indicated an elevated C-reactive protein (CRP) concentration to 287 mg/l (normal range < 5 mg/l), white blood count (WBC) was 6.4 × 10 3/μl, haemoglobin concentration 10.6 g/dl, serum procalcitonin was negative. Urinalysis showed proteinuria 0.1 g/l, and 15 to 20 leukocytes /higher-power field (HPF), with no erythrocytes in urinary sediment. The graft function was stable (serum creatinine concentration (sCr) 95 μmol/l with estimated glomerular filtration rate (eGFRCKD-EPI) - 57.2 ml/min/1.73m2), serum uric acid was 7.8 mg/dl (normal range 4.2–6.8 mg/dl), alanine and aspartate aminotransferase as well as bilirubin concentration were within normal limits. The blood level of CsA was in the range appropriate to the period after KTx. Hepatitis B, hepatitis C, HIV and CMV DNA tests were negative. Urine and blood culture were negative. Echocardiography was performed, but revealed nothing specific and endocarditis was excluded. The empiric antibiotic therapy with clindamycin was started. Nuclear magnetic resonance (NMR) of the lumbar spine was firstly described as inconclusive, although the patient complained of constant pain aggravation. On the tenth day of hospitalization oedema with a tenderness of the left knee appeared. Due to exudates and excessive warmth of the left knee, arthrocentesis was performed. Sixty millilitres of turbid fluid was withdrawn. The synovial fluid was positive for Streptococcus sp. (saprophytic flora) thus a prolonged, targeted vancomycin therapy was started (the patient was allergic to penicillin). Gout was excluded. Moreover, because of the resistant pain and oedema of the left lower limb, Doppler ultrasound was performed and showed active deep vein thrombosis. Low molecular weight heparin therapy was administered in therapeutic dose. A control ultrasound examination revealed no features of thrombosis or valvular insufficiency. Despite antibiotic treatment further high inflammation parameters were still noted (CRP 149.4 mg/l), thus further diagnosis for atypical infection was performed (the direct examination of synovial fluid for tuberculosis and in vitro QuantiFERON test, anti - Borrelia burgdorferi antibodies in class IgM and IgG – all negative). After failure of treatment and the patient’s continuing complaints, the patient was referred to the Department of Rheumatology.
At the time of admission to the Department of Rheumatology the patient reported left knee pain sustained for more than a month and lumbar spine pain, severity independent of physical exercise, exacerbating during the night and accompanied by morning stiffness. Joint mobility within the normal range, soreness during loading and maximum limbs bent. In addition, Patrick sign was positive on the left side. After more detailed anamnesis the patient confirmed occurrence of typical inflammatory back pain of nearly 20 years. The pain typically worsened with inactivity and improved with exercise and non-steroid anti-inflammatory drugs (NSAIDs) treatment. Morning stiffness was prolonged to nearly all day. Nocturnal pain was not awakening her. The patient’s spine motion was markedly limited in all directions: Otto’s test 2 cm, Schober’s test 1.5 cm, chest expansion 3.5 cm deepening the cervical lordosis. Bath Ankylosing Spondylitis Disease Activity Index (BASDAI) was 6.2 whereas Bath Ankylosing Spondylitis Functional Index (BASFI) 2.5. There was neither edema nor mobility limitations in other peripheral joints. No other significant deviations from the norm in the rest of physical examination were noted. The symptoms were accompanied by high erythrocyte sedimentation rate (ESR) 98 mm/h, CRP 119.8 mg/l following an increase of creatinine concentration up to 144 μmol/l (GFRCKD-EPI 35.7 ml/min/1.73m2).
During hospitalization the antibiotic therapy started in the Department of Nephrology was completed, whilst the anti-coagulant therapy was continued. An x-ray of the lumbar spine and of the targeted sacroiliac joints revealed lesions characteristic of ankylosing spondylitis: vertebral body squaring, diffuse syndesmophyitic ankyloses giving a “bamboo spine” appearance and total ankyloses of sacroiliac joints (Fig. 1). The patient was HLA B27 positive, autoantibodies like the antinuclear antibodies (ANA), anti- cyclic citrullinated peptides antibodies and rheumatoid factor were negative. After the negative result of control culture of the synovial fluid, intrarticular injection of bethametazone and lignocaine mixture was administered. The fluid fulfilled the criteria for the inflammatory fluid type I (Table 1). Uric acid crystals were not detected. The NMR of the lumbar spine done in the Nephrology Unit was assessed once again by a more experienced radiologist in the Rheumatology Unit and was described as typical features of ankylosing spondylitis. A diagnosis of ankylosing spondylitis was posed (Tables 2 and 3) and the patient was started on oral sulphasalazine and NSAIDs. The treatment resulted in a significant decrease of CRP and improvement of the graft function (sCr 92 μmol/l, eGFR 61.4 ml/min/1.73 m2). The diagnosis of chronic kidney disease (CKD) and KTx determined a reduction of sulphasalazine dose to 2x500mg and after a short therapy the NSAIDs administration was reduced. Radiosynovectomy in the left knee joint was performed and after 2 weeks the patient, in good general condition, was discharged home.
Fig. 1 X-ray revealed diffuse syndesmophyitic ankylosis at all levels from Th12 to L1 (also seen above Th12), calcifications of spinal ligaments, features of vertebral body squaring, radiological signs of spondylodiscitis at levels from L1 to L4 with the widening of intervertebral space, blurring the trabecular structure of L5 and L6 narrowing of intervertebral spaces L4-S1. Left site scoliosis
Table 1 Synovial fluid parameters
Synovial fluid parameters
Volume 60 ml
Colour Yellow
Clarity Transparent
Viscosity High
Total protein 50.3 g/l
Glucose level Lower than blood
WBC 800/mm3
PMNs > 50%
Culture Negative
Table 2 Amor diagnostic criteria for spondyloarthropathy
Amor Criteria Our patient
Inflammatory back pain 1 point +
Unilateral buttock pain 1 point –
Alternating buttock pain 2 point –
Enthesitis 2 point +/−
Peripheral arthritis 2 point +
Dactylitis (sausage digit) 2 point –
Acute anterior uveitis 2 point –
HLA-B27
–positive or family history of spondyloarthropathy 2 point +
Good response to NSAIDs 2 point +
Diagnosis of spondyloarthropathy with 6 or more points 7–9 points
Table 3 New York diagnostic criteria for spondyloarthropathy
New York Criteria Our patient
Low back pain with inflammatory characteristics +
Limitation of lumbar spine motion in sagittal and frontal planes +
Decreased chest expansion +
Bilateral sacroiliitis grade 2 or higher +
Unilateral sacroiliitis grade 3 or higher
Definite ankylosing spondylitis when the fourth or fifth criterion mentioned presents with any clinical criteria 4 points
After 6 years of follow up during the routine visits in out-patient Transplantation Department the patient does not present any complaints associated with the left knee (no pain, tenderness, oedema). The graft function is still stable – creatinine concentration 90 μmol/l, GFRCKD-EPI 62 ml/min/1.73m2, she has been treated long-term with her base immunosuppressive therapy (stable dose of CsA 75 mg bid, stable dose of MMF 500 mg bid, and temporarily, increased steroid dose up to 20 mg qd at the moment of AS diagnosis with the subsequent dose reduction to 5 mg qd), with reduced sulphasalazine dose (2 × 500 mg), with no adverse effects of such treatment.
Discussion and conclusion
Joint pain is a frequent problem in individuals with kidney disease and is common both before and after KTx [11]. However, kidney involvement can be one of the complications following rheumatic diseases and can occur as a secondary amyloidosis which is the most common cause of nephrotic syndrome in AS followed by IgA nephropathy, mesangioproliferative glomerulonephritis as well as, rarely, by membranous nephropathy or focal segmental glomerulosclerosis [10]. A study by Hill et al. showed an 18% prevalence of CKD stages 3 to 5 in the rheumatic outpatient group, as compared to 5% reported within the general population [12]. On the other hand, it was shown that rheumatic diseases were the cause of ESRD and KTx in 14% of recipients transplanted in Poland between 1998 and 2015 years [13]. The authors showed that patients and graft survival were distinctly better in nonrheumatic recipients in comparison with rheumatic patients [13].
Differential diagnosis of joint and back pain in patients after successful KTx should take into account common complications of dialysis including crystal deposition disease, β2- microglobulin amyloidosis, secondary hyperparathyroidism, or aluminium overload as well as articular complications followed by hepatitis B and C or a variety of other infections [14]. In KTx recipients some new musculoskeletal and articular disorders, like infection-related arthralgia, polyarticular gout, rheumatoid arthritis flare, or a medication-related adverse reaction, namely steroid induced osteopenia or osteoporosis, may occur [11].
To the best of our knowledge, the present work is the first case report of late onset of seronegative spondyloarthropathy in a transplanted patient despite ongoing immunosuppressive treatment. De novo seropositive erosive rheumatoid arthritis in a patient 7 years after KTx was described by Forslund et al. in 2005 [15].
Immunosuppressive treatment after transplantation on the one hand prevents rejection of the transplanted organ, and on the other hand is an excellent treatment for diseases of the autoimmune and inflammatory background, preventing an exaggerated immune response. However certain injuries may alter this balance leading to dysregulation of the intestinal immune environment promoting the development of chronic inflammatory disease [16]. Immunosuppression heightens susceptibility to infectious agents that may damage the epithelial barrier of the intestinal mucosa resulting in prolonged exposure to luminal antigens followed by chronic immune stimulation [16].
Calcineurin inhibitors including CsA and tacrolimus strongly inhibit production of interleukin-2 (IL-2), which is normally produced by T cells to induce expansion of antigen-specific clones in response to a previously encountered antigen. Deficiency of IL-2 can result in T-cell dysregulation, leading to the development of chronic inflammation [17]. Arthralgia, muscular side effects and osteoarthropathy are some of the described side effects of CsA associated therapy. It was shown that high CsA levels (> 200 ng/ml) are the risk factors of joint pain in KTx recipients [11]. Our patient had the CsA trough level low, appropriate to time passed after KTx.
It has been found that mycophenolate mofetil can be associated with an acute inflammatory response characterized by fever, arthralgia, oligoarthritis and raised inflammatory markers appearing 3 to 5 days after initiation of therapy with MMF. Symptoms rapidly resolve with mycophenolate cessation. The pathogenesis has been associated with paradoxical pro-inflammatory reaction of polymorphonuclear neutrophils [18]. Our patient was treated with MMF for years, thus it is unlikely to have been the cause of symptoms.
The appearance of inflammatory disease regardless of adequate immunosuppressive therapy in transplant recipients is not unusual or impossible, however there is no data available associated with new onset of AS after transplantation. Moreover the most typical risk group of AS are young men, whereas the presented patient is a 58 year old woman. Very rarely does AS begin after the age of 40 resulting in difficulties in making the diagnosis, since standard classification scales are not validated for patients above 45 years old [19, 20].
The diagnosis of arthritis is primarily clinical. The most typical clinical features of arthritis of native joints are acute joint pain, swelling, warmth, erythema, decreased range of motion, fever, and general malaise. AS is characterised by the presence of spinal pain, resulting in limitation of spinal mobility reported also by our patient. These symptoms can be supported by laboratory evidence like leukocytosis or inflammatory markers including CRP, procalcitonin and ESR, which can be useful especially in patients with native joints without underlying haematological or rheumatological conditions. However, all of these laboratory tests have quite low sensitivity and specificity. Laboratory tests are usually followed by X-ray, ultrasound, computer tomography (CT) or magnetic resonance imaging (MRI) of the involved joint. To diagnose joint infection aspiration of the joints can be performed, however mainly in large joints.
As written above the immunosuppressive treatment can be associated with increased risk of infectious diseases. Therefore, the most common cause of monoarticular arthritis in both immunocompetent and immunocompromised patients is septic arthritis [21]. Symptoms of AS (low back pain) were reported by our patient for 20 years, but as low back pain is a common condition and the patient did not present other features of spondyloarthropathy like enthesitis, dactylitis, uveitis, diarrhoea or family clustering, the patient was not referred to a rheumatologist and the complaints were described as non-specific, mechanical low back pain. It cannot be excluded that the symptoms of AS were present earlier but were masked by anti-inflammatory properties of immunosuppressive drugs.
Although most cases of viral and reactive arthritis are connected with infectious background, they are usually not categorized as septic arthritis [21]. Monoarticular arthritis can result from viral infection caused by parvovirus B19, HIV or rubella, as well as from the deposition of immune complexes and complement components in hepatitis B and C infections [19]. In our patient the viral infections were excluded.
Reactive arthritis usually arises from an acute infection of the genitourinary or gastrointestinal tract caused by Shigella spp., Salmonella spp., Campylobacter jejuni, or Yersinia enterocolitica. It may also be one of the manifestations of Lyme disease [21, 22].
In the traditional understanding of septic arthritis the most commonly implicated organisms causing bacteremic septic arthritis are Staphylococcus aureus, Streptococcus pyogenes, Neisseria meningitides, Neisseria gonorrhoeae, Klebsiella pneumonia, Escherichia coli, Proteus spp., Salmonella spp., Morganella morganii, Citrobacter spp., Serratias spp or Pseudomonas aerginosa [22–24]. Septic arthritis can also result from mycobacteria (Mycobacterium tuberculosis), or fungi infections (Histoplasma capsulatum, Blastomyces dermatitidis, Coccidioides immitis) [21].
The most common predisposing factors for septic arthritis include age greater than 80 years, diabetes mellitus, rheumatoid arthritis, prosthetic joint, recent joint surgery, skin infection and skin ulcers, intravenous drug abuse and alcoholism, and previous intra-articular corticosteroid administration [25].
Transplant patients are particularly susceptible to develop septic arthritis caused by unusual organisms. These infections are commonly disseminated, involving both the bones and joints [25]. In the first few weeks after transplantation, joint infections are often hematogenous and caused by health-care-associated pathogens such as Staphylococcus aureus (including MRSA) and gram-negative bacilli like Pseudomonas aeruginosa [26]. However, in the months following transplantation, as patients are maintained on immunosuppressive therapy, they are more prone to infections caused by fungi and mycobacteria [26]. In our recipients fungi and mycobacteria were excluded.
Gout etiology was thought unlikely in our patient as no crystals were present on joint aspirate and the patient had no history of gout, with only slight elevated serum uric acid concentration [19] – thus this diagnosis was excluded in our case.
Following the modified New York criteria for AS it has been shown that radiographic sacroilitis is a rather late finding in the disease course of many patients [3]. The most typical radiological evidence for AS are structural changes in the sacroiliac joints and the spine. In our patient the typical features like vertebral body squaring, diffuse syndesmophyitic ankyloses giving a “bamboo spine” appearance and total ankyloses of sacroiliac joints were described on X-ray, whereas MRI revealed nothing specific.
Progression of AS varies among individuals, but some general trends can be observed. Younger age (≤40 years) at disease onset is usually associated with a predominance of axial symptoms, whereas patients with a later disease onset tend to present more peripheral manifestations [9]. Symptoms presented by our patient were associated with the spinal column despite her belonging to an older group.
The main purpose of treating the patient with AS is to improve long-term health-related quality of life by controlling the symptoms of the disease and averting continuous structural damage, thus leading to better joint function followed by improved social participation [3]. The treatment of AS should be personalised according to the present symptoms of the disease, patient’s comorbidities, possible complications resulting from the treatment and psychosocial factors [3].
The first-line drug treatment for patients complaining of pain and stiffness are NSAIDs administered up to the maximum dose, taking into consideration risks and benefits resulting from the treatment [27, 28]. Data from some studies revealed that in young patients failure to administered NSAIDs is associated with an increased mortality [29, 30]. For patients with good response to NSAIDs continuous use is recommended [3]. This first-line treatment should be enhanced by physical therapy including home exercises and by smoking cessation [31]. In patients who are contraindicated to NSAIDs or poorly tolerate this treatment, analgesics such as paracetamol and opioid-(like) drugs should be considered [3].
Lack of efficacy or presence of toxicity with NSAIDs is an indication to consider alternative treatments either with glucocorticoid, sulfasalazine or biological disease-modifying antirheumatic drugs (bDMARDs) [3].
Steroid injections directed to the local site of musculoskeletal inflammation may be recommended in patients with predominant peripheral manifestation as an option to treat arthritis and enthesitis, although direct evidence is lacking. Patients with axial disease should not be treated with systemic glucocorticoids for a long time [3].
Sulfasalazine may be considered in patients with peripheral arthritis, however it does not alleviate axial symptoms [32].
High disease activity defined as BASDAI ≥4 despite conventional treatment, elevated CRP, presence of inflammation on MRI of the SI joints and/or spine or presence of radiographic sacroiliitis is an indication to start bDMARDs and current practice is to start with tumour necrosis factor inhibitor (TNFi) therapy [31].
Our patient due to KTx was put on immunosuppressive therapy including CsA, MMF and steroids. Given the ongoing severity of the patient’s symptoms, no response to maintenance immunosuppressive therapy, contraindication to NSAIDs, a change in management was instituted by the administration of sulfasalazine. Improvement in the patient’s inflammatory markers and arthritis was noticed with subsidence of pain complaints and normalization of CRP within 2 weeks. She has had no further recurrence of acute inflammatory arthritis.
The establishing of proper diagnosis and management of a patient after KTx is difficult. Despite long-term immunosuppressive treatment in solid organ transplant recipients, in the differential diagnosis of joint pain the development of de novo arthritis should be considered, and when conclusive diagnosis is made, the patient may require administration of additional immunosuppressive drugs.
Abbreviations
ANAAntinuclear antibodies
anti-CCPAnti- cyclic citrullinated peptides
ASAnkylosing spondylitis
BASDAIBath Ankylosing Spondylitis Disease Activity Index
BASFIBath Ankylosing Spondylitis Functional Index
bDMARDsBiological disease-modifying antirheumatic drugs
CKDChronic kidney disease
CRPC-reactive protein
CsACyclosporine A
CTComputer tomography
eGFREstimated glomerular filtration rate
ESRErythrocyte sedimentation rate
ESRDEnd-stage renal disease
HPFHigher-power field
KtxKidney transplantation
MMFMycophenolate mofetil
MRIMagnetic resonance imaging
NMRNuclear magnetic resonance
NSAIDsNon-steroid anti-inflammatory drugs
SCrSerum creatinine concentration
TNFiTumour necrosis factor inhibitor
WBCWhite blood count
Publisher’s Note
Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
Acknowledgements
Not applicable.
Authors’ contributions
All authors have read and have approved the submitted version of the manuscript. AZB: designed the case report plan, described the subject medical history and was the primary author for the manuscript; OB: helped design the case report plan, IK helped in writing the manuscript, JM helped in writing the manuscript. All authors have agreed both to be personally accountable for the author’s own contributions and to ensure that questions related to the accuracy or integrity of any part of the work, even ones in which the author was not personally involved, are appropriately investigated, resolved, and the resolution documented in the literature.
Funding
Not applicable.
Availability of data and materials
The patient results used and/or analysed during the current case report are available from the corresponding author on reasonable request.
Ethics approval and consent to participate
Not applicable (case report).
Consent for publication
The patient in written consent agreed to publish the laboratory as well as radiological results.
Competing interests
None of the authors claims a conflict of interest. All authors declare no financial and non-financial competing interests. | Recovered | ReactionOutcome | CC BY | 33517879 | 19,003,793 | 2021-01-31 |
Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Cholecystitis acute'. | A Recurrent Case of Adult-onset Still's Disease with Concurrent Acalculous Cholecystitis and Macrophage Activation Syndrome/Hemophagocytic Lymphohistiocytosis Successfully Treated with Combination Immunosuppressive Therapy.
We herein report the case of 21-year-old female diagnosed with adult-onset Still's disease (AOSD) three years earlier who presented with fever and right upper abdominal pain. She was diagnosed with acute acalculous cholecystitis (AAC) based on hepatic dysfunction, elevated C-reactive protein, and gallbladder wall thickening on abdominal ultrasound. Based on the presence of pancytopenia, hyperferritinemia, and hemophagocytosis by a bone marrow examination, she was diagnosed with macrophage activation syndrome (MAS)/hemophagocytic lymphohistiocytosis (HLH) which was refractory to glucocorticoid pulse therapy. The combination of intravenous cyclosporine A with glucocorticoids was able to successfully control the disease activity of AOSD-related AAC and MAS/HLH.
Introduction
Adult-onset Still's disease (AOSD) is a systemic inflammatory disease of unknown etiology that is characterized by fever, arthritis, characteristic rash, hepatosplenomegaly, and hyperferritinemia. The pathogenesis of AOSD is considered to involve various inflammatory cytokines such as tumor necrosis factor-α, interleukin (IL)-1, IL-6, IL-18, and interferon-γ (1). Some cases might be complicated by macrophage activation syndrome (MAS)/hemophagocytic lymphohistiocytosis (HLH), a fatal condition caused by hypercytokinemia which can lead to multi-organ failure (2). Conversely, acute acalculous cholecystitis (AAC), a relatively rare organ complication of AOSD (3,4), has been reported to be complicated by connective tissue diseases including systemic lupus erythematosus (SLE). Since it is a rare complication of AOSD, there is no consensus on the course of treatment for AOSD related AAC, partly because it can be observed as AOSD-related organ failure following surgical cholecystectomy (4,5). We herein report the case of a patient presenting with concurrent MAS/HLH and AAC at the time of AOSD relapse who was successfully treated only with glucocorticoids and cyclosporine A (CsA).
Case Report
A 21-year-old female patient was diagnosed with AOSD three years prior to the present admission based on the findings of fever, erythema of the extremities and trunk, polyarthritis, hepatic dysfunction, hyperferritinemia, elevated inflammatory response, and splenomegaly. She was treated with 30 mg/day prednisolone, which was tapered off after achieving an improvement of the disease activity. Eleven months before hospitalization, she developed arthritis in her right knee and was diagnosed with a minor flare of AOSD. She was initiated on 7.5 mg/day prednisolone and 8 mg/week methotrexate the following month. After obtaining an improvement of the arthritis in the right knee, prednisolone was tapered off and discontinued three months prior to the current admission and remission was maintained with a methotrexate dose of 8 mg/week thereafter. She had a history of paroxysmal supraventricular tachycardia, no allergies, and no family history of rheumatic disease.
Two months before the hospitalization, a urticaria-like rash with itching appeared on her extremities. A week before this hospitalization, she also developed a fever ranging between 39℃ and 40℃ and pain in both shoulders and knees. In mid-April, she developed nausea, vomiting, and right hypochondriac pain. At the time of examination, she had fever, right hypochondralgia, and tenderness in both shoulder and knee joints. Laboratory tests showed elevated hepatobiliary enzymes (aspartate aminotransferase, 734 U/L; alanine aminotransferase, 429 U/L; lactate dehydrogenase, 2,941 U/L; gamma-glutamyl transferase, 272 U/L) and C-reactive protein (CRP, 5.34 mg/dL). Abdominal ultrasonography (Fig. 1a) and abdominal computed tomography scans (Fig. 1b) showed gallbladder enlargement and wall thickening without any biliary stones.
Figure 1. Ultrasonography and computed tomography (CT) images on admission. (a) Ultrasonography images of the gallbladder. (b, c) CT images of the gallbladder (arrows), liver, and spleen. (d) CT images of the cervical lymph nodes (arrow). (e) Changes in the gallbladder ultrasonography findings on day 26.
She was admitted to the hospital with the diagnosis of AAC because the common bile duct was not obstructed and the possibility of obstructive cholangitis was considered unlikely. She was managed by fasting and antibiotic treatment with tazobactam/piperacillin. However, pancytopenia (WBC, 2,300 /μL; hemoglobin, 11.0 g/dL; platelet count, 7.9×104/μL) developed on the second day with no improvement in hepatic dysfunction. The laboratory findings on the second day before the initiation of immunosuppressive therapy including glucocorticoids are presented in Table 1.
Table 1. Laboratory Findings at the Time of Hospitalization before the Start of Immunosuppressive Therapy.
Complete blood count LDH 2,549 U/L Rheumatoid factor 3 U/mL
WBC 2,300 /μL γ-GTP 272 U/L anti-CCP Ab 0.5 U/mL
Neutro 93.0 % CK 113 U/L MPO-ANCA <1.0 U/mL
Lympho 3.5 % TG 142 mg/dL PR3-ANCA <1.0 U/mL
Mono 3.0 % T-Cho 93 mg/dL anti-U1 RNP Ab <2.0 U/mL
Baso 0.5 % HDL-Cho 23 mg/dL Infection
Eosino 0.0 % BUN 5.5 mg/dL HBs Ag negative
RBC 365.0 ×104/μL Cre 0.61 mg/dL HBs Ab negative
Hb 11.0 g/dL Na 130 mEq/L HBc Ab negative
HCT 31.1 % K 4.1 mEq/L HCV Ab negative
MCV 85.2 Fl glucose 84 mg/dL Cytomegalovirus antigenemia negative
PLT 7.9 ×104/μL HbA1c 5.5 % EBVCA IgG positive
Coagulation Ferritin 20,811 ng/mL EBVCA IgM negative
PT-INR 1.09 sIL-2R 5,421 U/mL Parvo B19 IgM negative
APTT 40.9 sec CRP 6.11 mg/dL T-spot negative
Fibrinogen 194 mg/dL β-glucan 15.0 pg/mL
D-dimer 6.28 μg/mL Erythrocyte sedimentation ratio Procalcitonin 1.99 ng/mL
FDP 16.6 μg/mL 18 mm/h Blood culture negative
AT-3 98 % Immunology Urine culture negative
Biochemistry IgG 1,162 mg/dL Urine
TP 5.3 g/dL IgA 228 mg/dL pH 6.5
ALB 2.5 g/dL IgM 266 mg/dL Occult blood negative
T-Bil 2.15 mg/dL C3 77 mg/dL Protein negative
D-Bil 1.56 mg/dL C4 33.5 mg/dL Cast negative
AST 763 U/L anti-nuclear Ab <1:40 WBC negative
ALT 469 U/L anti-ds-DNA Ab 1.99 U/mL
ALP 1,586 U/L anti-Smith Ab <1.0 U/mL
Neutro: neutrophil, Lympho: lymphocyte, Mono: monocyte, Baso: basophil, Eosino: eosinophil, RBC: red blood cell, HCT: hematocrit, MCV: mean cell volume, PLT: platelet, PT-INR: prothrombin-international normalized ratio, APTT: activated partial thromboplastin time, FDP: fibrin degradation product, AT-3: antithrombin 3, TP: total protein, ALB: albumin, T-Bil: total bilirubin, D-Bil: direct bilirubin, AST: aspartate transaminase, ALT: alanine aminotransferase, ALP: alkaline phosphatase, LDH: lactate dehydrogenase, γ-GTP: γ-glutamyl transpeptidase, CK: creatine kinase, TG: triglyceride, T-Cho: total cholesterol, HDL-Cho: high-density lipoprotein cholesterol, BUN: blood urea nitrogen, Cre: creatinine, Na: sodium, K: potassium, sIL-2R: soluble interleukin-2 receptor, CRP: C-reactive protein, anti-CCP Ab: anti-cyclic citrullinated peptides antibodies, MPO-ANCA: myeloperoxidase anti-neutrophil cytoplasmic antibody, PR3-ANCA: proteinase3 anti-neutrophil cytoplasmic antibody, anti U1-RNP Ab: anti U1-ribonucleoprotein antibody, HCV: hepatitis C virus, EBV: Epstein-Barr virus
The patient was diagnosed with AOSD recurrence based on a fever ≥39°C lasting more than one week, arthralgia lasting more than two weeks, typical rash, splenomegaly (Fig. 1c), cervical lymphadenopathy (Fig. 1d), hepatic dysfunction, and negative rheumatoid factor and antinuclear antibodies, according to the AOSD diagnostic criteria by Yamaguchi et al. (6). In addition, she was diagnosed with MAS/HLH based on fever, splenomegaly, cytopenia of two or more lineages, hepatitis-like findings, and pathological changes in myeloid markers by bone marrow biopsy examination (Fig. 2), including hemophagocytosis, elevated serum ferritin, and elevated soluble IL-2 receptor, which fulfilled the criteria of the MAS/HLH diagnosis (7). There were no findings suggesting active viral infection and a viral etiology was ruled out for MAS/HLH, which was therefore considered to be due to AOSD recurrence. AAC was diagnosed as an organ complication associated with AOSD recurrence as it was associated with an exacerbated disease activity including MAS/HLH. Because of her poor general condition and severe thrombocytopenia associated with MAS/HLH, the patient was not considered to be a good candidate for invasive procedures such as cholecystectomy and percutaneous transhepatic gallbladder drainage for AAC, and therefore immunosuppressive therapy for AOSD was prioritized. Glucocorticoid pulse therapy with methylprednisolone (1 g/day) on days 2-4 of hospitalization was initiated for AOSD with a high disease activity, AAC, and MAS/HLH. After the initiation of glucocorticoid pulse therapy, the platelet count continued to decrease and the serum ferritin level tended to increase; therefore, the glucocorticoid therapy alone was considered to be insufficient for controlling the disease activity. After obtaining approval from the institutional ethics committee and informed consent from the patient, 125 mg continuous intravenous CsA was initiated on day four (Fig. 3). With the combination of glucocorticoids and intravenous CsA, the disease activity improved. Therefore, the glucocorticoid dose was reduced on day 15 with a switch to 4.0 mg/day oral betamethasone; the patient was also switched to 150 mg oral CsA the same day. Betamethasone was reduced from 4.0 to 3.0 mg on day 30. There was no recurrence of the disease activity after the initiation of the glucocorticoid taper, and abdominal ultrasound on day 26 showed an improvement in the gallbladder enlargement and gallbladder wall thickening observed at the time of admission (Fig. 1e). Pancytopenia, hepatic dysfunction, and hyperferritinemia also improved (platelet count, 20.4×104/μL on day 44; aspartate aminotransferase, 43 U/L on day 44; alanine aminotransferase, 32 U/L on day 44; ferritin, 20,811 and 185 ng/mL on days 2 and 43, respectively), and she was discharged on day 47.
Figure 2. Histopathological findings of a bone marrow biopsy sample. (a) Hematopoiesis in the bone marrow is preserved. Histiocytes are shown (red circles) (magnification: 400×). (b) Activated macrophages exhibiting phagocytosis (red arrow) (magnification: 1,000×).
Figure 3. Clinical course of the patient. CsA: cyclosporine A, i.v.: intravenous, mPSL: methylprednisolone, PLT: platelet count, p.o.: per os, TAZ/PIPC: tazobactam/piperacillin
Discussion
The risk factors for AAC, which accounts for 5-15% of all acute cholecystitis cases, include surgery, trauma, prolonged intensive care unit stay, infection, burn, intravenous feeding, vasculitis, and collagen diseases such as SLE (4,8-11). Bile stasis, ischemia, and infection have also been suggested to be involved in the pathogenesis of AAC (12,13). The present patient neither had these typical risk factors for AAC nor any severe thrombogenic tendency that could cause organ ischemia. Moreover, there were no findings (anti-neutrophil cytoplasmic antibody positivity, rapidly progressive glomerulonephritis, interstitial lung disease, multiple mononeuropathy, etc.) that would lead to a suspicion of vasculitis, which led us to consider the possibility of AAC associated with AOSD. The present patient had hepatic dysfunction with aspartate aminotransferase elevation as well as the elevated levels of total bilirubin and and biliary enzymes including alkaline phosphatase and gamma-glutamyl transferase. Although cholecystectomy and liver biopsy were not performed and there was no histopathological examination, the recurrence of AOSD and hepatocellular damage caused by MAS/HLH might have had an adverse effect in the biliary system, resulting in secondary biliary stasis and AAC. Serositis has been proposed to be associated with the pathogenesis of AAC in patients with SLE complicated by AAC (5). Albeit less frequent, AOSD has been reported to be associated with serositis such as pleurisy and pericarditis (14,15). In the present case, there were no signs of advanced ascites or extensive peritoneal irritation. Although extensive peritonitis was unlikely, the present patient might have had AAC as a result of localized serositis in the gallbladder associated with a severe systemic inflammatory response. AAC complicated with AOSD is relatively rare and it has also been less frequently reported. One possible explanation for the paucity of studies is that some cases of AAC complicated with AOSD may be asymptomatic. Although the background disease is different, asymptomatic AAC cases have been reported (5,16,17). A certain number of cases of AAC associated with autoimmune diseases may be asymptomatic because high-dose glucocorticoid treatment may be initiated before performing imaging studies, such as abdominal ultrasonography and computed tomography. Therefore, AAC may remain asymptomatic and improve with immunosupressive treatment. Previously reported cases of AAC associated with AOSD are summarized in Table 2 (3,4). All patients, including the present patient, were female, with relapsing or recurrent cases of AOSD with high disease activity, complicated with HPS or DIC. The results of infectious disease examinations, such as blood culture, were negative, and antibiotic treatment did not improve the disease condition. The findings in the previous two casessuggested complications of serositis (peritonitis). Therefore, serositis may have been involved in the development of AAC. In terms of treatment, cholecystectomy was performed in one patient, but all patients showed an improvement with immunosuppressive therapy, including steroids. In the case reported by Vallianou et al., cholecystectomy was performed (4). However, after cholecystectomy, the patient presented with high fever associated with increased disease activity of AOSD and was eventually treated with steroids and naproxen, which improved the patient's condition. Since cholecystectomy did not improve the disease activity, Vallianou et al. suggested that immunosuppressive therapy, including steroids, may be more beneficial than surgical treatment for AAC complicated with AOSD. Similar to calculous cholecystitis, the treatment of AAC is often surgical, including cholecystectomy; however, conservative treatment may be an alternative approach in high-risk cases. In the 2018 Tokyo guidelines for the management of acute cholecystitis, patients with a Charlson comorbidity index score of ≤5 and an American Society of Anesthesiologists-Physical Status score of ≤2 are considered to be in a sufficently good general condition to safely undergo surgery (18). The present patient had a Charlson comorbidity index score of 1, but surgery was not recommended as she was in American Society of Anesthesiologists-Physical Status class IV. In addition, because of the severe thrombocytopenia caused by MAS/HLH associated with AOSD, invasive treatment approaches such as surgical cholecystectomy and percutaneous transhepatic gallbladder drainage were considered to be risky and conservative treatment was therefore prioritized. Although the patient's general condition was poor, she did not harbor any risk factors for AAC and the disease activity was very high based on the presence of MAS/HLH. In the present case, the early clinical diagnosis of AOSD-related AAC led to the prompt initiation of immunosuppressive therapy, which might have been a factor in the favorable outcome in the current case.
Table 2. Case Summaries of AAC Associated with AOSD.
Age Sex Abdominal findings other than AAC HPS/HLH DIC Antibiotics Treatment
Present case 21 Female Hepatosplenomegaly + - TAZ/PIPC High-dose glucocorticoids, CsA
(3) 49 Female Hepatosplenomegaly + + CTRX High-dose glucocorticoids,
CsA, IVIG
Serositis (a small amount of right
pleural effusion and ascites)
Enterocolitis
(4) 28 Female Peritonitis Unknown + MNZ,
MEPM,
CPFX Prednisone, naproxen,
cholecystectomy
DIC: disseminated intravascular coagulation, TAZ/PIPC: tazobactam/piperacillin, CTRX: ceftriaxone, MNZ: metronidazole, MEPM: meropenem, CPFX: ciprofloxacin, IVIG: intravenous immunoglobulin
The treatment with glucocorticoids and CsA resulted in an improvement in both MAS/HLH and AAC, suggesting that AAC might be caused by a common pathophysiology shared with AOSD-related MAS/HLH. Because the patient was refractory to glucocorticoids, we initiated concomitant treatment with CsA. CsA inhibits the production of cytokines such as IL-2, IL-5, IL-6, interferon-γ, and tumor necrosis factor-α, thereby inhibiting lymphocyte proliferation and differentiation (19,20). Park et al. reported the successful treatment of refractory AOSD complicated by MAS/HLH, desseminated intravascular coagulation, and AAC with glucocorticoids or oral CsA (3); therefore, CsA was chosen as a concomitant immunosuppressive agent in the present case. In a study by Park et al., glucocorticoids and CsA were started simultaneously, and improvement was achieved. Although it is unknown whether glucocorticoids alone are sufficient, the concomitant use of glucocorticoids and CsA is recommended to achieve an early therapeutic effect in severe cases of AOSD, such as those complicated with MAS and/or DIC. Although CsA was administered orally in the previous report, intravenous CsA administration was chosen in the present case to achieve a rapid effect and improve fever and laboratory abnormalities within 12-24 hours after treatment initiation (21). Intravenous CsA might be a useful immunosuppressant to achieve a rapid effect in AOSD with fatal organ complications such as MAS/HLH or AAC, for which immediate treatment is essential.
Tocilizumab has been reported to be effective for the treatment of AOSD (22). In the present case, tocilizumab was also considered prior to the administration of CsA. AAC is a rapidly worsening condition with a high risk of gallbladder perforation and secondary infection (23). In the present case, surgery remained a potential treatment direction due to the possibility of gallbladder perforation as a complication. In general, biologics are often discontinued for several weeks during the perioperative period due to the risk of infection. Tocilizumab was not initiated in the present case and treatment including immunosuppressive agents with a short half-life was desired because of the potential for surgery in the near future. In addition, cytopenia is a relatively common adverse event associated with tocilizumab and the patient had severe thrombocytopenia, which would be difficult to treat if it persisted or worsened after the introduction of tocilizumab (24). In the present case, the treatment with CsA was successful without any significant adverse events. However, CsA has been reported to cause drug-induced thrombotic microangiopathy (TMA) as a serious adverse event (25). While CsA is expected to have an immediate effect in patients with MAS/HLH and severe thrombocytopenia, CsA can cause TMA with severe thrombocytopenia and critical organ damage such as renal impairment as an adverse event. Therefore, CsA should be used with care and should be promptly discontinued if TMA is suspected for reconsideration of the treatment strategy.
Conclusion
AAC complicated by AOSD reccurence or exacerbated disease activity requires careful consideration when making a diagnosis, as it may be a manifestation of AOSD-related organ dysfunction. Immunosuppressive therapy with glucocorticoids or CsA might be a useful therapeutic option for AAC complicated by increased disease activity in patients with refractory AOSD.
For this case report, informed consent was obtained in writing from the patient.
The authors state that they have no Conflict of Interest (COI). | METHOTREXATE SODIUM, PREDNISOLONE | DrugsGivenReaction | CC BY-NC-ND | 33518559 | 19,623,958 | 2021-06-15 |
What was the outcome of reaction 'Cholecystitis acute'? | A Recurrent Case of Adult-onset Still's Disease with Concurrent Acalculous Cholecystitis and Macrophage Activation Syndrome/Hemophagocytic Lymphohistiocytosis Successfully Treated with Combination Immunosuppressive Therapy.
We herein report the case of 21-year-old female diagnosed with adult-onset Still's disease (AOSD) three years earlier who presented with fever and right upper abdominal pain. She was diagnosed with acute acalculous cholecystitis (AAC) based on hepatic dysfunction, elevated C-reactive protein, and gallbladder wall thickening on abdominal ultrasound. Based on the presence of pancytopenia, hyperferritinemia, and hemophagocytosis by a bone marrow examination, she was diagnosed with macrophage activation syndrome (MAS)/hemophagocytic lymphohistiocytosis (HLH) which was refractory to glucocorticoid pulse therapy. The combination of intravenous cyclosporine A with glucocorticoids was able to successfully control the disease activity of AOSD-related AAC and MAS/HLH.
Introduction
Adult-onset Still's disease (AOSD) is a systemic inflammatory disease of unknown etiology that is characterized by fever, arthritis, characteristic rash, hepatosplenomegaly, and hyperferritinemia. The pathogenesis of AOSD is considered to involve various inflammatory cytokines such as tumor necrosis factor-α, interleukin (IL)-1, IL-6, IL-18, and interferon-γ (1). Some cases might be complicated by macrophage activation syndrome (MAS)/hemophagocytic lymphohistiocytosis (HLH), a fatal condition caused by hypercytokinemia which can lead to multi-organ failure (2). Conversely, acute acalculous cholecystitis (AAC), a relatively rare organ complication of AOSD (3,4), has been reported to be complicated by connective tissue diseases including systemic lupus erythematosus (SLE). Since it is a rare complication of AOSD, there is no consensus on the course of treatment for AOSD related AAC, partly because it can be observed as AOSD-related organ failure following surgical cholecystectomy (4,5). We herein report the case of a patient presenting with concurrent MAS/HLH and AAC at the time of AOSD relapse who was successfully treated only with glucocorticoids and cyclosporine A (CsA).
Case Report
A 21-year-old female patient was diagnosed with AOSD three years prior to the present admission based on the findings of fever, erythema of the extremities and trunk, polyarthritis, hepatic dysfunction, hyperferritinemia, elevated inflammatory response, and splenomegaly. She was treated with 30 mg/day prednisolone, which was tapered off after achieving an improvement of the disease activity. Eleven months before hospitalization, she developed arthritis in her right knee and was diagnosed with a minor flare of AOSD. She was initiated on 7.5 mg/day prednisolone and 8 mg/week methotrexate the following month. After obtaining an improvement of the arthritis in the right knee, prednisolone was tapered off and discontinued three months prior to the current admission and remission was maintained with a methotrexate dose of 8 mg/week thereafter. She had a history of paroxysmal supraventricular tachycardia, no allergies, and no family history of rheumatic disease.
Two months before the hospitalization, a urticaria-like rash with itching appeared on her extremities. A week before this hospitalization, she also developed a fever ranging between 39℃ and 40℃ and pain in both shoulders and knees. In mid-April, she developed nausea, vomiting, and right hypochondriac pain. At the time of examination, she had fever, right hypochondralgia, and tenderness in both shoulder and knee joints. Laboratory tests showed elevated hepatobiliary enzymes (aspartate aminotransferase, 734 U/L; alanine aminotransferase, 429 U/L; lactate dehydrogenase, 2,941 U/L; gamma-glutamyl transferase, 272 U/L) and C-reactive protein (CRP, 5.34 mg/dL). Abdominal ultrasonography (Fig. 1a) and abdominal computed tomography scans (Fig. 1b) showed gallbladder enlargement and wall thickening without any biliary stones.
Figure 1. Ultrasonography and computed tomography (CT) images on admission. (a) Ultrasonography images of the gallbladder. (b, c) CT images of the gallbladder (arrows), liver, and spleen. (d) CT images of the cervical lymph nodes (arrow). (e) Changes in the gallbladder ultrasonography findings on day 26.
She was admitted to the hospital with the diagnosis of AAC because the common bile duct was not obstructed and the possibility of obstructive cholangitis was considered unlikely. She was managed by fasting and antibiotic treatment with tazobactam/piperacillin. However, pancytopenia (WBC, 2,300 /μL; hemoglobin, 11.0 g/dL; platelet count, 7.9×104/μL) developed on the second day with no improvement in hepatic dysfunction. The laboratory findings on the second day before the initiation of immunosuppressive therapy including glucocorticoids are presented in Table 1.
Table 1. Laboratory Findings at the Time of Hospitalization before the Start of Immunosuppressive Therapy.
Complete blood count LDH 2,549 U/L Rheumatoid factor 3 U/mL
WBC 2,300 /μL γ-GTP 272 U/L anti-CCP Ab 0.5 U/mL
Neutro 93.0 % CK 113 U/L MPO-ANCA <1.0 U/mL
Lympho 3.5 % TG 142 mg/dL PR3-ANCA <1.0 U/mL
Mono 3.0 % T-Cho 93 mg/dL anti-U1 RNP Ab <2.0 U/mL
Baso 0.5 % HDL-Cho 23 mg/dL Infection
Eosino 0.0 % BUN 5.5 mg/dL HBs Ag negative
RBC 365.0 ×104/μL Cre 0.61 mg/dL HBs Ab negative
Hb 11.0 g/dL Na 130 mEq/L HBc Ab negative
HCT 31.1 % K 4.1 mEq/L HCV Ab negative
MCV 85.2 Fl glucose 84 mg/dL Cytomegalovirus antigenemia negative
PLT 7.9 ×104/μL HbA1c 5.5 % EBVCA IgG positive
Coagulation Ferritin 20,811 ng/mL EBVCA IgM negative
PT-INR 1.09 sIL-2R 5,421 U/mL Parvo B19 IgM negative
APTT 40.9 sec CRP 6.11 mg/dL T-spot negative
Fibrinogen 194 mg/dL β-glucan 15.0 pg/mL
D-dimer 6.28 μg/mL Erythrocyte sedimentation ratio Procalcitonin 1.99 ng/mL
FDP 16.6 μg/mL 18 mm/h Blood culture negative
AT-3 98 % Immunology Urine culture negative
Biochemistry IgG 1,162 mg/dL Urine
TP 5.3 g/dL IgA 228 mg/dL pH 6.5
ALB 2.5 g/dL IgM 266 mg/dL Occult blood negative
T-Bil 2.15 mg/dL C3 77 mg/dL Protein negative
D-Bil 1.56 mg/dL C4 33.5 mg/dL Cast negative
AST 763 U/L anti-nuclear Ab <1:40 WBC negative
ALT 469 U/L anti-ds-DNA Ab 1.99 U/mL
ALP 1,586 U/L anti-Smith Ab <1.0 U/mL
Neutro: neutrophil, Lympho: lymphocyte, Mono: monocyte, Baso: basophil, Eosino: eosinophil, RBC: red blood cell, HCT: hematocrit, MCV: mean cell volume, PLT: platelet, PT-INR: prothrombin-international normalized ratio, APTT: activated partial thromboplastin time, FDP: fibrin degradation product, AT-3: antithrombin 3, TP: total protein, ALB: albumin, T-Bil: total bilirubin, D-Bil: direct bilirubin, AST: aspartate transaminase, ALT: alanine aminotransferase, ALP: alkaline phosphatase, LDH: lactate dehydrogenase, γ-GTP: γ-glutamyl transpeptidase, CK: creatine kinase, TG: triglyceride, T-Cho: total cholesterol, HDL-Cho: high-density lipoprotein cholesterol, BUN: blood urea nitrogen, Cre: creatinine, Na: sodium, K: potassium, sIL-2R: soluble interleukin-2 receptor, CRP: C-reactive protein, anti-CCP Ab: anti-cyclic citrullinated peptides antibodies, MPO-ANCA: myeloperoxidase anti-neutrophil cytoplasmic antibody, PR3-ANCA: proteinase3 anti-neutrophil cytoplasmic antibody, anti U1-RNP Ab: anti U1-ribonucleoprotein antibody, HCV: hepatitis C virus, EBV: Epstein-Barr virus
The patient was diagnosed with AOSD recurrence based on a fever ≥39°C lasting more than one week, arthralgia lasting more than two weeks, typical rash, splenomegaly (Fig. 1c), cervical lymphadenopathy (Fig. 1d), hepatic dysfunction, and negative rheumatoid factor and antinuclear antibodies, according to the AOSD diagnostic criteria by Yamaguchi et al. (6). In addition, she was diagnosed with MAS/HLH based on fever, splenomegaly, cytopenia of two or more lineages, hepatitis-like findings, and pathological changes in myeloid markers by bone marrow biopsy examination (Fig. 2), including hemophagocytosis, elevated serum ferritin, and elevated soluble IL-2 receptor, which fulfilled the criteria of the MAS/HLH diagnosis (7). There were no findings suggesting active viral infection and a viral etiology was ruled out for MAS/HLH, which was therefore considered to be due to AOSD recurrence. AAC was diagnosed as an organ complication associated with AOSD recurrence as it was associated with an exacerbated disease activity including MAS/HLH. Because of her poor general condition and severe thrombocytopenia associated with MAS/HLH, the patient was not considered to be a good candidate for invasive procedures such as cholecystectomy and percutaneous transhepatic gallbladder drainage for AAC, and therefore immunosuppressive therapy for AOSD was prioritized. Glucocorticoid pulse therapy with methylprednisolone (1 g/day) on days 2-4 of hospitalization was initiated for AOSD with a high disease activity, AAC, and MAS/HLH. After the initiation of glucocorticoid pulse therapy, the platelet count continued to decrease and the serum ferritin level tended to increase; therefore, the glucocorticoid therapy alone was considered to be insufficient for controlling the disease activity. After obtaining approval from the institutional ethics committee and informed consent from the patient, 125 mg continuous intravenous CsA was initiated on day four (Fig. 3). With the combination of glucocorticoids and intravenous CsA, the disease activity improved. Therefore, the glucocorticoid dose was reduced on day 15 with a switch to 4.0 mg/day oral betamethasone; the patient was also switched to 150 mg oral CsA the same day. Betamethasone was reduced from 4.0 to 3.0 mg on day 30. There was no recurrence of the disease activity after the initiation of the glucocorticoid taper, and abdominal ultrasound on day 26 showed an improvement in the gallbladder enlargement and gallbladder wall thickening observed at the time of admission (Fig. 1e). Pancytopenia, hepatic dysfunction, and hyperferritinemia also improved (platelet count, 20.4×104/μL on day 44; aspartate aminotransferase, 43 U/L on day 44; alanine aminotransferase, 32 U/L on day 44; ferritin, 20,811 and 185 ng/mL on days 2 and 43, respectively), and she was discharged on day 47.
Figure 2. Histopathological findings of a bone marrow biopsy sample. (a) Hematopoiesis in the bone marrow is preserved. Histiocytes are shown (red circles) (magnification: 400×). (b) Activated macrophages exhibiting phagocytosis (red arrow) (magnification: 1,000×).
Figure 3. Clinical course of the patient. CsA: cyclosporine A, i.v.: intravenous, mPSL: methylprednisolone, PLT: platelet count, p.o.: per os, TAZ/PIPC: tazobactam/piperacillin
Discussion
The risk factors for AAC, which accounts for 5-15% of all acute cholecystitis cases, include surgery, trauma, prolonged intensive care unit stay, infection, burn, intravenous feeding, vasculitis, and collagen diseases such as SLE (4,8-11). Bile stasis, ischemia, and infection have also been suggested to be involved in the pathogenesis of AAC (12,13). The present patient neither had these typical risk factors for AAC nor any severe thrombogenic tendency that could cause organ ischemia. Moreover, there were no findings (anti-neutrophil cytoplasmic antibody positivity, rapidly progressive glomerulonephritis, interstitial lung disease, multiple mononeuropathy, etc.) that would lead to a suspicion of vasculitis, which led us to consider the possibility of AAC associated with AOSD. The present patient had hepatic dysfunction with aspartate aminotransferase elevation as well as the elevated levels of total bilirubin and and biliary enzymes including alkaline phosphatase and gamma-glutamyl transferase. Although cholecystectomy and liver biopsy were not performed and there was no histopathological examination, the recurrence of AOSD and hepatocellular damage caused by MAS/HLH might have had an adverse effect in the biliary system, resulting in secondary biliary stasis and AAC. Serositis has been proposed to be associated with the pathogenesis of AAC in patients with SLE complicated by AAC (5). Albeit less frequent, AOSD has been reported to be associated with serositis such as pleurisy and pericarditis (14,15). In the present case, there were no signs of advanced ascites or extensive peritoneal irritation. Although extensive peritonitis was unlikely, the present patient might have had AAC as a result of localized serositis in the gallbladder associated with a severe systemic inflammatory response. AAC complicated with AOSD is relatively rare and it has also been less frequently reported. One possible explanation for the paucity of studies is that some cases of AAC complicated with AOSD may be asymptomatic. Although the background disease is different, asymptomatic AAC cases have been reported (5,16,17). A certain number of cases of AAC associated with autoimmune diseases may be asymptomatic because high-dose glucocorticoid treatment may be initiated before performing imaging studies, such as abdominal ultrasonography and computed tomography. Therefore, AAC may remain asymptomatic and improve with immunosupressive treatment. Previously reported cases of AAC associated with AOSD are summarized in Table 2 (3,4). All patients, including the present patient, were female, with relapsing or recurrent cases of AOSD with high disease activity, complicated with HPS or DIC. The results of infectious disease examinations, such as blood culture, were negative, and antibiotic treatment did not improve the disease condition. The findings in the previous two casessuggested complications of serositis (peritonitis). Therefore, serositis may have been involved in the development of AAC. In terms of treatment, cholecystectomy was performed in one patient, but all patients showed an improvement with immunosuppressive therapy, including steroids. In the case reported by Vallianou et al., cholecystectomy was performed (4). However, after cholecystectomy, the patient presented with high fever associated with increased disease activity of AOSD and was eventually treated with steroids and naproxen, which improved the patient's condition. Since cholecystectomy did not improve the disease activity, Vallianou et al. suggested that immunosuppressive therapy, including steroids, may be more beneficial than surgical treatment for AAC complicated with AOSD. Similar to calculous cholecystitis, the treatment of AAC is often surgical, including cholecystectomy; however, conservative treatment may be an alternative approach in high-risk cases. In the 2018 Tokyo guidelines for the management of acute cholecystitis, patients with a Charlson comorbidity index score of ≤5 and an American Society of Anesthesiologists-Physical Status score of ≤2 are considered to be in a sufficently good general condition to safely undergo surgery (18). The present patient had a Charlson comorbidity index score of 1, but surgery was not recommended as she was in American Society of Anesthesiologists-Physical Status class IV. In addition, because of the severe thrombocytopenia caused by MAS/HLH associated with AOSD, invasive treatment approaches such as surgical cholecystectomy and percutaneous transhepatic gallbladder drainage were considered to be risky and conservative treatment was therefore prioritized. Although the patient's general condition was poor, she did not harbor any risk factors for AAC and the disease activity was very high based on the presence of MAS/HLH. In the present case, the early clinical diagnosis of AOSD-related AAC led to the prompt initiation of immunosuppressive therapy, which might have been a factor in the favorable outcome in the current case.
Table 2. Case Summaries of AAC Associated with AOSD.
Age Sex Abdominal findings other than AAC HPS/HLH DIC Antibiotics Treatment
Present case 21 Female Hepatosplenomegaly + - TAZ/PIPC High-dose glucocorticoids, CsA
(3) 49 Female Hepatosplenomegaly + + CTRX High-dose glucocorticoids,
CsA, IVIG
Serositis (a small amount of right
pleural effusion and ascites)
Enterocolitis
(4) 28 Female Peritonitis Unknown + MNZ,
MEPM,
CPFX Prednisone, naproxen,
cholecystectomy
DIC: disseminated intravascular coagulation, TAZ/PIPC: tazobactam/piperacillin, CTRX: ceftriaxone, MNZ: metronidazole, MEPM: meropenem, CPFX: ciprofloxacin, IVIG: intravenous immunoglobulin
The treatment with glucocorticoids and CsA resulted in an improvement in both MAS/HLH and AAC, suggesting that AAC might be caused by a common pathophysiology shared with AOSD-related MAS/HLH. Because the patient was refractory to glucocorticoids, we initiated concomitant treatment with CsA. CsA inhibits the production of cytokines such as IL-2, IL-5, IL-6, interferon-γ, and tumor necrosis factor-α, thereby inhibiting lymphocyte proliferation and differentiation (19,20). Park et al. reported the successful treatment of refractory AOSD complicated by MAS/HLH, desseminated intravascular coagulation, and AAC with glucocorticoids or oral CsA (3); therefore, CsA was chosen as a concomitant immunosuppressive agent in the present case. In a study by Park et al., glucocorticoids and CsA were started simultaneously, and improvement was achieved. Although it is unknown whether glucocorticoids alone are sufficient, the concomitant use of glucocorticoids and CsA is recommended to achieve an early therapeutic effect in severe cases of AOSD, such as those complicated with MAS and/or DIC. Although CsA was administered orally in the previous report, intravenous CsA administration was chosen in the present case to achieve a rapid effect and improve fever and laboratory abnormalities within 12-24 hours after treatment initiation (21). Intravenous CsA might be a useful immunosuppressant to achieve a rapid effect in AOSD with fatal organ complications such as MAS/HLH or AAC, for which immediate treatment is essential.
Tocilizumab has been reported to be effective for the treatment of AOSD (22). In the present case, tocilizumab was also considered prior to the administration of CsA. AAC is a rapidly worsening condition with a high risk of gallbladder perforation and secondary infection (23). In the present case, surgery remained a potential treatment direction due to the possibility of gallbladder perforation as a complication. In general, biologics are often discontinued for several weeks during the perioperative period due to the risk of infection. Tocilizumab was not initiated in the present case and treatment including immunosuppressive agents with a short half-life was desired because of the potential for surgery in the near future. In addition, cytopenia is a relatively common adverse event associated with tocilizumab and the patient had severe thrombocytopenia, which would be difficult to treat if it persisted or worsened after the introduction of tocilizumab (24). In the present case, the treatment with CsA was successful without any significant adverse events. However, CsA has been reported to cause drug-induced thrombotic microangiopathy (TMA) as a serious adverse event (25). While CsA is expected to have an immediate effect in patients with MAS/HLH and severe thrombocytopenia, CsA can cause TMA with severe thrombocytopenia and critical organ damage such as renal impairment as an adverse event. Therefore, CsA should be used with care and should be promptly discontinued if TMA is suspected for reconsideration of the treatment strategy.
Conclusion
AAC complicated by AOSD reccurence or exacerbated disease activity requires careful consideration when making a diagnosis, as it may be a manifestation of AOSD-related organ dysfunction. Immunosuppressive therapy with glucocorticoids or CsA might be a useful therapeutic option for AAC complicated by increased disease activity in patients with refractory AOSD.
For this case report, informed consent was obtained in writing from the patient.
The authors state that they have no Conflict of Interest (COI). | Recovered | ReactionOutcome | CC BY-NC-ND | 33518559 | 19,623,958 | 2021-06-15 |
Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Condition aggravated'. | Refractory IgG4-related Pleural Disease with Chylothorax: A Case Report and Literature Review.
We herein report a rare case of a 66-year-old man with refractory chylothorax. Although he had been treated with moderate doses of prednisolone (PSL) on suspicion of pleuritis with Sjögren syndrome, the pleural effusion expanded after the reduction of PSL. Further workup including histopathological examinations of pleura led to the diagnosis of IgG4-RD with bilateral chylothorax without any leakage from the thoracic duct. Combination therapy with high-dose PSL plus rituximab successfully decreased the pleural effusion. This is a very rare case of IgG4-related pleuritis with chylothorax and the first report of its successful treatment with rituximab.
Introduction
Immunoglobulin G4-related disease (IgG4-RD) is a systemic fibro-inflammatory disease characterized by serum IgG4 elevation and distinctive histopathological findings, such as lymphoplasmacytic infiltrate with abundant IgG4-positive plasma cells, storiform fibrosis, and obliterative phlebitis (1,2). Almost all organs in the body, such as the central nervous system (CNS), lacrimal glands, salivary glands, thyroid, lungs, pancreas, biliary duct, liver, gastrointestinal tract, kidneys, prostate, retroperitoneum and lymph nodes, can be affected by IgG4-RD (3).
While the lungs are involved in 9-18% of IgG4-RD patients (4-7), pleural involvement is observed in only 4% (4,5). Pleural effusion is uncommon, but previous reports have shown that it is usually exudative (8).
Chylothorax, which is characterized by milky-appearing pleural fluid with elevated triglyceride levels or the presence of chylomicrons, is caused by the extravasation of chyle into the pleural space due to obstruction or damage of a thoracic duct or its tributaries or transdiaphragmatic flow from the peritoneal cavity (9). The etiologies of chylothorax include several causes, such as trauma (surgical or non-surgical), malignancy, lymphatic disorders, infection, chylous ascites, and other miscellaneous causes (10); however, chylothorax due to IgG4-RD has almost never been reported.
We experienced a rare case of IgG4-RD with refractory chylothorax that was successfully treated with high-dose prednisolone (PSL) and rituximab (RTX). We report this case with a review of previous case reports of IgG4-related pleuritis.
Case Report
A 66-year-old Japanese man with a history of pollen allergy and thyroidectomy for Graves-Basedow disease was admitted to another hospital with a 2-month history of leg edema, eyelid edema, and dyspnea on exertion. Computed tomography (CT) demonstrated pleural and pericardial effusions, and a pericardiocentesis revealed the fluid as a nonspecific inflammatory effusion with increased numbers of lymphocytes without any infection. Increasing the levothyroxine dose for latent hypothyroidism and initiation of furosemide therapy did not decrease the effusion. He was transferred to our department.
At his first admission to our hospital, whole-body CT demonstrated pericardial effusion, bilateral pleural effusion, and testicular hydrocele. No swelling of the lacrimal or salivary glands nor pancreatic enlargement was observed. The right pleural effusion was exudative with a total cell count of 2,410/mm3 (lymphocytes, 75%) and neither malignant cells nor bacteria. Serum anti-SS-A/Ro antibody was slightly positive (15.4 U/mL; normal range, <10.0 U/mL) on an enzyme-linked immunosorbent assay but negative with the double immunodiffusion method. Other autoantibodies, including anti-SS-B/La, anti-CCP, anti-dsDNA, anti-RNP, anti-Scl70, and anti-neutrophil cytoplasmic antibodies, were all negative. Sialometry showed a rate of 1.008 mL/minute (within normal range), while salivary gland scintigraphy showed a slightly decreased uptake and secretory function. A lip biopsy demonstrated grade 2 lymphocytic infiltration according to Greenspan's classification (11), with only a few IgG4-positive plasma cells. The Schirmer test and rose bengal dye staining test were positive only in the left eye. Although he did not meet the ACR 2012 classification criteria (12), we suspected Sjögren syndrome with serositis.
PSL 40 mg/day (0.5 mg/kg) was initiated. Both the pleural and pericardial effusion amount decreased; however, tapering of the PSL led to exacerbation of the pleural effusion.
At his second admission, he presented with swelling of the lacrimal glands. Laboratory data are shown in Table 1. The white blood cell count in the peripheral blood was 8,200/μL (neutrophil 87.7%, lymphocyte 8.7%). Serum IgG and IgG4 levels were 1,500 mg/dL and 264 mg/dL, respectively. Autoantibodies were all negative. Serum levels of C-reactive protein (CRP), soluble interleukin-2 receptor (IL-2R), free T3, free T4, and thyroid-stimulating hormone (TSH) were also within the normal ranges (0.04 mg/dL, 394 U/mL, 2.9 pg/mL, 1.7 ng/dL and 1.67 μIU/mL, respectively). Chest CT showed marked bilateral pleural effusion with passive atelectasis and slight pericardial effusion (Fig. 1B). Thoracentesis for the right pleural effusion (Table 1) revealed turbid yellow fluid (Fig. 1A) with a total cell count of 810/mm3 (lymphocytes 84%), total protein 5.7 g/dL, adenosine deaminase (ADA) 25.1 U/L, total cholesterol 84 mg/dL, triglyceride 300 mg/dL, and the presence of chylomicrons, compatible with chylothorax. A cytologic examination was negative for malignancy. General bacterial and mycobacterial cultures of the pleural fluid were negative. He had no history of trauma or thoracic surgery. Lymphangiography did not show any leakage or obstruction of the thoracic duct (Fig. 2). While thoracoscopy did not reveal any tumor, amyloid deposits, or leakage from the thoracic duct, a thoracoscopic surgical pleural biopsy demonstrated infiltration by lymphocytes and plasma cells with ectopic germinal centers under the pleural mesothelium. Approximately 50% of IgG-positive plasma cells were IgG4-positive (Fig. 3). Storiform fibrosis and obstructive phlebitis were not found in this small specimen.
Table 1. Laboratory Data on 2nd Admission.
Peripheral blood CRP 0.04 mg/dL Pleural effusion
WBC 8,200 /μL ESR 15 mm/hr Cell count 810 /μL
Neut 87.7 % Ferritin 85 ng/mL poly 0 /μL
Lymp 8.7 % IgG 1,500 mg/dL mono 680 /μL
Mono 3.2 % IgG4 264 mg/dL others 130 /μL
Eosino 0.2 % IgA 226 mg/dL pH 7.5
Baso 0.2 % IgM 70 mg/dL specific gravity 1.016
RBC 5.05 ×106/μL C3 109 mg/dL TP 5.7 g/dL
Hb 15.5 g/dL C4 24 mg/dL Alb 3.3 g/dL
Plt 288 ×103/μL CH50 59.3 U/mL Amy 45 U/L
Cryoglobulin negative Glu 131 mg/dL
Biochemistry/Serology LDH 88 U/L
TP 7.4 g/dL Antibody T-cho 84 mg/dL
Alb 4.2 g/dL ANA negative TG 300 mg/dL
T-Bil 0.5 mg/dL SS-A 3.3 U/mL ADA 25.1 U/L
BUN 24.2 mg/dL SS-B <1.0 U/mL Hyaluronic Acid 6,670 ng/mL
Cre 1.25 mg/dL ds-DNA 3.8 U/mL CEA 1.8 ng/mL
UA 9.2 mg/dL RNP <2.0 U/mL
Na 139.5 mEq/L MPO-ANCA <1.0 U/mL
K 3.8 mEq/L PR3-ANCA <1.0 U/mL
Cl 100 mEq/L
AST 13 U/L Tumor marker
ALT 10 U/L sIL-2R 394 U/mL
LDH 163 U/L CEA 1.6 ng/mL
ALP 235 U/L CYFRA 1.7 ng/mL
γ-GTP 55 U/L SCC 0.7 ng/mL
Amy 62 U/L proGRP 41.5 ng/mL
CK 70 U/L
T-cho 192 mg/dL Infection marker
HbA1c 7.0 % procalcitonin <0.03 ng/mL
KL-6 193 U/mL T-SPOT negative
BNP 8.0 pg/mL GPLcore-IgA negative
fT3 2.9 ng/dL CMV-Ag negative
fT4 1.7 ng/dL β-D <6.0 pg/mL
TSH 1.67 μIU/mL
TP: total protein, Alb: albumin, T-Bil: total bilirubin, BUN: blood urea nitrogen, Cre: creatinine, UA: uric acid, Amy: amylase, T-cho: total cholesterol, KL-6: Krebs von den Lungen-6, BNP: brain natriuretic peptide, fT3: free triiodothyronine, fT4: free thyroxine, TSH: thyroid-stimulating hormone, CRP: C-reactive protein, ESR: erythrocyte sedimentation rate, ANA: antinuclear antibody, SS-A: anti-SS-A/Ro antibody, SS-B: anti-SS-B/La antibody, ds-DNA: anti-double-stranded DNA antibody, RNP: anti-RNP antibody, MPO-ANCA: myeloperoxidase-anti-neutrophil cytoplasmic antibody, PR3-ANCA: proteinase3-anti-neutrophil antibody, sIL-2R: soluble interleukin-2 receptor, GPLcore-IgA: glycopeptidolipid core IgA antibody, CMV-Ag: cytomegalovirus antigenemia, β-D: (1-3-)β-D-glucan, ADA: adenosine deaminase
Figure 1. Pleural effusion and CT images before and after treatment. The right pleural effusion appeared as turbid yellow fluid (A). Bilateral pleural effusion and pericardial effusion were seen at the second admission (B). After treatment with a combination of high-dose corticosteroids and rituximab, the pleural and pericardial effusion was significantly decreased (C).
Figure 2. Lymphangiography images. Lymphangiography showed the intact structure of the thoracic duct (yellow arrows) and revealed no leakage or obstruction of the duct.
Figure 3. Histopathological images from the pleural biopsy. A pleural biopsy showed the infiltration of lymphocytes and plasma cells with ectopic germinal centers under the pleural mesothelium, and more than 50% of IgG-positive plasma cells were IgG4-positive. HE: Hematoxylin and Eosin staining, LPF: low-power field, HPF: high-power field
We performed another lip biopsy, and the specimen showed excessive IgG4-positive plasma cell infiltration [48 cells/high-power field (HPF)] with >50% IgG4/IgG (Fig. 4). According to the diagnostic criteria of IgG4-related respiratory disease (13), the patient met the following: i) pleural involvement with CT, ii) elevated serum IgG4 level, iii) pleural biopsy findings (lymphoplasmacytic infiltration and increased IgG4 positive cells), and iv) IgG4-related sialadenitis confirmed with a lip biopsy. Thus, we diagnosed him with “definite” IgG4-related disease.
Figure 4. Histopathological images from the lip biopsy. A lip biopsy revealed focal IgG4-positive plasma cell infiltration, with up to 48 cells/HPF and an IgG4/IgG ratio exceeding 50%. HE: Hematoxylin and Eosin staining, LPF: low-power field, HPF: high-power field
Regarding mimickers of IgG4-RD, sarcoidosis was considered unlikely because of the lack of any elevation in the level of angiotensin-converting enzyme (ACE) or hypercalcemia on blood tests and no findings of granulomas in the biopsy specimens. The pleural specimens did not show angiocentricity or granuloma formation, so lymphomatoid granulomatosis was also deemed unlikely in this case. No fever or high CRP levels were observed in this patient, which made Multicentric Castleman disease unlikely.
The treatment and clinical course of this patient are shown in Fig. 5. We first performed continuous drainage of the pleural fluid with fasting, intravenous hyperalimentation, and octreotide for two weeks. The octreotide was used in an off-label manner with the patient's consent to reduce lymphatic flow in the thoracic duct (14). The pleural drainage decreased the effusion temporarily, but the production of new fluid did not cease, resulting in the marked loss of serum levels of albumin, IgG, and IgG4. We started high-dose PSL 70 mg (1 mg/kg/day) with RTX (375 mg/m2, weekly, 4 times). The off-label use of RTX for IgG4-RD was approved by the authorized committee in our hospital [approval number: 2020-012] with informed consent from the patient. The pleural effusion gradually decreased. Later, we switched from PSL to methylprednisolone (mPSL) due to the latter's lower mineralocorticoid activity and better transferability to the lung (15,16). Six months from induction therapy, the pleural effusion had significantly improved (Fig. 1C).
Figure 5. Summary of clinical course of this patient. The pleuritis showed an insufficient response to the first induction therapy with moderate-dose PSL and diuretics. However, the second induction therapy with high-dose PSL and RTX resulted in the significant improvement of pleuritis and a reduction in the serum IgG4 levels. PSL: prednisolone, mPSL: methylprednisolone, RTX: rituximab, Tx: treatment
Discussion
The present patient developed refractory chylothorax due to IgG4-RD diagnosed histopathologically with a pleural specimen. The response to a moderate dose of PSL was poor. High-dose PSL and additional RTX resulted in marked improvement. Chylothorax presenting as IgG4-related pleuritis is quite rare, and to our knowledge, this is the first report of the successful treatment of IgG4-related pleuritis with RTX.
Pleural involvement is reportedly rare; indeed, Fei et al. found that 87 of 248 patients with IgG4-RD in a prospective cohort (35.1%) had intrathoracic involvement (17), although the involvement was mainly in the lungs and lymph nodes, including hilar and mediastinal lymphadenopathy, in 52.9%, solid nodules in the lungs in 25.3%, alveolointerstitial opacities in 20.7%, round ground-glass opacities in 9.2%, and bronchovascular opacities in 20.7%. Pleural nodules and thickening were observed in 16.1%, but pleural effusion was seen in only 4.6%.
We summarized 37 previous case reports with IgG4-RD related pleuritis in Table 2 (18-48). Patients with IgG4-related pleuritis were predominantly men (78%), and the mean age was 63.5±14.7 years old. Bilateral pleural effusion was seen in 21 cases, while 11 cases (right, n=7 cases; left, n=4) had unilateral effusion. In the 24 cases with pleural effusion findings available, 22 showed an exudative pattern, while bloody effusion was seen in 2 cases and transudative effusion in 1 case. Pleural effusion cytometry revealed predominantly lymphocytes among total cases, with a high concentration of IgG4 revealed in 10 cases. Our present findings were consistent with those of previous cases with regard to the age, percentage of men, and rate of bilateral exudative pleural effusion.
Table 2. A Summary of 37 Previous Case Reports with IgG4-RD Related Pleuritis.
Case No. Reference Age Gender Side Pleural effusion test Pleural biopsy Serum Associated diseases Initial
PSL dose
(/day) Immunosuppressant PSL effect for pleuritis
Cell count (/μL) Lymph
(%) IgG (mg/dL) IgG4 (mg/dL) ADA (IU/L) IgG4-positive plasma cells (/HPF) IgG4/IgG IgG
(mg/dL) IgG4
(mg/dL)
Non-chylothorax cases
1 18 74 M Right N/D N/D N/D N/D N/D N/D N/D 46 N/D N/D none none - Good response
2 19 65 M Left Exudative N/D lymp 32%, Plasma 32% 3,005 1,510 N/D N/D N/D 3,142 1194% Mikulicz’s disease 30 mg - Good response
3-7 (5 cases) 20 62 (49-76) M (all) N/D N/D N/D N/D N/D N/D N/D N/D N/D high in 3/3 cases (100%) high in 2/4 cases (50%) 3/5 cases N/D N/D N/D
8 21 63 F Bilateral bloody N/D lymphocyte and plasma cells dominant N/D N/D N/D N/D N/D 2,450 420 history of autoimmune pancreatitis dose unknown - Good response
9 22 78 M Bilateral Exudative N/D mononuclear cell dominant N/D 590 34.1-46.7 17.6 85.4 1,604 483 - none - Partial response
10 23 85 M Bilateral (Left dominant) Exudative 2,600 87% 3,403 2,090 122 N/D N/D 4,121 2,740 salivary glands, lymph nodes, orbital lesion, bile duct, gastric glands 30 mg - Good response
11 24 73 M Right Exudative (bloody) 741 69% 3,358 907 59.8 N/D N/D 4,219 1,500 pericarditis, retroperitoneal fibrosis 30 mg - Good response
12 68 M Left Exudative 4,800 92% 2,809 571 104.4 N/D N/D 1,471 372 Mikulicz’s disease 30 mg - Good response
13 25 29 F Bilateral Exudative N/D 93% N/D N/D N/D >30 92% N/D 136 pericardium 40 mg - Good response
14 26 57 M Bilateral N/D N/D N/D N/D N/D N/D N/D >40% N/D 970 none N/D - Good response
15 27 69 M Right Exudative N/D dominant 4,276 N/D 70.6 N/D 50% 3,570 2,380 lymph node 0.5 mg/kg - Good response
16 28 71 F Right N/D N/D N/D N/D N/D N/D 27.3 84% 1,756 684 periaortitis 40 mg - Good response
17 29 74 F Bilateral Exudative N/D N/D N/D N/D normal 91 91% N/D 740 interstitital pneumonia 25 mg (0.5mg/kg) - Good response
18 30 48 M Bilateral Exudative N/D lymphocyte dominant N/D N/D N/D N/D 24% N/D 248 lymph node 0.6 mg/kg - Good response
19 31 63 M Right Exudative N/D N/D N/D N/D N/D 73 >40% N/D 284 none 40 mg MTX
(for PsA) Good response
20 32 74 M Left Transudative N/D N/D N/D N/D N/D N/D 30% 1,300 217 lymph node, neuromyopathy 40 mg - Good response
21 33 68 F Bilateral Exudative N/D N/D N/D N/D N/D N/D N/D N/D 307 uterine enlargement 0.6 mg/kg - Good response
22 34 58 M Bilateral N/D N/D N/D N/D N/D N/D 52 50% 1,200 141 none 37.5 mg AZP→
MTX Good response
23 35 32 M Biateral N/D N/D N/D N/D N/D N/D N/D N/D N/D 550 pericarditis 30 mg - Good response
24 36 78 M Bilateral N/D N/D N/D N/D N/D N/D 100 70% N/D 760 Sclerosing cholangitis, constrictive pericarditis N/D - Good response
25 37 70 M Bilateral N/D N/D N/D N/D N/D N/D none (after treatment) none (after treatment) normal 437 pericarditis, Aortitis high dose mPSL 3days→PSL 1mg/kg CYC Good response
26 70 M Right Exudative N/D dominant N/D N/D N/D N/D >50% N/D 224 mediastinitis 0.6 mg/kg - Good response
27 38 70 M Bilateral (Right dominant) Exudative 5,400 93.80% 4,409 1,070 75.6 >10 >40% 2,518 1,030 none 40 mg - Good response
28 39 84 M Bilateral N/D 448 Plasma 53% N/D N/D N/D 45 N/D N/D 306 none 40 mg - Good response
29 40 43 F Right Exudative N/D 80-97% N/D N/D 4.6-7.0 80 >40% normal 125 Pericardial effusion, abdominal effusion 30 mg - Good response
30 41 55 M Bilateral Exudative 1,952 52% N/D N/D N/D N/D N/D 3,260 534 pericarditis, lacrimal gland, 80 mg MMF N/D
31 42 65 M Bilateral Exudative 2,700/7,160 90%/97% N/D 124/125 23.0/20.5 50 40% 1,490 164 none 30 mg AZP Partial response
32 43 81 M Bilateral Exudative 3,450 69% N/D N/D 85.0 >50 <40% 2,807 233 none 30 mg - Partial response
33 44 70 F Bilateral Exudative N/D N/D 3,269 1,280 75.4 N/D N/D 3,877 >1,500 pericarditis N/D N/D Good response
34 45 72 F Left Exudative 5,483 99% N/D N/D 80.2 >50 >40% 5,310 >1,500 lymph node none - (naturally dissappered)
35 46 46 M Bilateral Exudative N/D 68% N/D 256 36.4 (normal) 22 42% N/D 142 N/D 30 mg - Good response
Cylorhorax cases
36 47 69 M Bilateral Exudative (Chylothorax) 3980/5,870 92%/88.5% 2,696/2,647 571/653 40.8/39.9 N/D 90% 1,539 277 none 30 mg - Partial response
37 48 16 M Bilateral Exudative (Chylothorax) N/D N/D N/D N/D 15 62 40% (mediastinal biopsy) N/D 1,650 none 1 mg/kg AZP Poor response (surgical obliteration)
present case Sakata et al. 66 M Bilateral Exudative (Chylothorax) 810 84% N/D N/D 25.1 50% 1500 264 lacrimal and salivery gland, pericarditis 70mg RTX Poor response
M: male, F: female, N/D: not determined, MTX: methotrexate, AZP: azathioprine, CYC: 381 cyclophosphamide, MMF: mycophenolate mofetil, RTX: rituximab
Interestingly, in previously reported cases of IgG4-related pleuritis, 10 out of 15 cases showed high levels of ADA in the pleural fluid (>40 U/L), which is usually measured as an auxiliary tool for the diagnosis of tuberculous pleuritis (49). Although careful ruling out of tuberculous pleuritis is necessary using other examinations, such as Ziehl-Neelsen staining (50), elevated ADA levels in pleural fluid may be useful for identifying IgG4-RD pleuritis because such a condition reflects the strong activation of lymphocytes. The levels of ADA in the pleural fluid of the present case were within normal limits.
Only two previous cases of IgG4-related pleuritis presenting as chylothorax have been reported (47,48). Kato et al. reported a 69-year-old man with IgG4-related pleuritis, demonstrating right-sided chylothorax and left-sided non-chylothorax pleuritis (47). The right-side chylothorax persisted while the left-side pleuritis improved with corticosteroids. Another case, reported by Goag et al., was a young man with bilateral chylothorax (48) unresponsive to high-dose PSL with azathioprine or octreotide and a limited low-fat diet with medium-chain triglyceride supplementation. He ultimately had to undergo exploratory thoracotomy and surgical obliteration. In contrast to most non-chylothorax IgG4-pleuritis patients, who tend to show a good response to treatment, IgG4-related pleuritis with chylothorax is likely to have a poor response to PSL. The pathogenesis of chylothorax in IgG4-RD is unclear. Lymphangiography in our case did not reveal any leakage from the thoracic duct, suggesting potential micro-damage to the lymphatic channels hampering centripetal lymph propulsion from the periphery of the pleural surface. However, we lacked histological evidence of this, so more cases need to be accumulated to clarify the mechanism involved.
Many kinds of immunosuppressant drugs, such as azathioprine, methotrexate, cyclophosphamide, and mycophenolate mofetil, have been used to try to treat refractory IgG4-RD, but the optimal drug in combination with PSL is still unclear (51). Reports of the effectiveness of RTX in IgG4-RD have been increasing (51-54). Regarding the mechanisms underlying IgG4-RD, RTX, which depletes peripheral B cells, is a reasonable addition to therapy not only to prevent the repletion of short-lived plasmablasts and plasma cells but also to interfere with the maintenance of CD4+ T cell memory (55). Furthermore, a French nationwide study demonstrated the efficacy of RTX for both induction therapy and the maintenance of remission (56). Therefore, we selected RTX in our refractory case, and his pleural effusion gradually disappeared with a steroid-sparing effect. To our knowledge, this is the first case report suggesting the effectiveness of RTX in IgG4-related pleuritis.
In conclusion, we experienced a case of refractory IgG4-related pleuritis with chylothorax that was improved with high-dose PSL and RTX. More cases need to be accumulated in order to clarify the clinical manifestations of IgG4-RD pleuritis and its appropriate treatment.
We declare that we have obtained written informed consent from this patient to publish this case report.
The authors state that they have no Conflict of Interest (COI). | FUROSEMIDE, LEVOTHYROXINE, PREDNISOLONE, SPIRONOLACTONE, TOLVAPTAN, TORSEMIDE | DrugsGivenReaction | CC BY-NC-ND | 33518567 | 20,037,195 | 2021-07-01 |
Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Drug ineffective'. | Refractory IgG4-related Pleural Disease with Chylothorax: A Case Report and Literature Review.
We herein report a rare case of a 66-year-old man with refractory chylothorax. Although he had been treated with moderate doses of prednisolone (PSL) on suspicion of pleuritis with Sjögren syndrome, the pleural effusion expanded after the reduction of PSL. Further workup including histopathological examinations of pleura led to the diagnosis of IgG4-RD with bilateral chylothorax without any leakage from the thoracic duct. Combination therapy with high-dose PSL plus rituximab successfully decreased the pleural effusion. This is a very rare case of IgG4-related pleuritis with chylothorax and the first report of its successful treatment with rituximab.
Introduction
Immunoglobulin G4-related disease (IgG4-RD) is a systemic fibro-inflammatory disease characterized by serum IgG4 elevation and distinctive histopathological findings, such as lymphoplasmacytic infiltrate with abundant IgG4-positive plasma cells, storiform fibrosis, and obliterative phlebitis (1,2). Almost all organs in the body, such as the central nervous system (CNS), lacrimal glands, salivary glands, thyroid, lungs, pancreas, biliary duct, liver, gastrointestinal tract, kidneys, prostate, retroperitoneum and lymph nodes, can be affected by IgG4-RD (3).
While the lungs are involved in 9-18% of IgG4-RD patients (4-7), pleural involvement is observed in only 4% (4,5). Pleural effusion is uncommon, but previous reports have shown that it is usually exudative (8).
Chylothorax, which is characterized by milky-appearing pleural fluid with elevated triglyceride levels or the presence of chylomicrons, is caused by the extravasation of chyle into the pleural space due to obstruction or damage of a thoracic duct or its tributaries or transdiaphragmatic flow from the peritoneal cavity (9). The etiologies of chylothorax include several causes, such as trauma (surgical or non-surgical), malignancy, lymphatic disorders, infection, chylous ascites, and other miscellaneous causes (10); however, chylothorax due to IgG4-RD has almost never been reported.
We experienced a rare case of IgG4-RD with refractory chylothorax that was successfully treated with high-dose prednisolone (PSL) and rituximab (RTX). We report this case with a review of previous case reports of IgG4-related pleuritis.
Case Report
A 66-year-old Japanese man with a history of pollen allergy and thyroidectomy for Graves-Basedow disease was admitted to another hospital with a 2-month history of leg edema, eyelid edema, and dyspnea on exertion. Computed tomography (CT) demonstrated pleural and pericardial effusions, and a pericardiocentesis revealed the fluid as a nonspecific inflammatory effusion with increased numbers of lymphocytes without any infection. Increasing the levothyroxine dose for latent hypothyroidism and initiation of furosemide therapy did not decrease the effusion. He was transferred to our department.
At his first admission to our hospital, whole-body CT demonstrated pericardial effusion, bilateral pleural effusion, and testicular hydrocele. No swelling of the lacrimal or salivary glands nor pancreatic enlargement was observed. The right pleural effusion was exudative with a total cell count of 2,410/mm3 (lymphocytes, 75%) and neither malignant cells nor bacteria. Serum anti-SS-A/Ro antibody was slightly positive (15.4 U/mL; normal range, <10.0 U/mL) on an enzyme-linked immunosorbent assay but negative with the double immunodiffusion method. Other autoantibodies, including anti-SS-B/La, anti-CCP, anti-dsDNA, anti-RNP, anti-Scl70, and anti-neutrophil cytoplasmic antibodies, were all negative. Sialometry showed a rate of 1.008 mL/minute (within normal range), while salivary gland scintigraphy showed a slightly decreased uptake and secretory function. A lip biopsy demonstrated grade 2 lymphocytic infiltration according to Greenspan's classification (11), with only a few IgG4-positive plasma cells. The Schirmer test and rose bengal dye staining test were positive only in the left eye. Although he did not meet the ACR 2012 classification criteria (12), we suspected Sjögren syndrome with serositis.
PSL 40 mg/day (0.5 mg/kg) was initiated. Both the pleural and pericardial effusion amount decreased; however, tapering of the PSL led to exacerbation of the pleural effusion.
At his second admission, he presented with swelling of the lacrimal glands. Laboratory data are shown in Table 1. The white blood cell count in the peripheral blood was 8,200/μL (neutrophil 87.7%, lymphocyte 8.7%). Serum IgG and IgG4 levels were 1,500 mg/dL and 264 mg/dL, respectively. Autoantibodies were all negative. Serum levels of C-reactive protein (CRP), soluble interleukin-2 receptor (IL-2R), free T3, free T4, and thyroid-stimulating hormone (TSH) were also within the normal ranges (0.04 mg/dL, 394 U/mL, 2.9 pg/mL, 1.7 ng/dL and 1.67 μIU/mL, respectively). Chest CT showed marked bilateral pleural effusion with passive atelectasis and slight pericardial effusion (Fig. 1B). Thoracentesis for the right pleural effusion (Table 1) revealed turbid yellow fluid (Fig. 1A) with a total cell count of 810/mm3 (lymphocytes 84%), total protein 5.7 g/dL, adenosine deaminase (ADA) 25.1 U/L, total cholesterol 84 mg/dL, triglyceride 300 mg/dL, and the presence of chylomicrons, compatible with chylothorax. A cytologic examination was negative for malignancy. General bacterial and mycobacterial cultures of the pleural fluid were negative. He had no history of trauma or thoracic surgery. Lymphangiography did not show any leakage or obstruction of the thoracic duct (Fig. 2). While thoracoscopy did not reveal any tumor, amyloid deposits, or leakage from the thoracic duct, a thoracoscopic surgical pleural biopsy demonstrated infiltration by lymphocytes and plasma cells with ectopic germinal centers under the pleural mesothelium. Approximately 50% of IgG-positive plasma cells were IgG4-positive (Fig. 3). Storiform fibrosis and obstructive phlebitis were not found in this small specimen.
Table 1. Laboratory Data on 2nd Admission.
Peripheral blood CRP 0.04 mg/dL Pleural effusion
WBC 8,200 /μL ESR 15 mm/hr Cell count 810 /μL
Neut 87.7 % Ferritin 85 ng/mL poly 0 /μL
Lymp 8.7 % IgG 1,500 mg/dL mono 680 /μL
Mono 3.2 % IgG4 264 mg/dL others 130 /μL
Eosino 0.2 % IgA 226 mg/dL pH 7.5
Baso 0.2 % IgM 70 mg/dL specific gravity 1.016
RBC 5.05 ×106/μL C3 109 mg/dL TP 5.7 g/dL
Hb 15.5 g/dL C4 24 mg/dL Alb 3.3 g/dL
Plt 288 ×103/μL CH50 59.3 U/mL Amy 45 U/L
Cryoglobulin negative Glu 131 mg/dL
Biochemistry/Serology LDH 88 U/L
TP 7.4 g/dL Antibody T-cho 84 mg/dL
Alb 4.2 g/dL ANA negative TG 300 mg/dL
T-Bil 0.5 mg/dL SS-A 3.3 U/mL ADA 25.1 U/L
BUN 24.2 mg/dL SS-B <1.0 U/mL Hyaluronic Acid 6,670 ng/mL
Cre 1.25 mg/dL ds-DNA 3.8 U/mL CEA 1.8 ng/mL
UA 9.2 mg/dL RNP <2.0 U/mL
Na 139.5 mEq/L MPO-ANCA <1.0 U/mL
K 3.8 mEq/L PR3-ANCA <1.0 U/mL
Cl 100 mEq/L
AST 13 U/L Tumor marker
ALT 10 U/L sIL-2R 394 U/mL
LDH 163 U/L CEA 1.6 ng/mL
ALP 235 U/L CYFRA 1.7 ng/mL
γ-GTP 55 U/L SCC 0.7 ng/mL
Amy 62 U/L proGRP 41.5 ng/mL
CK 70 U/L
T-cho 192 mg/dL Infection marker
HbA1c 7.0 % procalcitonin <0.03 ng/mL
KL-6 193 U/mL T-SPOT negative
BNP 8.0 pg/mL GPLcore-IgA negative
fT3 2.9 ng/dL CMV-Ag negative
fT4 1.7 ng/dL β-D <6.0 pg/mL
TSH 1.67 μIU/mL
TP: total protein, Alb: albumin, T-Bil: total bilirubin, BUN: blood urea nitrogen, Cre: creatinine, UA: uric acid, Amy: amylase, T-cho: total cholesterol, KL-6: Krebs von den Lungen-6, BNP: brain natriuretic peptide, fT3: free triiodothyronine, fT4: free thyroxine, TSH: thyroid-stimulating hormone, CRP: C-reactive protein, ESR: erythrocyte sedimentation rate, ANA: antinuclear antibody, SS-A: anti-SS-A/Ro antibody, SS-B: anti-SS-B/La antibody, ds-DNA: anti-double-stranded DNA antibody, RNP: anti-RNP antibody, MPO-ANCA: myeloperoxidase-anti-neutrophil cytoplasmic antibody, PR3-ANCA: proteinase3-anti-neutrophil antibody, sIL-2R: soluble interleukin-2 receptor, GPLcore-IgA: glycopeptidolipid core IgA antibody, CMV-Ag: cytomegalovirus antigenemia, β-D: (1-3-)β-D-glucan, ADA: adenosine deaminase
Figure 1. Pleural effusion and CT images before and after treatment. The right pleural effusion appeared as turbid yellow fluid (A). Bilateral pleural effusion and pericardial effusion were seen at the second admission (B). After treatment with a combination of high-dose corticosteroids and rituximab, the pleural and pericardial effusion was significantly decreased (C).
Figure 2. Lymphangiography images. Lymphangiography showed the intact structure of the thoracic duct (yellow arrows) and revealed no leakage or obstruction of the duct.
Figure 3. Histopathological images from the pleural biopsy. A pleural biopsy showed the infiltration of lymphocytes and plasma cells with ectopic germinal centers under the pleural mesothelium, and more than 50% of IgG-positive plasma cells were IgG4-positive. HE: Hematoxylin and Eosin staining, LPF: low-power field, HPF: high-power field
We performed another lip biopsy, and the specimen showed excessive IgG4-positive plasma cell infiltration [48 cells/high-power field (HPF)] with >50% IgG4/IgG (Fig. 4). According to the diagnostic criteria of IgG4-related respiratory disease (13), the patient met the following: i) pleural involvement with CT, ii) elevated serum IgG4 level, iii) pleural biopsy findings (lymphoplasmacytic infiltration and increased IgG4 positive cells), and iv) IgG4-related sialadenitis confirmed with a lip biopsy. Thus, we diagnosed him with “definite” IgG4-related disease.
Figure 4. Histopathological images from the lip biopsy. A lip biopsy revealed focal IgG4-positive plasma cell infiltration, with up to 48 cells/HPF and an IgG4/IgG ratio exceeding 50%. HE: Hematoxylin and Eosin staining, LPF: low-power field, HPF: high-power field
Regarding mimickers of IgG4-RD, sarcoidosis was considered unlikely because of the lack of any elevation in the level of angiotensin-converting enzyme (ACE) or hypercalcemia on blood tests and no findings of granulomas in the biopsy specimens. The pleural specimens did not show angiocentricity or granuloma formation, so lymphomatoid granulomatosis was also deemed unlikely in this case. No fever or high CRP levels were observed in this patient, which made Multicentric Castleman disease unlikely.
The treatment and clinical course of this patient are shown in Fig. 5. We first performed continuous drainage of the pleural fluid with fasting, intravenous hyperalimentation, and octreotide for two weeks. The octreotide was used in an off-label manner with the patient's consent to reduce lymphatic flow in the thoracic duct (14). The pleural drainage decreased the effusion temporarily, but the production of new fluid did not cease, resulting in the marked loss of serum levels of albumin, IgG, and IgG4. We started high-dose PSL 70 mg (1 mg/kg/day) with RTX (375 mg/m2, weekly, 4 times). The off-label use of RTX for IgG4-RD was approved by the authorized committee in our hospital [approval number: 2020-012] with informed consent from the patient. The pleural effusion gradually decreased. Later, we switched from PSL to methylprednisolone (mPSL) due to the latter's lower mineralocorticoid activity and better transferability to the lung (15,16). Six months from induction therapy, the pleural effusion had significantly improved (Fig. 1C).
Figure 5. Summary of clinical course of this patient. The pleuritis showed an insufficient response to the first induction therapy with moderate-dose PSL and diuretics. However, the second induction therapy with high-dose PSL and RTX resulted in the significant improvement of pleuritis and a reduction in the serum IgG4 levels. PSL: prednisolone, mPSL: methylprednisolone, RTX: rituximab, Tx: treatment
Discussion
The present patient developed refractory chylothorax due to IgG4-RD diagnosed histopathologically with a pleural specimen. The response to a moderate dose of PSL was poor. High-dose PSL and additional RTX resulted in marked improvement. Chylothorax presenting as IgG4-related pleuritis is quite rare, and to our knowledge, this is the first report of the successful treatment of IgG4-related pleuritis with RTX.
Pleural involvement is reportedly rare; indeed, Fei et al. found that 87 of 248 patients with IgG4-RD in a prospective cohort (35.1%) had intrathoracic involvement (17), although the involvement was mainly in the lungs and lymph nodes, including hilar and mediastinal lymphadenopathy, in 52.9%, solid nodules in the lungs in 25.3%, alveolointerstitial opacities in 20.7%, round ground-glass opacities in 9.2%, and bronchovascular opacities in 20.7%. Pleural nodules and thickening were observed in 16.1%, but pleural effusion was seen in only 4.6%.
We summarized 37 previous case reports with IgG4-RD related pleuritis in Table 2 (18-48). Patients with IgG4-related pleuritis were predominantly men (78%), and the mean age was 63.5±14.7 years old. Bilateral pleural effusion was seen in 21 cases, while 11 cases (right, n=7 cases; left, n=4) had unilateral effusion. In the 24 cases with pleural effusion findings available, 22 showed an exudative pattern, while bloody effusion was seen in 2 cases and transudative effusion in 1 case. Pleural effusion cytometry revealed predominantly lymphocytes among total cases, with a high concentration of IgG4 revealed in 10 cases. Our present findings were consistent with those of previous cases with regard to the age, percentage of men, and rate of bilateral exudative pleural effusion.
Table 2. A Summary of 37 Previous Case Reports with IgG4-RD Related Pleuritis.
Case No. Reference Age Gender Side Pleural effusion test Pleural biopsy Serum Associated diseases Initial
PSL dose
(/day) Immunosuppressant PSL effect for pleuritis
Cell count (/μL) Lymph
(%) IgG (mg/dL) IgG4 (mg/dL) ADA (IU/L) IgG4-positive plasma cells (/HPF) IgG4/IgG IgG
(mg/dL) IgG4
(mg/dL)
Non-chylothorax cases
1 18 74 M Right N/D N/D N/D N/D N/D N/D N/D 46 N/D N/D none none - Good response
2 19 65 M Left Exudative N/D lymp 32%, Plasma 32% 3,005 1,510 N/D N/D N/D 3,142 1194% Mikulicz’s disease 30 mg - Good response
3-7 (5 cases) 20 62 (49-76) M (all) N/D N/D N/D N/D N/D N/D N/D N/D N/D high in 3/3 cases (100%) high in 2/4 cases (50%) 3/5 cases N/D N/D N/D
8 21 63 F Bilateral bloody N/D lymphocyte and plasma cells dominant N/D N/D N/D N/D N/D 2,450 420 history of autoimmune pancreatitis dose unknown - Good response
9 22 78 M Bilateral Exudative N/D mononuclear cell dominant N/D 590 34.1-46.7 17.6 85.4 1,604 483 - none - Partial response
10 23 85 M Bilateral (Left dominant) Exudative 2,600 87% 3,403 2,090 122 N/D N/D 4,121 2,740 salivary glands, lymph nodes, orbital lesion, bile duct, gastric glands 30 mg - Good response
11 24 73 M Right Exudative (bloody) 741 69% 3,358 907 59.8 N/D N/D 4,219 1,500 pericarditis, retroperitoneal fibrosis 30 mg - Good response
12 68 M Left Exudative 4,800 92% 2,809 571 104.4 N/D N/D 1,471 372 Mikulicz’s disease 30 mg - Good response
13 25 29 F Bilateral Exudative N/D 93% N/D N/D N/D >30 92% N/D 136 pericardium 40 mg - Good response
14 26 57 M Bilateral N/D N/D N/D N/D N/D N/D N/D >40% N/D 970 none N/D - Good response
15 27 69 M Right Exudative N/D dominant 4,276 N/D 70.6 N/D 50% 3,570 2,380 lymph node 0.5 mg/kg - Good response
16 28 71 F Right N/D N/D N/D N/D N/D N/D 27.3 84% 1,756 684 periaortitis 40 mg - Good response
17 29 74 F Bilateral Exudative N/D N/D N/D N/D normal 91 91% N/D 740 interstitital pneumonia 25 mg (0.5mg/kg) - Good response
18 30 48 M Bilateral Exudative N/D lymphocyte dominant N/D N/D N/D N/D 24% N/D 248 lymph node 0.6 mg/kg - Good response
19 31 63 M Right Exudative N/D N/D N/D N/D N/D 73 >40% N/D 284 none 40 mg MTX
(for PsA) Good response
20 32 74 M Left Transudative N/D N/D N/D N/D N/D N/D 30% 1,300 217 lymph node, neuromyopathy 40 mg - Good response
21 33 68 F Bilateral Exudative N/D N/D N/D N/D N/D N/D N/D N/D 307 uterine enlargement 0.6 mg/kg - Good response
22 34 58 M Bilateral N/D N/D N/D N/D N/D N/D 52 50% 1,200 141 none 37.5 mg AZP→
MTX Good response
23 35 32 M Biateral N/D N/D N/D N/D N/D N/D N/D N/D N/D 550 pericarditis 30 mg - Good response
24 36 78 M Bilateral N/D N/D N/D N/D N/D N/D 100 70% N/D 760 Sclerosing cholangitis, constrictive pericarditis N/D - Good response
25 37 70 M Bilateral N/D N/D N/D N/D N/D N/D none (after treatment) none (after treatment) normal 437 pericarditis, Aortitis high dose mPSL 3days→PSL 1mg/kg CYC Good response
26 70 M Right Exudative N/D dominant N/D N/D N/D N/D >50% N/D 224 mediastinitis 0.6 mg/kg - Good response
27 38 70 M Bilateral (Right dominant) Exudative 5,400 93.80% 4,409 1,070 75.6 >10 >40% 2,518 1,030 none 40 mg - Good response
28 39 84 M Bilateral N/D 448 Plasma 53% N/D N/D N/D 45 N/D N/D 306 none 40 mg - Good response
29 40 43 F Right Exudative N/D 80-97% N/D N/D 4.6-7.0 80 >40% normal 125 Pericardial effusion, abdominal effusion 30 mg - Good response
30 41 55 M Bilateral Exudative 1,952 52% N/D N/D N/D N/D N/D 3,260 534 pericarditis, lacrimal gland, 80 mg MMF N/D
31 42 65 M Bilateral Exudative 2,700/7,160 90%/97% N/D 124/125 23.0/20.5 50 40% 1,490 164 none 30 mg AZP Partial response
32 43 81 M Bilateral Exudative 3,450 69% N/D N/D 85.0 >50 <40% 2,807 233 none 30 mg - Partial response
33 44 70 F Bilateral Exudative N/D N/D 3,269 1,280 75.4 N/D N/D 3,877 >1,500 pericarditis N/D N/D Good response
34 45 72 F Left Exudative 5,483 99% N/D N/D 80.2 >50 >40% 5,310 >1,500 lymph node none - (naturally dissappered)
35 46 46 M Bilateral Exudative N/D 68% N/D 256 36.4 (normal) 22 42% N/D 142 N/D 30 mg - Good response
Cylorhorax cases
36 47 69 M Bilateral Exudative (Chylothorax) 3980/5,870 92%/88.5% 2,696/2,647 571/653 40.8/39.9 N/D 90% 1,539 277 none 30 mg - Partial response
37 48 16 M Bilateral Exudative (Chylothorax) N/D N/D N/D N/D 15 62 40% (mediastinal biopsy) N/D 1,650 none 1 mg/kg AZP Poor response (surgical obliteration)
present case Sakata et al. 66 M Bilateral Exudative (Chylothorax) 810 84% N/D N/D 25.1 50% 1500 264 lacrimal and salivery gland, pericarditis 70mg RTX Poor response
M: male, F: female, N/D: not determined, MTX: methotrexate, AZP: azathioprine, CYC: 381 cyclophosphamide, MMF: mycophenolate mofetil, RTX: rituximab
Interestingly, in previously reported cases of IgG4-related pleuritis, 10 out of 15 cases showed high levels of ADA in the pleural fluid (>40 U/L), which is usually measured as an auxiliary tool for the diagnosis of tuberculous pleuritis (49). Although careful ruling out of tuberculous pleuritis is necessary using other examinations, such as Ziehl-Neelsen staining (50), elevated ADA levels in pleural fluid may be useful for identifying IgG4-RD pleuritis because such a condition reflects the strong activation of lymphocytes. The levels of ADA in the pleural fluid of the present case were within normal limits.
Only two previous cases of IgG4-related pleuritis presenting as chylothorax have been reported (47,48). Kato et al. reported a 69-year-old man with IgG4-related pleuritis, demonstrating right-sided chylothorax and left-sided non-chylothorax pleuritis (47). The right-side chylothorax persisted while the left-side pleuritis improved with corticosteroids. Another case, reported by Goag et al., was a young man with bilateral chylothorax (48) unresponsive to high-dose PSL with azathioprine or octreotide and a limited low-fat diet with medium-chain triglyceride supplementation. He ultimately had to undergo exploratory thoracotomy and surgical obliteration. In contrast to most non-chylothorax IgG4-pleuritis patients, who tend to show a good response to treatment, IgG4-related pleuritis with chylothorax is likely to have a poor response to PSL. The pathogenesis of chylothorax in IgG4-RD is unclear. Lymphangiography in our case did not reveal any leakage from the thoracic duct, suggesting potential micro-damage to the lymphatic channels hampering centripetal lymph propulsion from the periphery of the pleural surface. However, we lacked histological evidence of this, so more cases need to be accumulated to clarify the mechanism involved.
Many kinds of immunosuppressant drugs, such as azathioprine, methotrexate, cyclophosphamide, and mycophenolate mofetil, have been used to try to treat refractory IgG4-RD, but the optimal drug in combination with PSL is still unclear (51). Reports of the effectiveness of RTX in IgG4-RD have been increasing (51-54). Regarding the mechanisms underlying IgG4-RD, RTX, which depletes peripheral B cells, is a reasonable addition to therapy not only to prevent the repletion of short-lived plasmablasts and plasma cells but also to interfere with the maintenance of CD4+ T cell memory (55). Furthermore, a French nationwide study demonstrated the efficacy of RTX for both induction therapy and the maintenance of remission (56). Therefore, we selected RTX in our refractory case, and his pleural effusion gradually disappeared with a steroid-sparing effect. To our knowledge, this is the first case report suggesting the effectiveness of RTX in IgG4-related pleuritis.
In conclusion, we experienced a case of refractory IgG4-related pleuritis with chylothorax that was improved with high-dose PSL and RTX. More cases need to be accumulated in order to clarify the clinical manifestations of IgG4-RD pleuritis and its appropriate treatment.
We declare that we have obtained written informed consent from this patient to publish this case report.
The authors state that they have no Conflict of Interest (COI). | FUROSEMIDE, LEVOTHYROXINE, OCTREOTIDE, PREDNISOLONE, RITUXIMAB, SPIRONOLACTONE, TOLVAPTAN, TORSEMIDE | DrugsGivenReaction | CC BY-NC-ND | 33518567 | 20,058,618 | 2021-07-01 |
Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Off label use'. | Refractory IgG4-related Pleural Disease with Chylothorax: A Case Report and Literature Review.
We herein report a rare case of a 66-year-old man with refractory chylothorax. Although he had been treated with moderate doses of prednisolone (PSL) on suspicion of pleuritis with Sjögren syndrome, the pleural effusion expanded after the reduction of PSL. Further workup including histopathological examinations of pleura led to the diagnosis of IgG4-RD with bilateral chylothorax without any leakage from the thoracic duct. Combination therapy with high-dose PSL plus rituximab successfully decreased the pleural effusion. This is a very rare case of IgG4-related pleuritis with chylothorax and the first report of its successful treatment with rituximab.
Introduction
Immunoglobulin G4-related disease (IgG4-RD) is a systemic fibro-inflammatory disease characterized by serum IgG4 elevation and distinctive histopathological findings, such as lymphoplasmacytic infiltrate with abundant IgG4-positive plasma cells, storiform fibrosis, and obliterative phlebitis (1,2). Almost all organs in the body, such as the central nervous system (CNS), lacrimal glands, salivary glands, thyroid, lungs, pancreas, biliary duct, liver, gastrointestinal tract, kidneys, prostate, retroperitoneum and lymph nodes, can be affected by IgG4-RD (3).
While the lungs are involved in 9-18% of IgG4-RD patients (4-7), pleural involvement is observed in only 4% (4,5). Pleural effusion is uncommon, but previous reports have shown that it is usually exudative (8).
Chylothorax, which is characterized by milky-appearing pleural fluid with elevated triglyceride levels or the presence of chylomicrons, is caused by the extravasation of chyle into the pleural space due to obstruction or damage of a thoracic duct or its tributaries or transdiaphragmatic flow from the peritoneal cavity (9). The etiologies of chylothorax include several causes, such as trauma (surgical or non-surgical), malignancy, lymphatic disorders, infection, chylous ascites, and other miscellaneous causes (10); however, chylothorax due to IgG4-RD has almost never been reported.
We experienced a rare case of IgG4-RD with refractory chylothorax that was successfully treated with high-dose prednisolone (PSL) and rituximab (RTX). We report this case with a review of previous case reports of IgG4-related pleuritis.
Case Report
A 66-year-old Japanese man with a history of pollen allergy and thyroidectomy for Graves-Basedow disease was admitted to another hospital with a 2-month history of leg edema, eyelid edema, and dyspnea on exertion. Computed tomography (CT) demonstrated pleural and pericardial effusions, and a pericardiocentesis revealed the fluid as a nonspecific inflammatory effusion with increased numbers of lymphocytes without any infection. Increasing the levothyroxine dose for latent hypothyroidism and initiation of furosemide therapy did not decrease the effusion. He was transferred to our department.
At his first admission to our hospital, whole-body CT demonstrated pericardial effusion, bilateral pleural effusion, and testicular hydrocele. No swelling of the lacrimal or salivary glands nor pancreatic enlargement was observed. The right pleural effusion was exudative with a total cell count of 2,410/mm3 (lymphocytes, 75%) and neither malignant cells nor bacteria. Serum anti-SS-A/Ro antibody was slightly positive (15.4 U/mL; normal range, <10.0 U/mL) on an enzyme-linked immunosorbent assay but negative with the double immunodiffusion method. Other autoantibodies, including anti-SS-B/La, anti-CCP, anti-dsDNA, anti-RNP, anti-Scl70, and anti-neutrophil cytoplasmic antibodies, were all negative. Sialometry showed a rate of 1.008 mL/minute (within normal range), while salivary gland scintigraphy showed a slightly decreased uptake and secretory function. A lip biopsy demonstrated grade 2 lymphocytic infiltration according to Greenspan's classification (11), with only a few IgG4-positive plasma cells. The Schirmer test and rose bengal dye staining test were positive only in the left eye. Although he did not meet the ACR 2012 classification criteria (12), we suspected Sjögren syndrome with serositis.
PSL 40 mg/day (0.5 mg/kg) was initiated. Both the pleural and pericardial effusion amount decreased; however, tapering of the PSL led to exacerbation of the pleural effusion.
At his second admission, he presented with swelling of the lacrimal glands. Laboratory data are shown in Table 1. The white blood cell count in the peripheral blood was 8,200/μL (neutrophil 87.7%, lymphocyte 8.7%). Serum IgG and IgG4 levels were 1,500 mg/dL and 264 mg/dL, respectively. Autoantibodies were all negative. Serum levels of C-reactive protein (CRP), soluble interleukin-2 receptor (IL-2R), free T3, free T4, and thyroid-stimulating hormone (TSH) were also within the normal ranges (0.04 mg/dL, 394 U/mL, 2.9 pg/mL, 1.7 ng/dL and 1.67 μIU/mL, respectively). Chest CT showed marked bilateral pleural effusion with passive atelectasis and slight pericardial effusion (Fig. 1B). Thoracentesis for the right pleural effusion (Table 1) revealed turbid yellow fluid (Fig. 1A) with a total cell count of 810/mm3 (lymphocytes 84%), total protein 5.7 g/dL, adenosine deaminase (ADA) 25.1 U/L, total cholesterol 84 mg/dL, triglyceride 300 mg/dL, and the presence of chylomicrons, compatible with chylothorax. A cytologic examination was negative for malignancy. General bacterial and mycobacterial cultures of the pleural fluid were negative. He had no history of trauma or thoracic surgery. Lymphangiography did not show any leakage or obstruction of the thoracic duct (Fig. 2). While thoracoscopy did not reveal any tumor, amyloid deposits, or leakage from the thoracic duct, a thoracoscopic surgical pleural biopsy demonstrated infiltration by lymphocytes and plasma cells with ectopic germinal centers under the pleural mesothelium. Approximately 50% of IgG-positive plasma cells were IgG4-positive (Fig. 3). Storiform fibrosis and obstructive phlebitis were not found in this small specimen.
Table 1. Laboratory Data on 2nd Admission.
Peripheral blood CRP 0.04 mg/dL Pleural effusion
WBC 8,200 /μL ESR 15 mm/hr Cell count 810 /μL
Neut 87.7 % Ferritin 85 ng/mL poly 0 /μL
Lymp 8.7 % IgG 1,500 mg/dL mono 680 /μL
Mono 3.2 % IgG4 264 mg/dL others 130 /μL
Eosino 0.2 % IgA 226 mg/dL pH 7.5
Baso 0.2 % IgM 70 mg/dL specific gravity 1.016
RBC 5.05 ×106/μL C3 109 mg/dL TP 5.7 g/dL
Hb 15.5 g/dL C4 24 mg/dL Alb 3.3 g/dL
Plt 288 ×103/μL CH50 59.3 U/mL Amy 45 U/L
Cryoglobulin negative Glu 131 mg/dL
Biochemistry/Serology LDH 88 U/L
TP 7.4 g/dL Antibody T-cho 84 mg/dL
Alb 4.2 g/dL ANA negative TG 300 mg/dL
T-Bil 0.5 mg/dL SS-A 3.3 U/mL ADA 25.1 U/L
BUN 24.2 mg/dL SS-B <1.0 U/mL Hyaluronic Acid 6,670 ng/mL
Cre 1.25 mg/dL ds-DNA 3.8 U/mL CEA 1.8 ng/mL
UA 9.2 mg/dL RNP <2.0 U/mL
Na 139.5 mEq/L MPO-ANCA <1.0 U/mL
K 3.8 mEq/L PR3-ANCA <1.0 U/mL
Cl 100 mEq/L
AST 13 U/L Tumor marker
ALT 10 U/L sIL-2R 394 U/mL
LDH 163 U/L CEA 1.6 ng/mL
ALP 235 U/L CYFRA 1.7 ng/mL
γ-GTP 55 U/L SCC 0.7 ng/mL
Amy 62 U/L proGRP 41.5 ng/mL
CK 70 U/L
T-cho 192 mg/dL Infection marker
HbA1c 7.0 % procalcitonin <0.03 ng/mL
KL-6 193 U/mL T-SPOT negative
BNP 8.0 pg/mL GPLcore-IgA negative
fT3 2.9 ng/dL CMV-Ag negative
fT4 1.7 ng/dL β-D <6.0 pg/mL
TSH 1.67 μIU/mL
TP: total protein, Alb: albumin, T-Bil: total bilirubin, BUN: blood urea nitrogen, Cre: creatinine, UA: uric acid, Amy: amylase, T-cho: total cholesterol, KL-6: Krebs von den Lungen-6, BNP: brain natriuretic peptide, fT3: free triiodothyronine, fT4: free thyroxine, TSH: thyroid-stimulating hormone, CRP: C-reactive protein, ESR: erythrocyte sedimentation rate, ANA: antinuclear antibody, SS-A: anti-SS-A/Ro antibody, SS-B: anti-SS-B/La antibody, ds-DNA: anti-double-stranded DNA antibody, RNP: anti-RNP antibody, MPO-ANCA: myeloperoxidase-anti-neutrophil cytoplasmic antibody, PR3-ANCA: proteinase3-anti-neutrophil antibody, sIL-2R: soluble interleukin-2 receptor, GPLcore-IgA: glycopeptidolipid core IgA antibody, CMV-Ag: cytomegalovirus antigenemia, β-D: (1-3-)β-D-glucan, ADA: adenosine deaminase
Figure 1. Pleural effusion and CT images before and after treatment. The right pleural effusion appeared as turbid yellow fluid (A). Bilateral pleural effusion and pericardial effusion were seen at the second admission (B). After treatment with a combination of high-dose corticosteroids and rituximab, the pleural and pericardial effusion was significantly decreased (C).
Figure 2. Lymphangiography images. Lymphangiography showed the intact structure of the thoracic duct (yellow arrows) and revealed no leakage or obstruction of the duct.
Figure 3. Histopathological images from the pleural biopsy. A pleural biopsy showed the infiltration of lymphocytes and plasma cells with ectopic germinal centers under the pleural mesothelium, and more than 50% of IgG-positive plasma cells were IgG4-positive. HE: Hematoxylin and Eosin staining, LPF: low-power field, HPF: high-power field
We performed another lip biopsy, and the specimen showed excessive IgG4-positive plasma cell infiltration [48 cells/high-power field (HPF)] with >50% IgG4/IgG (Fig. 4). According to the diagnostic criteria of IgG4-related respiratory disease (13), the patient met the following: i) pleural involvement with CT, ii) elevated serum IgG4 level, iii) pleural biopsy findings (lymphoplasmacytic infiltration and increased IgG4 positive cells), and iv) IgG4-related sialadenitis confirmed with a lip biopsy. Thus, we diagnosed him with “definite” IgG4-related disease.
Figure 4. Histopathological images from the lip biopsy. A lip biopsy revealed focal IgG4-positive plasma cell infiltration, with up to 48 cells/HPF and an IgG4/IgG ratio exceeding 50%. HE: Hematoxylin and Eosin staining, LPF: low-power field, HPF: high-power field
Regarding mimickers of IgG4-RD, sarcoidosis was considered unlikely because of the lack of any elevation in the level of angiotensin-converting enzyme (ACE) or hypercalcemia on blood tests and no findings of granulomas in the biopsy specimens. The pleural specimens did not show angiocentricity or granuloma formation, so lymphomatoid granulomatosis was also deemed unlikely in this case. No fever or high CRP levels were observed in this patient, which made Multicentric Castleman disease unlikely.
The treatment and clinical course of this patient are shown in Fig. 5. We first performed continuous drainage of the pleural fluid with fasting, intravenous hyperalimentation, and octreotide for two weeks. The octreotide was used in an off-label manner with the patient's consent to reduce lymphatic flow in the thoracic duct (14). The pleural drainage decreased the effusion temporarily, but the production of new fluid did not cease, resulting in the marked loss of serum levels of albumin, IgG, and IgG4. We started high-dose PSL 70 mg (1 mg/kg/day) with RTX (375 mg/m2, weekly, 4 times). The off-label use of RTX for IgG4-RD was approved by the authorized committee in our hospital [approval number: 2020-012] with informed consent from the patient. The pleural effusion gradually decreased. Later, we switched from PSL to methylprednisolone (mPSL) due to the latter's lower mineralocorticoid activity and better transferability to the lung (15,16). Six months from induction therapy, the pleural effusion had significantly improved (Fig. 1C).
Figure 5. Summary of clinical course of this patient. The pleuritis showed an insufficient response to the first induction therapy with moderate-dose PSL and diuretics. However, the second induction therapy with high-dose PSL and RTX resulted in the significant improvement of pleuritis and a reduction in the serum IgG4 levels. PSL: prednisolone, mPSL: methylprednisolone, RTX: rituximab, Tx: treatment
Discussion
The present patient developed refractory chylothorax due to IgG4-RD diagnosed histopathologically with a pleural specimen. The response to a moderate dose of PSL was poor. High-dose PSL and additional RTX resulted in marked improvement. Chylothorax presenting as IgG4-related pleuritis is quite rare, and to our knowledge, this is the first report of the successful treatment of IgG4-related pleuritis with RTX.
Pleural involvement is reportedly rare; indeed, Fei et al. found that 87 of 248 patients with IgG4-RD in a prospective cohort (35.1%) had intrathoracic involvement (17), although the involvement was mainly in the lungs and lymph nodes, including hilar and mediastinal lymphadenopathy, in 52.9%, solid nodules in the lungs in 25.3%, alveolointerstitial opacities in 20.7%, round ground-glass opacities in 9.2%, and bronchovascular opacities in 20.7%. Pleural nodules and thickening were observed in 16.1%, but pleural effusion was seen in only 4.6%.
We summarized 37 previous case reports with IgG4-RD related pleuritis in Table 2 (18-48). Patients with IgG4-related pleuritis were predominantly men (78%), and the mean age was 63.5±14.7 years old. Bilateral pleural effusion was seen in 21 cases, while 11 cases (right, n=7 cases; left, n=4) had unilateral effusion. In the 24 cases with pleural effusion findings available, 22 showed an exudative pattern, while bloody effusion was seen in 2 cases and transudative effusion in 1 case. Pleural effusion cytometry revealed predominantly lymphocytes among total cases, with a high concentration of IgG4 revealed in 10 cases. Our present findings were consistent with those of previous cases with regard to the age, percentage of men, and rate of bilateral exudative pleural effusion.
Table 2. A Summary of 37 Previous Case Reports with IgG4-RD Related Pleuritis.
Case No. Reference Age Gender Side Pleural effusion test Pleural biopsy Serum Associated diseases Initial
PSL dose
(/day) Immunosuppressant PSL effect for pleuritis
Cell count (/μL) Lymph
(%) IgG (mg/dL) IgG4 (mg/dL) ADA (IU/L) IgG4-positive plasma cells (/HPF) IgG4/IgG IgG
(mg/dL) IgG4
(mg/dL)
Non-chylothorax cases
1 18 74 M Right N/D N/D N/D N/D N/D N/D N/D 46 N/D N/D none none - Good response
2 19 65 M Left Exudative N/D lymp 32%, Plasma 32% 3,005 1,510 N/D N/D N/D 3,142 1194% Mikulicz’s disease 30 mg - Good response
3-7 (5 cases) 20 62 (49-76) M (all) N/D N/D N/D N/D N/D N/D N/D N/D N/D high in 3/3 cases (100%) high in 2/4 cases (50%) 3/5 cases N/D N/D N/D
8 21 63 F Bilateral bloody N/D lymphocyte and plasma cells dominant N/D N/D N/D N/D N/D 2,450 420 history of autoimmune pancreatitis dose unknown - Good response
9 22 78 M Bilateral Exudative N/D mononuclear cell dominant N/D 590 34.1-46.7 17.6 85.4 1,604 483 - none - Partial response
10 23 85 M Bilateral (Left dominant) Exudative 2,600 87% 3,403 2,090 122 N/D N/D 4,121 2,740 salivary glands, lymph nodes, orbital lesion, bile duct, gastric glands 30 mg - Good response
11 24 73 M Right Exudative (bloody) 741 69% 3,358 907 59.8 N/D N/D 4,219 1,500 pericarditis, retroperitoneal fibrosis 30 mg - Good response
12 68 M Left Exudative 4,800 92% 2,809 571 104.4 N/D N/D 1,471 372 Mikulicz’s disease 30 mg - Good response
13 25 29 F Bilateral Exudative N/D 93% N/D N/D N/D >30 92% N/D 136 pericardium 40 mg - Good response
14 26 57 M Bilateral N/D N/D N/D N/D N/D N/D N/D >40% N/D 970 none N/D - Good response
15 27 69 M Right Exudative N/D dominant 4,276 N/D 70.6 N/D 50% 3,570 2,380 lymph node 0.5 mg/kg - Good response
16 28 71 F Right N/D N/D N/D N/D N/D N/D 27.3 84% 1,756 684 periaortitis 40 mg - Good response
17 29 74 F Bilateral Exudative N/D N/D N/D N/D normal 91 91% N/D 740 interstitital pneumonia 25 mg (0.5mg/kg) - Good response
18 30 48 M Bilateral Exudative N/D lymphocyte dominant N/D N/D N/D N/D 24% N/D 248 lymph node 0.6 mg/kg - Good response
19 31 63 M Right Exudative N/D N/D N/D N/D N/D 73 >40% N/D 284 none 40 mg MTX
(for PsA) Good response
20 32 74 M Left Transudative N/D N/D N/D N/D N/D N/D 30% 1,300 217 lymph node, neuromyopathy 40 mg - Good response
21 33 68 F Bilateral Exudative N/D N/D N/D N/D N/D N/D N/D N/D 307 uterine enlargement 0.6 mg/kg - Good response
22 34 58 M Bilateral N/D N/D N/D N/D N/D N/D 52 50% 1,200 141 none 37.5 mg AZP→
MTX Good response
23 35 32 M Biateral N/D N/D N/D N/D N/D N/D N/D N/D N/D 550 pericarditis 30 mg - Good response
24 36 78 M Bilateral N/D N/D N/D N/D N/D N/D 100 70% N/D 760 Sclerosing cholangitis, constrictive pericarditis N/D - Good response
25 37 70 M Bilateral N/D N/D N/D N/D N/D N/D none (after treatment) none (after treatment) normal 437 pericarditis, Aortitis high dose mPSL 3days→PSL 1mg/kg CYC Good response
26 70 M Right Exudative N/D dominant N/D N/D N/D N/D >50% N/D 224 mediastinitis 0.6 mg/kg - Good response
27 38 70 M Bilateral (Right dominant) Exudative 5,400 93.80% 4,409 1,070 75.6 >10 >40% 2,518 1,030 none 40 mg - Good response
28 39 84 M Bilateral N/D 448 Plasma 53% N/D N/D N/D 45 N/D N/D 306 none 40 mg - Good response
29 40 43 F Right Exudative N/D 80-97% N/D N/D 4.6-7.0 80 >40% normal 125 Pericardial effusion, abdominal effusion 30 mg - Good response
30 41 55 M Bilateral Exudative 1,952 52% N/D N/D N/D N/D N/D 3,260 534 pericarditis, lacrimal gland, 80 mg MMF N/D
31 42 65 M Bilateral Exudative 2,700/7,160 90%/97% N/D 124/125 23.0/20.5 50 40% 1,490 164 none 30 mg AZP Partial response
32 43 81 M Bilateral Exudative 3,450 69% N/D N/D 85.0 >50 <40% 2,807 233 none 30 mg - Partial response
33 44 70 F Bilateral Exudative N/D N/D 3,269 1,280 75.4 N/D N/D 3,877 >1,500 pericarditis N/D N/D Good response
34 45 72 F Left Exudative 5,483 99% N/D N/D 80.2 >50 >40% 5,310 >1,500 lymph node none - (naturally dissappered)
35 46 46 M Bilateral Exudative N/D 68% N/D 256 36.4 (normal) 22 42% N/D 142 N/D 30 mg - Good response
Cylorhorax cases
36 47 69 M Bilateral Exudative (Chylothorax) 3980/5,870 92%/88.5% 2,696/2,647 571/653 40.8/39.9 N/D 90% 1,539 277 none 30 mg - Partial response
37 48 16 M Bilateral Exudative (Chylothorax) N/D N/D N/D N/D 15 62 40% (mediastinal biopsy) N/D 1,650 none 1 mg/kg AZP Poor response (surgical obliteration)
present case Sakata et al. 66 M Bilateral Exudative (Chylothorax) 810 84% N/D N/D 25.1 50% 1500 264 lacrimal and salivery gland, pericarditis 70mg RTX Poor response
M: male, F: female, N/D: not determined, MTX: methotrexate, AZP: azathioprine, CYC: 381 cyclophosphamide, MMF: mycophenolate mofetil, RTX: rituximab
Interestingly, in previously reported cases of IgG4-related pleuritis, 10 out of 15 cases showed high levels of ADA in the pleural fluid (>40 U/L), which is usually measured as an auxiliary tool for the diagnosis of tuberculous pleuritis (49). Although careful ruling out of tuberculous pleuritis is necessary using other examinations, such as Ziehl-Neelsen staining (50), elevated ADA levels in pleural fluid may be useful for identifying IgG4-RD pleuritis because such a condition reflects the strong activation of lymphocytes. The levels of ADA in the pleural fluid of the present case were within normal limits.
Only two previous cases of IgG4-related pleuritis presenting as chylothorax have been reported (47,48). Kato et al. reported a 69-year-old man with IgG4-related pleuritis, demonstrating right-sided chylothorax and left-sided non-chylothorax pleuritis (47). The right-side chylothorax persisted while the left-side pleuritis improved with corticosteroids. Another case, reported by Goag et al., was a young man with bilateral chylothorax (48) unresponsive to high-dose PSL with azathioprine or octreotide and a limited low-fat diet with medium-chain triglyceride supplementation. He ultimately had to undergo exploratory thoracotomy and surgical obliteration. In contrast to most non-chylothorax IgG4-pleuritis patients, who tend to show a good response to treatment, IgG4-related pleuritis with chylothorax is likely to have a poor response to PSL. The pathogenesis of chylothorax in IgG4-RD is unclear. Lymphangiography in our case did not reveal any leakage from the thoracic duct, suggesting potential micro-damage to the lymphatic channels hampering centripetal lymph propulsion from the periphery of the pleural surface. However, we lacked histological evidence of this, so more cases need to be accumulated to clarify the mechanism involved.
Many kinds of immunosuppressant drugs, such as azathioprine, methotrexate, cyclophosphamide, and mycophenolate mofetil, have been used to try to treat refractory IgG4-RD, but the optimal drug in combination with PSL is still unclear (51). Reports of the effectiveness of RTX in IgG4-RD have been increasing (51-54). Regarding the mechanisms underlying IgG4-RD, RTX, which depletes peripheral B cells, is a reasonable addition to therapy not only to prevent the repletion of short-lived plasmablasts and plasma cells but also to interfere with the maintenance of CD4+ T cell memory (55). Furthermore, a French nationwide study demonstrated the efficacy of RTX for both induction therapy and the maintenance of remission (56). Therefore, we selected RTX in our refractory case, and his pleural effusion gradually disappeared with a steroid-sparing effect. To our knowledge, this is the first case report suggesting the effectiveness of RTX in IgG4-related pleuritis.
In conclusion, we experienced a case of refractory IgG4-related pleuritis with chylothorax that was improved with high-dose PSL and RTX. More cases need to be accumulated in order to clarify the clinical manifestations of IgG4-RD pleuritis and its appropriate treatment.
We declare that we have obtained written informed consent from this patient to publish this case report.
The authors state that they have no Conflict of Interest (COI). | FUROSEMIDE, LEVOTHYROXINE, OCTREOTIDE, PREDNISOLONE, RITUXIMAB, SPIRONOLACTONE, TOLVAPTAN, TORSEMIDE | DrugsGivenReaction | CC BY-NC-ND | 33518567 | 20,058,618 | 2021-07-01 |
What was the dosage of drug 'RITUXIMAB'? | Refractory IgG4-related Pleural Disease with Chylothorax: A Case Report and Literature Review.
We herein report a rare case of a 66-year-old man with refractory chylothorax. Although he had been treated with moderate doses of prednisolone (PSL) on suspicion of pleuritis with Sjögren syndrome, the pleural effusion expanded after the reduction of PSL. Further workup including histopathological examinations of pleura led to the diagnosis of IgG4-RD with bilateral chylothorax without any leakage from the thoracic duct. Combination therapy with high-dose PSL plus rituximab successfully decreased the pleural effusion. This is a very rare case of IgG4-related pleuritis with chylothorax and the first report of its successful treatment with rituximab.
Introduction
Immunoglobulin G4-related disease (IgG4-RD) is a systemic fibro-inflammatory disease characterized by serum IgG4 elevation and distinctive histopathological findings, such as lymphoplasmacytic infiltrate with abundant IgG4-positive plasma cells, storiform fibrosis, and obliterative phlebitis (1,2). Almost all organs in the body, such as the central nervous system (CNS), lacrimal glands, salivary glands, thyroid, lungs, pancreas, biliary duct, liver, gastrointestinal tract, kidneys, prostate, retroperitoneum and lymph nodes, can be affected by IgG4-RD (3).
While the lungs are involved in 9-18% of IgG4-RD patients (4-7), pleural involvement is observed in only 4% (4,5). Pleural effusion is uncommon, but previous reports have shown that it is usually exudative (8).
Chylothorax, which is characterized by milky-appearing pleural fluid with elevated triglyceride levels or the presence of chylomicrons, is caused by the extravasation of chyle into the pleural space due to obstruction or damage of a thoracic duct or its tributaries or transdiaphragmatic flow from the peritoneal cavity (9). The etiologies of chylothorax include several causes, such as trauma (surgical or non-surgical), malignancy, lymphatic disorders, infection, chylous ascites, and other miscellaneous causes (10); however, chylothorax due to IgG4-RD has almost never been reported.
We experienced a rare case of IgG4-RD with refractory chylothorax that was successfully treated with high-dose prednisolone (PSL) and rituximab (RTX). We report this case with a review of previous case reports of IgG4-related pleuritis.
Case Report
A 66-year-old Japanese man with a history of pollen allergy and thyroidectomy for Graves-Basedow disease was admitted to another hospital with a 2-month history of leg edema, eyelid edema, and dyspnea on exertion. Computed tomography (CT) demonstrated pleural and pericardial effusions, and a pericardiocentesis revealed the fluid as a nonspecific inflammatory effusion with increased numbers of lymphocytes without any infection. Increasing the levothyroxine dose for latent hypothyroidism and initiation of furosemide therapy did not decrease the effusion. He was transferred to our department.
At his first admission to our hospital, whole-body CT demonstrated pericardial effusion, bilateral pleural effusion, and testicular hydrocele. No swelling of the lacrimal or salivary glands nor pancreatic enlargement was observed. The right pleural effusion was exudative with a total cell count of 2,410/mm3 (lymphocytes, 75%) and neither malignant cells nor bacteria. Serum anti-SS-A/Ro antibody was slightly positive (15.4 U/mL; normal range, <10.0 U/mL) on an enzyme-linked immunosorbent assay but negative with the double immunodiffusion method. Other autoantibodies, including anti-SS-B/La, anti-CCP, anti-dsDNA, anti-RNP, anti-Scl70, and anti-neutrophil cytoplasmic antibodies, were all negative. Sialometry showed a rate of 1.008 mL/minute (within normal range), while salivary gland scintigraphy showed a slightly decreased uptake and secretory function. A lip biopsy demonstrated grade 2 lymphocytic infiltration according to Greenspan's classification (11), with only a few IgG4-positive plasma cells. The Schirmer test and rose bengal dye staining test were positive only in the left eye. Although he did not meet the ACR 2012 classification criteria (12), we suspected Sjögren syndrome with serositis.
PSL 40 mg/day (0.5 mg/kg) was initiated. Both the pleural and pericardial effusion amount decreased; however, tapering of the PSL led to exacerbation of the pleural effusion.
At his second admission, he presented with swelling of the lacrimal glands. Laboratory data are shown in Table 1. The white blood cell count in the peripheral blood was 8,200/μL (neutrophil 87.7%, lymphocyte 8.7%). Serum IgG and IgG4 levels were 1,500 mg/dL and 264 mg/dL, respectively. Autoantibodies were all negative. Serum levels of C-reactive protein (CRP), soluble interleukin-2 receptor (IL-2R), free T3, free T4, and thyroid-stimulating hormone (TSH) were also within the normal ranges (0.04 mg/dL, 394 U/mL, 2.9 pg/mL, 1.7 ng/dL and 1.67 μIU/mL, respectively). Chest CT showed marked bilateral pleural effusion with passive atelectasis and slight pericardial effusion (Fig. 1B). Thoracentesis for the right pleural effusion (Table 1) revealed turbid yellow fluid (Fig. 1A) with a total cell count of 810/mm3 (lymphocytes 84%), total protein 5.7 g/dL, adenosine deaminase (ADA) 25.1 U/L, total cholesterol 84 mg/dL, triglyceride 300 mg/dL, and the presence of chylomicrons, compatible with chylothorax. A cytologic examination was negative for malignancy. General bacterial and mycobacterial cultures of the pleural fluid were negative. He had no history of trauma or thoracic surgery. Lymphangiography did not show any leakage or obstruction of the thoracic duct (Fig. 2). While thoracoscopy did not reveal any tumor, amyloid deposits, or leakage from the thoracic duct, a thoracoscopic surgical pleural biopsy demonstrated infiltration by lymphocytes and plasma cells with ectopic germinal centers under the pleural mesothelium. Approximately 50% of IgG-positive plasma cells were IgG4-positive (Fig. 3). Storiform fibrosis and obstructive phlebitis were not found in this small specimen.
Table 1. Laboratory Data on 2nd Admission.
Peripheral blood CRP 0.04 mg/dL Pleural effusion
WBC 8,200 /μL ESR 15 mm/hr Cell count 810 /μL
Neut 87.7 % Ferritin 85 ng/mL poly 0 /μL
Lymp 8.7 % IgG 1,500 mg/dL mono 680 /μL
Mono 3.2 % IgG4 264 mg/dL others 130 /μL
Eosino 0.2 % IgA 226 mg/dL pH 7.5
Baso 0.2 % IgM 70 mg/dL specific gravity 1.016
RBC 5.05 ×106/μL C3 109 mg/dL TP 5.7 g/dL
Hb 15.5 g/dL C4 24 mg/dL Alb 3.3 g/dL
Plt 288 ×103/μL CH50 59.3 U/mL Amy 45 U/L
Cryoglobulin negative Glu 131 mg/dL
Biochemistry/Serology LDH 88 U/L
TP 7.4 g/dL Antibody T-cho 84 mg/dL
Alb 4.2 g/dL ANA negative TG 300 mg/dL
T-Bil 0.5 mg/dL SS-A 3.3 U/mL ADA 25.1 U/L
BUN 24.2 mg/dL SS-B <1.0 U/mL Hyaluronic Acid 6,670 ng/mL
Cre 1.25 mg/dL ds-DNA 3.8 U/mL CEA 1.8 ng/mL
UA 9.2 mg/dL RNP <2.0 U/mL
Na 139.5 mEq/L MPO-ANCA <1.0 U/mL
K 3.8 mEq/L PR3-ANCA <1.0 U/mL
Cl 100 mEq/L
AST 13 U/L Tumor marker
ALT 10 U/L sIL-2R 394 U/mL
LDH 163 U/L CEA 1.6 ng/mL
ALP 235 U/L CYFRA 1.7 ng/mL
γ-GTP 55 U/L SCC 0.7 ng/mL
Amy 62 U/L proGRP 41.5 ng/mL
CK 70 U/L
T-cho 192 mg/dL Infection marker
HbA1c 7.0 % procalcitonin <0.03 ng/mL
KL-6 193 U/mL T-SPOT negative
BNP 8.0 pg/mL GPLcore-IgA negative
fT3 2.9 ng/dL CMV-Ag negative
fT4 1.7 ng/dL β-D <6.0 pg/mL
TSH 1.67 μIU/mL
TP: total protein, Alb: albumin, T-Bil: total bilirubin, BUN: blood urea nitrogen, Cre: creatinine, UA: uric acid, Amy: amylase, T-cho: total cholesterol, KL-6: Krebs von den Lungen-6, BNP: brain natriuretic peptide, fT3: free triiodothyronine, fT4: free thyroxine, TSH: thyroid-stimulating hormone, CRP: C-reactive protein, ESR: erythrocyte sedimentation rate, ANA: antinuclear antibody, SS-A: anti-SS-A/Ro antibody, SS-B: anti-SS-B/La antibody, ds-DNA: anti-double-stranded DNA antibody, RNP: anti-RNP antibody, MPO-ANCA: myeloperoxidase-anti-neutrophil cytoplasmic antibody, PR3-ANCA: proteinase3-anti-neutrophil antibody, sIL-2R: soluble interleukin-2 receptor, GPLcore-IgA: glycopeptidolipid core IgA antibody, CMV-Ag: cytomegalovirus antigenemia, β-D: (1-3-)β-D-glucan, ADA: adenosine deaminase
Figure 1. Pleural effusion and CT images before and after treatment. The right pleural effusion appeared as turbid yellow fluid (A). Bilateral pleural effusion and pericardial effusion were seen at the second admission (B). After treatment with a combination of high-dose corticosteroids and rituximab, the pleural and pericardial effusion was significantly decreased (C).
Figure 2. Lymphangiography images. Lymphangiography showed the intact structure of the thoracic duct (yellow arrows) and revealed no leakage or obstruction of the duct.
Figure 3. Histopathological images from the pleural biopsy. A pleural biopsy showed the infiltration of lymphocytes and plasma cells with ectopic germinal centers under the pleural mesothelium, and more than 50% of IgG-positive plasma cells were IgG4-positive. HE: Hematoxylin and Eosin staining, LPF: low-power field, HPF: high-power field
We performed another lip biopsy, and the specimen showed excessive IgG4-positive plasma cell infiltration [48 cells/high-power field (HPF)] with >50% IgG4/IgG (Fig. 4). According to the diagnostic criteria of IgG4-related respiratory disease (13), the patient met the following: i) pleural involvement with CT, ii) elevated serum IgG4 level, iii) pleural biopsy findings (lymphoplasmacytic infiltration and increased IgG4 positive cells), and iv) IgG4-related sialadenitis confirmed with a lip biopsy. Thus, we diagnosed him with “definite” IgG4-related disease.
Figure 4. Histopathological images from the lip biopsy. A lip biopsy revealed focal IgG4-positive plasma cell infiltration, with up to 48 cells/HPF and an IgG4/IgG ratio exceeding 50%. HE: Hematoxylin and Eosin staining, LPF: low-power field, HPF: high-power field
Regarding mimickers of IgG4-RD, sarcoidosis was considered unlikely because of the lack of any elevation in the level of angiotensin-converting enzyme (ACE) or hypercalcemia on blood tests and no findings of granulomas in the biopsy specimens. The pleural specimens did not show angiocentricity or granuloma formation, so lymphomatoid granulomatosis was also deemed unlikely in this case. No fever or high CRP levels were observed in this patient, which made Multicentric Castleman disease unlikely.
The treatment and clinical course of this patient are shown in Fig. 5. We first performed continuous drainage of the pleural fluid with fasting, intravenous hyperalimentation, and octreotide for two weeks. The octreotide was used in an off-label manner with the patient's consent to reduce lymphatic flow in the thoracic duct (14). The pleural drainage decreased the effusion temporarily, but the production of new fluid did not cease, resulting in the marked loss of serum levels of albumin, IgG, and IgG4. We started high-dose PSL 70 mg (1 mg/kg/day) with RTX (375 mg/m2, weekly, 4 times). The off-label use of RTX for IgG4-RD was approved by the authorized committee in our hospital [approval number: 2020-012] with informed consent from the patient. The pleural effusion gradually decreased. Later, we switched from PSL to methylprednisolone (mPSL) due to the latter's lower mineralocorticoid activity and better transferability to the lung (15,16). Six months from induction therapy, the pleural effusion had significantly improved (Fig. 1C).
Figure 5. Summary of clinical course of this patient. The pleuritis showed an insufficient response to the first induction therapy with moderate-dose PSL and diuretics. However, the second induction therapy with high-dose PSL and RTX resulted in the significant improvement of pleuritis and a reduction in the serum IgG4 levels. PSL: prednisolone, mPSL: methylprednisolone, RTX: rituximab, Tx: treatment
Discussion
The present patient developed refractory chylothorax due to IgG4-RD diagnosed histopathologically with a pleural specimen. The response to a moderate dose of PSL was poor. High-dose PSL and additional RTX resulted in marked improvement. Chylothorax presenting as IgG4-related pleuritis is quite rare, and to our knowledge, this is the first report of the successful treatment of IgG4-related pleuritis with RTX.
Pleural involvement is reportedly rare; indeed, Fei et al. found that 87 of 248 patients with IgG4-RD in a prospective cohort (35.1%) had intrathoracic involvement (17), although the involvement was mainly in the lungs and lymph nodes, including hilar and mediastinal lymphadenopathy, in 52.9%, solid nodules in the lungs in 25.3%, alveolointerstitial opacities in 20.7%, round ground-glass opacities in 9.2%, and bronchovascular opacities in 20.7%. Pleural nodules and thickening were observed in 16.1%, but pleural effusion was seen in only 4.6%.
We summarized 37 previous case reports with IgG4-RD related pleuritis in Table 2 (18-48). Patients with IgG4-related pleuritis were predominantly men (78%), and the mean age was 63.5±14.7 years old. Bilateral pleural effusion was seen in 21 cases, while 11 cases (right, n=7 cases; left, n=4) had unilateral effusion. In the 24 cases with pleural effusion findings available, 22 showed an exudative pattern, while bloody effusion was seen in 2 cases and transudative effusion in 1 case. Pleural effusion cytometry revealed predominantly lymphocytes among total cases, with a high concentration of IgG4 revealed in 10 cases. Our present findings were consistent with those of previous cases with regard to the age, percentage of men, and rate of bilateral exudative pleural effusion.
Table 2. A Summary of 37 Previous Case Reports with IgG4-RD Related Pleuritis.
Case No. Reference Age Gender Side Pleural effusion test Pleural biopsy Serum Associated diseases Initial
PSL dose
(/day) Immunosuppressant PSL effect for pleuritis
Cell count (/μL) Lymph
(%) IgG (mg/dL) IgG4 (mg/dL) ADA (IU/L) IgG4-positive plasma cells (/HPF) IgG4/IgG IgG
(mg/dL) IgG4
(mg/dL)
Non-chylothorax cases
1 18 74 M Right N/D N/D N/D N/D N/D N/D N/D 46 N/D N/D none none - Good response
2 19 65 M Left Exudative N/D lymp 32%, Plasma 32% 3,005 1,510 N/D N/D N/D 3,142 1194% Mikulicz’s disease 30 mg - Good response
3-7 (5 cases) 20 62 (49-76) M (all) N/D N/D N/D N/D N/D N/D N/D N/D N/D high in 3/3 cases (100%) high in 2/4 cases (50%) 3/5 cases N/D N/D N/D
8 21 63 F Bilateral bloody N/D lymphocyte and plasma cells dominant N/D N/D N/D N/D N/D 2,450 420 history of autoimmune pancreatitis dose unknown - Good response
9 22 78 M Bilateral Exudative N/D mononuclear cell dominant N/D 590 34.1-46.7 17.6 85.4 1,604 483 - none - Partial response
10 23 85 M Bilateral (Left dominant) Exudative 2,600 87% 3,403 2,090 122 N/D N/D 4,121 2,740 salivary glands, lymph nodes, orbital lesion, bile duct, gastric glands 30 mg - Good response
11 24 73 M Right Exudative (bloody) 741 69% 3,358 907 59.8 N/D N/D 4,219 1,500 pericarditis, retroperitoneal fibrosis 30 mg - Good response
12 68 M Left Exudative 4,800 92% 2,809 571 104.4 N/D N/D 1,471 372 Mikulicz’s disease 30 mg - Good response
13 25 29 F Bilateral Exudative N/D 93% N/D N/D N/D >30 92% N/D 136 pericardium 40 mg - Good response
14 26 57 M Bilateral N/D N/D N/D N/D N/D N/D N/D >40% N/D 970 none N/D - Good response
15 27 69 M Right Exudative N/D dominant 4,276 N/D 70.6 N/D 50% 3,570 2,380 lymph node 0.5 mg/kg - Good response
16 28 71 F Right N/D N/D N/D N/D N/D N/D 27.3 84% 1,756 684 periaortitis 40 mg - Good response
17 29 74 F Bilateral Exudative N/D N/D N/D N/D normal 91 91% N/D 740 interstitital pneumonia 25 mg (0.5mg/kg) - Good response
18 30 48 M Bilateral Exudative N/D lymphocyte dominant N/D N/D N/D N/D 24% N/D 248 lymph node 0.6 mg/kg - Good response
19 31 63 M Right Exudative N/D N/D N/D N/D N/D 73 >40% N/D 284 none 40 mg MTX
(for PsA) Good response
20 32 74 M Left Transudative N/D N/D N/D N/D N/D N/D 30% 1,300 217 lymph node, neuromyopathy 40 mg - Good response
21 33 68 F Bilateral Exudative N/D N/D N/D N/D N/D N/D N/D N/D 307 uterine enlargement 0.6 mg/kg - Good response
22 34 58 M Bilateral N/D N/D N/D N/D N/D N/D 52 50% 1,200 141 none 37.5 mg AZP→
MTX Good response
23 35 32 M Biateral N/D N/D N/D N/D N/D N/D N/D N/D N/D 550 pericarditis 30 mg - Good response
24 36 78 M Bilateral N/D N/D N/D N/D N/D N/D 100 70% N/D 760 Sclerosing cholangitis, constrictive pericarditis N/D - Good response
25 37 70 M Bilateral N/D N/D N/D N/D N/D N/D none (after treatment) none (after treatment) normal 437 pericarditis, Aortitis high dose mPSL 3days→PSL 1mg/kg CYC Good response
26 70 M Right Exudative N/D dominant N/D N/D N/D N/D >50% N/D 224 mediastinitis 0.6 mg/kg - Good response
27 38 70 M Bilateral (Right dominant) Exudative 5,400 93.80% 4,409 1,070 75.6 >10 >40% 2,518 1,030 none 40 mg - Good response
28 39 84 M Bilateral N/D 448 Plasma 53% N/D N/D N/D 45 N/D N/D 306 none 40 mg - Good response
29 40 43 F Right Exudative N/D 80-97% N/D N/D 4.6-7.0 80 >40% normal 125 Pericardial effusion, abdominal effusion 30 mg - Good response
30 41 55 M Bilateral Exudative 1,952 52% N/D N/D N/D N/D N/D 3,260 534 pericarditis, lacrimal gland, 80 mg MMF N/D
31 42 65 M Bilateral Exudative 2,700/7,160 90%/97% N/D 124/125 23.0/20.5 50 40% 1,490 164 none 30 mg AZP Partial response
32 43 81 M Bilateral Exudative 3,450 69% N/D N/D 85.0 >50 <40% 2,807 233 none 30 mg - Partial response
33 44 70 F Bilateral Exudative N/D N/D 3,269 1,280 75.4 N/D N/D 3,877 >1,500 pericarditis N/D N/D Good response
34 45 72 F Left Exudative 5,483 99% N/D N/D 80.2 >50 >40% 5,310 >1,500 lymph node none - (naturally dissappered)
35 46 46 M Bilateral Exudative N/D 68% N/D 256 36.4 (normal) 22 42% N/D 142 N/D 30 mg - Good response
Cylorhorax cases
36 47 69 M Bilateral Exudative (Chylothorax) 3980/5,870 92%/88.5% 2,696/2,647 571/653 40.8/39.9 N/D 90% 1,539 277 none 30 mg - Partial response
37 48 16 M Bilateral Exudative (Chylothorax) N/D N/D N/D N/D 15 62 40% (mediastinal biopsy) N/D 1,650 none 1 mg/kg AZP Poor response (surgical obliteration)
present case Sakata et al. 66 M Bilateral Exudative (Chylothorax) 810 84% N/D N/D 25.1 50% 1500 264 lacrimal and salivery gland, pericarditis 70mg RTX Poor response
M: male, F: female, N/D: not determined, MTX: methotrexate, AZP: azathioprine, CYC: 381 cyclophosphamide, MMF: mycophenolate mofetil, RTX: rituximab
Interestingly, in previously reported cases of IgG4-related pleuritis, 10 out of 15 cases showed high levels of ADA in the pleural fluid (>40 U/L), which is usually measured as an auxiliary tool for the diagnosis of tuberculous pleuritis (49). Although careful ruling out of tuberculous pleuritis is necessary using other examinations, such as Ziehl-Neelsen staining (50), elevated ADA levels in pleural fluid may be useful for identifying IgG4-RD pleuritis because such a condition reflects the strong activation of lymphocytes. The levels of ADA in the pleural fluid of the present case were within normal limits.
Only two previous cases of IgG4-related pleuritis presenting as chylothorax have been reported (47,48). Kato et al. reported a 69-year-old man with IgG4-related pleuritis, demonstrating right-sided chylothorax and left-sided non-chylothorax pleuritis (47). The right-side chylothorax persisted while the left-side pleuritis improved with corticosteroids. Another case, reported by Goag et al., was a young man with bilateral chylothorax (48) unresponsive to high-dose PSL with azathioprine or octreotide and a limited low-fat diet with medium-chain triglyceride supplementation. He ultimately had to undergo exploratory thoracotomy and surgical obliteration. In contrast to most non-chylothorax IgG4-pleuritis patients, who tend to show a good response to treatment, IgG4-related pleuritis with chylothorax is likely to have a poor response to PSL. The pathogenesis of chylothorax in IgG4-RD is unclear. Lymphangiography in our case did not reveal any leakage from the thoracic duct, suggesting potential micro-damage to the lymphatic channels hampering centripetal lymph propulsion from the periphery of the pleural surface. However, we lacked histological evidence of this, so more cases need to be accumulated to clarify the mechanism involved.
Many kinds of immunosuppressant drugs, such as azathioprine, methotrexate, cyclophosphamide, and mycophenolate mofetil, have been used to try to treat refractory IgG4-RD, but the optimal drug in combination with PSL is still unclear (51). Reports of the effectiveness of RTX in IgG4-RD have been increasing (51-54). Regarding the mechanisms underlying IgG4-RD, RTX, which depletes peripheral B cells, is a reasonable addition to therapy not only to prevent the repletion of short-lived plasmablasts and plasma cells but also to interfere with the maintenance of CD4+ T cell memory (55). Furthermore, a French nationwide study demonstrated the efficacy of RTX for both induction therapy and the maintenance of remission (56). Therefore, we selected RTX in our refractory case, and his pleural effusion gradually disappeared with a steroid-sparing effect. To our knowledge, this is the first case report suggesting the effectiveness of RTX in IgG4-related pleuritis.
In conclusion, we experienced a case of refractory IgG4-related pleuritis with chylothorax that was improved with high-dose PSL and RTX. More cases need to be accumulated in order to clarify the clinical manifestations of IgG4-RD pleuritis and its appropriate treatment.
We declare that we have obtained written informed consent from this patient to publish this case report.
The authors state that they have no Conflict of Interest (COI). | 53.5714 MG/M2 DAILY; FOUR TIMES | DrugDosageText | CC BY-NC-ND | 33518567 | 20,058,618 | 2021-07-01 |
What was the outcome of reaction 'Pleural effusion'? | Refractory IgG4-related Pleural Disease with Chylothorax: A Case Report and Literature Review.
We herein report a rare case of a 66-year-old man with refractory chylothorax. Although he had been treated with moderate doses of prednisolone (PSL) on suspicion of pleuritis with Sjögren syndrome, the pleural effusion expanded after the reduction of PSL. Further workup including histopathological examinations of pleura led to the diagnosis of IgG4-RD with bilateral chylothorax without any leakage from the thoracic duct. Combination therapy with high-dose PSL plus rituximab successfully decreased the pleural effusion. This is a very rare case of IgG4-related pleuritis with chylothorax and the first report of its successful treatment with rituximab.
Introduction
Immunoglobulin G4-related disease (IgG4-RD) is a systemic fibro-inflammatory disease characterized by serum IgG4 elevation and distinctive histopathological findings, such as lymphoplasmacytic infiltrate with abundant IgG4-positive plasma cells, storiform fibrosis, and obliterative phlebitis (1,2). Almost all organs in the body, such as the central nervous system (CNS), lacrimal glands, salivary glands, thyroid, lungs, pancreas, biliary duct, liver, gastrointestinal tract, kidneys, prostate, retroperitoneum and lymph nodes, can be affected by IgG4-RD (3).
While the lungs are involved in 9-18% of IgG4-RD patients (4-7), pleural involvement is observed in only 4% (4,5). Pleural effusion is uncommon, but previous reports have shown that it is usually exudative (8).
Chylothorax, which is characterized by milky-appearing pleural fluid with elevated triglyceride levels or the presence of chylomicrons, is caused by the extravasation of chyle into the pleural space due to obstruction or damage of a thoracic duct or its tributaries or transdiaphragmatic flow from the peritoneal cavity (9). The etiologies of chylothorax include several causes, such as trauma (surgical or non-surgical), malignancy, lymphatic disorders, infection, chylous ascites, and other miscellaneous causes (10); however, chylothorax due to IgG4-RD has almost never been reported.
We experienced a rare case of IgG4-RD with refractory chylothorax that was successfully treated with high-dose prednisolone (PSL) and rituximab (RTX). We report this case with a review of previous case reports of IgG4-related pleuritis.
Case Report
A 66-year-old Japanese man with a history of pollen allergy and thyroidectomy for Graves-Basedow disease was admitted to another hospital with a 2-month history of leg edema, eyelid edema, and dyspnea on exertion. Computed tomography (CT) demonstrated pleural and pericardial effusions, and a pericardiocentesis revealed the fluid as a nonspecific inflammatory effusion with increased numbers of lymphocytes without any infection. Increasing the levothyroxine dose for latent hypothyroidism and initiation of furosemide therapy did not decrease the effusion. He was transferred to our department.
At his first admission to our hospital, whole-body CT demonstrated pericardial effusion, bilateral pleural effusion, and testicular hydrocele. No swelling of the lacrimal or salivary glands nor pancreatic enlargement was observed. The right pleural effusion was exudative with a total cell count of 2,410/mm3 (lymphocytes, 75%) and neither malignant cells nor bacteria. Serum anti-SS-A/Ro antibody was slightly positive (15.4 U/mL; normal range, <10.0 U/mL) on an enzyme-linked immunosorbent assay but negative with the double immunodiffusion method. Other autoantibodies, including anti-SS-B/La, anti-CCP, anti-dsDNA, anti-RNP, anti-Scl70, and anti-neutrophil cytoplasmic antibodies, were all negative. Sialometry showed a rate of 1.008 mL/minute (within normal range), while salivary gland scintigraphy showed a slightly decreased uptake and secretory function. A lip biopsy demonstrated grade 2 lymphocytic infiltration according to Greenspan's classification (11), with only a few IgG4-positive plasma cells. The Schirmer test and rose bengal dye staining test were positive only in the left eye. Although he did not meet the ACR 2012 classification criteria (12), we suspected Sjögren syndrome with serositis.
PSL 40 mg/day (0.5 mg/kg) was initiated. Both the pleural and pericardial effusion amount decreased; however, tapering of the PSL led to exacerbation of the pleural effusion.
At his second admission, he presented with swelling of the lacrimal glands. Laboratory data are shown in Table 1. The white blood cell count in the peripheral blood was 8,200/μL (neutrophil 87.7%, lymphocyte 8.7%). Serum IgG and IgG4 levels were 1,500 mg/dL and 264 mg/dL, respectively. Autoantibodies were all negative. Serum levels of C-reactive protein (CRP), soluble interleukin-2 receptor (IL-2R), free T3, free T4, and thyroid-stimulating hormone (TSH) were also within the normal ranges (0.04 mg/dL, 394 U/mL, 2.9 pg/mL, 1.7 ng/dL and 1.67 μIU/mL, respectively). Chest CT showed marked bilateral pleural effusion with passive atelectasis and slight pericardial effusion (Fig. 1B). Thoracentesis for the right pleural effusion (Table 1) revealed turbid yellow fluid (Fig. 1A) with a total cell count of 810/mm3 (lymphocytes 84%), total protein 5.7 g/dL, adenosine deaminase (ADA) 25.1 U/L, total cholesterol 84 mg/dL, triglyceride 300 mg/dL, and the presence of chylomicrons, compatible with chylothorax. A cytologic examination was negative for malignancy. General bacterial and mycobacterial cultures of the pleural fluid were negative. He had no history of trauma or thoracic surgery. Lymphangiography did not show any leakage or obstruction of the thoracic duct (Fig. 2). While thoracoscopy did not reveal any tumor, amyloid deposits, or leakage from the thoracic duct, a thoracoscopic surgical pleural biopsy demonstrated infiltration by lymphocytes and plasma cells with ectopic germinal centers under the pleural mesothelium. Approximately 50% of IgG-positive plasma cells were IgG4-positive (Fig. 3). Storiform fibrosis and obstructive phlebitis were not found in this small specimen.
Table 1. Laboratory Data on 2nd Admission.
Peripheral blood CRP 0.04 mg/dL Pleural effusion
WBC 8,200 /μL ESR 15 mm/hr Cell count 810 /μL
Neut 87.7 % Ferritin 85 ng/mL poly 0 /μL
Lymp 8.7 % IgG 1,500 mg/dL mono 680 /μL
Mono 3.2 % IgG4 264 mg/dL others 130 /μL
Eosino 0.2 % IgA 226 mg/dL pH 7.5
Baso 0.2 % IgM 70 mg/dL specific gravity 1.016
RBC 5.05 ×106/μL C3 109 mg/dL TP 5.7 g/dL
Hb 15.5 g/dL C4 24 mg/dL Alb 3.3 g/dL
Plt 288 ×103/μL CH50 59.3 U/mL Amy 45 U/L
Cryoglobulin negative Glu 131 mg/dL
Biochemistry/Serology LDH 88 U/L
TP 7.4 g/dL Antibody T-cho 84 mg/dL
Alb 4.2 g/dL ANA negative TG 300 mg/dL
T-Bil 0.5 mg/dL SS-A 3.3 U/mL ADA 25.1 U/L
BUN 24.2 mg/dL SS-B <1.0 U/mL Hyaluronic Acid 6,670 ng/mL
Cre 1.25 mg/dL ds-DNA 3.8 U/mL CEA 1.8 ng/mL
UA 9.2 mg/dL RNP <2.0 U/mL
Na 139.5 mEq/L MPO-ANCA <1.0 U/mL
K 3.8 mEq/L PR3-ANCA <1.0 U/mL
Cl 100 mEq/L
AST 13 U/L Tumor marker
ALT 10 U/L sIL-2R 394 U/mL
LDH 163 U/L CEA 1.6 ng/mL
ALP 235 U/L CYFRA 1.7 ng/mL
γ-GTP 55 U/L SCC 0.7 ng/mL
Amy 62 U/L proGRP 41.5 ng/mL
CK 70 U/L
T-cho 192 mg/dL Infection marker
HbA1c 7.0 % procalcitonin <0.03 ng/mL
KL-6 193 U/mL T-SPOT negative
BNP 8.0 pg/mL GPLcore-IgA negative
fT3 2.9 ng/dL CMV-Ag negative
fT4 1.7 ng/dL β-D <6.0 pg/mL
TSH 1.67 μIU/mL
TP: total protein, Alb: albumin, T-Bil: total bilirubin, BUN: blood urea nitrogen, Cre: creatinine, UA: uric acid, Amy: amylase, T-cho: total cholesterol, KL-6: Krebs von den Lungen-6, BNP: brain natriuretic peptide, fT3: free triiodothyronine, fT4: free thyroxine, TSH: thyroid-stimulating hormone, CRP: C-reactive protein, ESR: erythrocyte sedimentation rate, ANA: antinuclear antibody, SS-A: anti-SS-A/Ro antibody, SS-B: anti-SS-B/La antibody, ds-DNA: anti-double-stranded DNA antibody, RNP: anti-RNP antibody, MPO-ANCA: myeloperoxidase-anti-neutrophil cytoplasmic antibody, PR3-ANCA: proteinase3-anti-neutrophil antibody, sIL-2R: soluble interleukin-2 receptor, GPLcore-IgA: glycopeptidolipid core IgA antibody, CMV-Ag: cytomegalovirus antigenemia, β-D: (1-3-)β-D-glucan, ADA: adenosine deaminase
Figure 1. Pleural effusion and CT images before and after treatment. The right pleural effusion appeared as turbid yellow fluid (A). Bilateral pleural effusion and pericardial effusion were seen at the second admission (B). After treatment with a combination of high-dose corticosteroids and rituximab, the pleural and pericardial effusion was significantly decreased (C).
Figure 2. Lymphangiography images. Lymphangiography showed the intact structure of the thoracic duct (yellow arrows) and revealed no leakage or obstruction of the duct.
Figure 3. Histopathological images from the pleural biopsy. A pleural biopsy showed the infiltration of lymphocytes and plasma cells with ectopic germinal centers under the pleural mesothelium, and more than 50% of IgG-positive plasma cells were IgG4-positive. HE: Hematoxylin and Eosin staining, LPF: low-power field, HPF: high-power field
We performed another lip biopsy, and the specimen showed excessive IgG4-positive plasma cell infiltration [48 cells/high-power field (HPF)] with >50% IgG4/IgG (Fig. 4). According to the diagnostic criteria of IgG4-related respiratory disease (13), the patient met the following: i) pleural involvement with CT, ii) elevated serum IgG4 level, iii) pleural biopsy findings (lymphoplasmacytic infiltration and increased IgG4 positive cells), and iv) IgG4-related sialadenitis confirmed with a lip biopsy. Thus, we diagnosed him with “definite” IgG4-related disease.
Figure 4. Histopathological images from the lip biopsy. A lip biopsy revealed focal IgG4-positive plasma cell infiltration, with up to 48 cells/HPF and an IgG4/IgG ratio exceeding 50%. HE: Hematoxylin and Eosin staining, LPF: low-power field, HPF: high-power field
Regarding mimickers of IgG4-RD, sarcoidosis was considered unlikely because of the lack of any elevation in the level of angiotensin-converting enzyme (ACE) or hypercalcemia on blood tests and no findings of granulomas in the biopsy specimens. The pleural specimens did not show angiocentricity or granuloma formation, so lymphomatoid granulomatosis was also deemed unlikely in this case. No fever or high CRP levels were observed in this patient, which made Multicentric Castleman disease unlikely.
The treatment and clinical course of this patient are shown in Fig. 5. We first performed continuous drainage of the pleural fluid with fasting, intravenous hyperalimentation, and octreotide for two weeks. The octreotide was used in an off-label manner with the patient's consent to reduce lymphatic flow in the thoracic duct (14). The pleural drainage decreased the effusion temporarily, but the production of new fluid did not cease, resulting in the marked loss of serum levels of albumin, IgG, and IgG4. We started high-dose PSL 70 mg (1 mg/kg/day) with RTX (375 mg/m2, weekly, 4 times). The off-label use of RTX for IgG4-RD was approved by the authorized committee in our hospital [approval number: 2020-012] with informed consent from the patient. The pleural effusion gradually decreased. Later, we switched from PSL to methylprednisolone (mPSL) due to the latter's lower mineralocorticoid activity and better transferability to the lung (15,16). Six months from induction therapy, the pleural effusion had significantly improved (Fig. 1C).
Figure 5. Summary of clinical course of this patient. The pleuritis showed an insufficient response to the first induction therapy with moderate-dose PSL and diuretics. However, the second induction therapy with high-dose PSL and RTX resulted in the significant improvement of pleuritis and a reduction in the serum IgG4 levels. PSL: prednisolone, mPSL: methylprednisolone, RTX: rituximab, Tx: treatment
Discussion
The present patient developed refractory chylothorax due to IgG4-RD diagnosed histopathologically with a pleural specimen. The response to a moderate dose of PSL was poor. High-dose PSL and additional RTX resulted in marked improvement. Chylothorax presenting as IgG4-related pleuritis is quite rare, and to our knowledge, this is the first report of the successful treatment of IgG4-related pleuritis with RTX.
Pleural involvement is reportedly rare; indeed, Fei et al. found that 87 of 248 patients with IgG4-RD in a prospective cohort (35.1%) had intrathoracic involvement (17), although the involvement was mainly in the lungs and lymph nodes, including hilar and mediastinal lymphadenopathy, in 52.9%, solid nodules in the lungs in 25.3%, alveolointerstitial opacities in 20.7%, round ground-glass opacities in 9.2%, and bronchovascular opacities in 20.7%. Pleural nodules and thickening were observed in 16.1%, but pleural effusion was seen in only 4.6%.
We summarized 37 previous case reports with IgG4-RD related pleuritis in Table 2 (18-48). Patients with IgG4-related pleuritis were predominantly men (78%), and the mean age was 63.5±14.7 years old. Bilateral pleural effusion was seen in 21 cases, while 11 cases (right, n=7 cases; left, n=4) had unilateral effusion. In the 24 cases with pleural effusion findings available, 22 showed an exudative pattern, while bloody effusion was seen in 2 cases and transudative effusion in 1 case. Pleural effusion cytometry revealed predominantly lymphocytes among total cases, with a high concentration of IgG4 revealed in 10 cases. Our present findings were consistent with those of previous cases with regard to the age, percentage of men, and rate of bilateral exudative pleural effusion.
Table 2. A Summary of 37 Previous Case Reports with IgG4-RD Related Pleuritis.
Case No. Reference Age Gender Side Pleural effusion test Pleural biopsy Serum Associated diseases Initial
PSL dose
(/day) Immunosuppressant PSL effect for pleuritis
Cell count (/μL) Lymph
(%) IgG (mg/dL) IgG4 (mg/dL) ADA (IU/L) IgG4-positive plasma cells (/HPF) IgG4/IgG IgG
(mg/dL) IgG4
(mg/dL)
Non-chylothorax cases
1 18 74 M Right N/D N/D N/D N/D N/D N/D N/D 46 N/D N/D none none - Good response
2 19 65 M Left Exudative N/D lymp 32%, Plasma 32% 3,005 1,510 N/D N/D N/D 3,142 1194% Mikulicz’s disease 30 mg - Good response
3-7 (5 cases) 20 62 (49-76) M (all) N/D N/D N/D N/D N/D N/D N/D N/D N/D high in 3/3 cases (100%) high in 2/4 cases (50%) 3/5 cases N/D N/D N/D
8 21 63 F Bilateral bloody N/D lymphocyte and plasma cells dominant N/D N/D N/D N/D N/D 2,450 420 history of autoimmune pancreatitis dose unknown - Good response
9 22 78 M Bilateral Exudative N/D mononuclear cell dominant N/D 590 34.1-46.7 17.6 85.4 1,604 483 - none - Partial response
10 23 85 M Bilateral (Left dominant) Exudative 2,600 87% 3,403 2,090 122 N/D N/D 4,121 2,740 salivary glands, lymph nodes, orbital lesion, bile duct, gastric glands 30 mg - Good response
11 24 73 M Right Exudative (bloody) 741 69% 3,358 907 59.8 N/D N/D 4,219 1,500 pericarditis, retroperitoneal fibrosis 30 mg - Good response
12 68 M Left Exudative 4,800 92% 2,809 571 104.4 N/D N/D 1,471 372 Mikulicz’s disease 30 mg - Good response
13 25 29 F Bilateral Exudative N/D 93% N/D N/D N/D >30 92% N/D 136 pericardium 40 mg - Good response
14 26 57 M Bilateral N/D N/D N/D N/D N/D N/D N/D >40% N/D 970 none N/D - Good response
15 27 69 M Right Exudative N/D dominant 4,276 N/D 70.6 N/D 50% 3,570 2,380 lymph node 0.5 mg/kg - Good response
16 28 71 F Right N/D N/D N/D N/D N/D N/D 27.3 84% 1,756 684 periaortitis 40 mg - Good response
17 29 74 F Bilateral Exudative N/D N/D N/D N/D normal 91 91% N/D 740 interstitital pneumonia 25 mg (0.5mg/kg) - Good response
18 30 48 M Bilateral Exudative N/D lymphocyte dominant N/D N/D N/D N/D 24% N/D 248 lymph node 0.6 mg/kg - Good response
19 31 63 M Right Exudative N/D N/D N/D N/D N/D 73 >40% N/D 284 none 40 mg MTX
(for PsA) Good response
20 32 74 M Left Transudative N/D N/D N/D N/D N/D N/D 30% 1,300 217 lymph node, neuromyopathy 40 mg - Good response
21 33 68 F Bilateral Exudative N/D N/D N/D N/D N/D N/D N/D N/D 307 uterine enlargement 0.6 mg/kg - Good response
22 34 58 M Bilateral N/D N/D N/D N/D N/D N/D 52 50% 1,200 141 none 37.5 mg AZP→
MTX Good response
23 35 32 M Biateral N/D N/D N/D N/D N/D N/D N/D N/D N/D 550 pericarditis 30 mg - Good response
24 36 78 M Bilateral N/D N/D N/D N/D N/D N/D 100 70% N/D 760 Sclerosing cholangitis, constrictive pericarditis N/D - Good response
25 37 70 M Bilateral N/D N/D N/D N/D N/D N/D none (after treatment) none (after treatment) normal 437 pericarditis, Aortitis high dose mPSL 3days→PSL 1mg/kg CYC Good response
26 70 M Right Exudative N/D dominant N/D N/D N/D N/D >50% N/D 224 mediastinitis 0.6 mg/kg - Good response
27 38 70 M Bilateral (Right dominant) Exudative 5,400 93.80% 4,409 1,070 75.6 >10 >40% 2,518 1,030 none 40 mg - Good response
28 39 84 M Bilateral N/D 448 Plasma 53% N/D N/D N/D 45 N/D N/D 306 none 40 mg - Good response
29 40 43 F Right Exudative N/D 80-97% N/D N/D 4.6-7.0 80 >40% normal 125 Pericardial effusion, abdominal effusion 30 mg - Good response
30 41 55 M Bilateral Exudative 1,952 52% N/D N/D N/D N/D N/D 3,260 534 pericarditis, lacrimal gland, 80 mg MMF N/D
31 42 65 M Bilateral Exudative 2,700/7,160 90%/97% N/D 124/125 23.0/20.5 50 40% 1,490 164 none 30 mg AZP Partial response
32 43 81 M Bilateral Exudative 3,450 69% N/D N/D 85.0 >50 <40% 2,807 233 none 30 mg - Partial response
33 44 70 F Bilateral Exudative N/D N/D 3,269 1,280 75.4 N/D N/D 3,877 >1,500 pericarditis N/D N/D Good response
34 45 72 F Left Exudative 5,483 99% N/D N/D 80.2 >50 >40% 5,310 >1,500 lymph node none - (naturally dissappered)
35 46 46 M Bilateral Exudative N/D 68% N/D 256 36.4 (normal) 22 42% N/D 142 N/D 30 mg - Good response
Cylorhorax cases
36 47 69 M Bilateral Exudative (Chylothorax) 3980/5,870 92%/88.5% 2,696/2,647 571/653 40.8/39.9 N/D 90% 1,539 277 none 30 mg - Partial response
37 48 16 M Bilateral Exudative (Chylothorax) N/D N/D N/D N/D 15 62 40% (mediastinal biopsy) N/D 1,650 none 1 mg/kg AZP Poor response (surgical obliteration)
present case Sakata et al. 66 M Bilateral Exudative (Chylothorax) 810 84% N/D N/D 25.1 50% 1500 264 lacrimal and salivery gland, pericarditis 70mg RTX Poor response
M: male, F: female, N/D: not determined, MTX: methotrexate, AZP: azathioprine, CYC: 381 cyclophosphamide, MMF: mycophenolate mofetil, RTX: rituximab
Interestingly, in previously reported cases of IgG4-related pleuritis, 10 out of 15 cases showed high levels of ADA in the pleural fluid (>40 U/L), which is usually measured as an auxiliary tool for the diagnosis of tuberculous pleuritis (49). Although careful ruling out of tuberculous pleuritis is necessary using other examinations, such as Ziehl-Neelsen staining (50), elevated ADA levels in pleural fluid may be useful for identifying IgG4-RD pleuritis because such a condition reflects the strong activation of lymphocytes. The levels of ADA in the pleural fluid of the present case were within normal limits.
Only two previous cases of IgG4-related pleuritis presenting as chylothorax have been reported (47,48). Kato et al. reported a 69-year-old man with IgG4-related pleuritis, demonstrating right-sided chylothorax and left-sided non-chylothorax pleuritis (47). The right-side chylothorax persisted while the left-side pleuritis improved with corticosteroids. Another case, reported by Goag et al., was a young man with bilateral chylothorax (48) unresponsive to high-dose PSL with azathioprine or octreotide and a limited low-fat diet with medium-chain triglyceride supplementation. He ultimately had to undergo exploratory thoracotomy and surgical obliteration. In contrast to most non-chylothorax IgG4-pleuritis patients, who tend to show a good response to treatment, IgG4-related pleuritis with chylothorax is likely to have a poor response to PSL. The pathogenesis of chylothorax in IgG4-RD is unclear. Lymphangiography in our case did not reveal any leakage from the thoracic duct, suggesting potential micro-damage to the lymphatic channels hampering centripetal lymph propulsion from the periphery of the pleural surface. However, we lacked histological evidence of this, so more cases need to be accumulated to clarify the mechanism involved.
Many kinds of immunosuppressant drugs, such as azathioprine, methotrexate, cyclophosphamide, and mycophenolate mofetil, have been used to try to treat refractory IgG4-RD, but the optimal drug in combination with PSL is still unclear (51). Reports of the effectiveness of RTX in IgG4-RD have been increasing (51-54). Regarding the mechanisms underlying IgG4-RD, RTX, which depletes peripheral B cells, is a reasonable addition to therapy not only to prevent the repletion of short-lived plasmablasts and plasma cells but also to interfere with the maintenance of CD4+ T cell memory (55). Furthermore, a French nationwide study demonstrated the efficacy of RTX for both induction therapy and the maintenance of remission (56). Therefore, we selected RTX in our refractory case, and his pleural effusion gradually disappeared with a steroid-sparing effect. To our knowledge, this is the first case report suggesting the effectiveness of RTX in IgG4-related pleuritis.
In conclusion, we experienced a case of refractory IgG4-related pleuritis with chylothorax that was improved with high-dose PSL and RTX. More cases need to be accumulated in order to clarify the clinical manifestations of IgG4-RD pleuritis and its appropriate treatment.
We declare that we have obtained written informed consent from this patient to publish this case report.
The authors state that they have no Conflict of Interest (COI). | Recovering | ReactionOutcome | CC BY-NC-ND | 33518567 | 20,058,618 | 2021-07-01 |
What was the outcome of reaction 'Rebound effect'? | Refractory IgG4-related Pleural Disease with Chylothorax: A Case Report and Literature Review.
We herein report a rare case of a 66-year-old man with refractory chylothorax. Although he had been treated with moderate doses of prednisolone (PSL) on suspicion of pleuritis with Sjögren syndrome, the pleural effusion expanded after the reduction of PSL. Further workup including histopathological examinations of pleura led to the diagnosis of IgG4-RD with bilateral chylothorax without any leakage from the thoracic duct. Combination therapy with high-dose PSL plus rituximab successfully decreased the pleural effusion. This is a very rare case of IgG4-related pleuritis with chylothorax and the first report of its successful treatment with rituximab.
Introduction
Immunoglobulin G4-related disease (IgG4-RD) is a systemic fibro-inflammatory disease characterized by serum IgG4 elevation and distinctive histopathological findings, such as lymphoplasmacytic infiltrate with abundant IgG4-positive plasma cells, storiform fibrosis, and obliterative phlebitis (1,2). Almost all organs in the body, such as the central nervous system (CNS), lacrimal glands, salivary glands, thyroid, lungs, pancreas, biliary duct, liver, gastrointestinal tract, kidneys, prostate, retroperitoneum and lymph nodes, can be affected by IgG4-RD (3).
While the lungs are involved in 9-18% of IgG4-RD patients (4-7), pleural involvement is observed in only 4% (4,5). Pleural effusion is uncommon, but previous reports have shown that it is usually exudative (8).
Chylothorax, which is characterized by milky-appearing pleural fluid with elevated triglyceride levels or the presence of chylomicrons, is caused by the extravasation of chyle into the pleural space due to obstruction or damage of a thoracic duct or its tributaries or transdiaphragmatic flow from the peritoneal cavity (9). The etiologies of chylothorax include several causes, such as trauma (surgical or non-surgical), malignancy, lymphatic disorders, infection, chylous ascites, and other miscellaneous causes (10); however, chylothorax due to IgG4-RD has almost never been reported.
We experienced a rare case of IgG4-RD with refractory chylothorax that was successfully treated with high-dose prednisolone (PSL) and rituximab (RTX). We report this case with a review of previous case reports of IgG4-related pleuritis.
Case Report
A 66-year-old Japanese man with a history of pollen allergy and thyroidectomy for Graves-Basedow disease was admitted to another hospital with a 2-month history of leg edema, eyelid edema, and dyspnea on exertion. Computed tomography (CT) demonstrated pleural and pericardial effusions, and a pericardiocentesis revealed the fluid as a nonspecific inflammatory effusion with increased numbers of lymphocytes without any infection. Increasing the levothyroxine dose for latent hypothyroidism and initiation of furosemide therapy did not decrease the effusion. He was transferred to our department.
At his first admission to our hospital, whole-body CT demonstrated pericardial effusion, bilateral pleural effusion, and testicular hydrocele. No swelling of the lacrimal or salivary glands nor pancreatic enlargement was observed. The right pleural effusion was exudative with a total cell count of 2,410/mm3 (lymphocytes, 75%) and neither malignant cells nor bacteria. Serum anti-SS-A/Ro antibody was slightly positive (15.4 U/mL; normal range, <10.0 U/mL) on an enzyme-linked immunosorbent assay but negative with the double immunodiffusion method. Other autoantibodies, including anti-SS-B/La, anti-CCP, anti-dsDNA, anti-RNP, anti-Scl70, and anti-neutrophil cytoplasmic antibodies, were all negative. Sialometry showed a rate of 1.008 mL/minute (within normal range), while salivary gland scintigraphy showed a slightly decreased uptake and secretory function. A lip biopsy demonstrated grade 2 lymphocytic infiltration according to Greenspan's classification (11), with only a few IgG4-positive plasma cells. The Schirmer test and rose bengal dye staining test were positive only in the left eye. Although he did not meet the ACR 2012 classification criteria (12), we suspected Sjögren syndrome with serositis.
PSL 40 mg/day (0.5 mg/kg) was initiated. Both the pleural and pericardial effusion amount decreased; however, tapering of the PSL led to exacerbation of the pleural effusion.
At his second admission, he presented with swelling of the lacrimal glands. Laboratory data are shown in Table 1. The white blood cell count in the peripheral blood was 8,200/μL (neutrophil 87.7%, lymphocyte 8.7%). Serum IgG and IgG4 levels were 1,500 mg/dL and 264 mg/dL, respectively. Autoantibodies were all negative. Serum levels of C-reactive protein (CRP), soluble interleukin-2 receptor (IL-2R), free T3, free T4, and thyroid-stimulating hormone (TSH) were also within the normal ranges (0.04 mg/dL, 394 U/mL, 2.9 pg/mL, 1.7 ng/dL and 1.67 μIU/mL, respectively). Chest CT showed marked bilateral pleural effusion with passive atelectasis and slight pericardial effusion (Fig. 1B). Thoracentesis for the right pleural effusion (Table 1) revealed turbid yellow fluid (Fig. 1A) with a total cell count of 810/mm3 (lymphocytes 84%), total protein 5.7 g/dL, adenosine deaminase (ADA) 25.1 U/L, total cholesterol 84 mg/dL, triglyceride 300 mg/dL, and the presence of chylomicrons, compatible with chylothorax. A cytologic examination was negative for malignancy. General bacterial and mycobacterial cultures of the pleural fluid were negative. He had no history of trauma or thoracic surgery. Lymphangiography did not show any leakage or obstruction of the thoracic duct (Fig. 2). While thoracoscopy did not reveal any tumor, amyloid deposits, or leakage from the thoracic duct, a thoracoscopic surgical pleural biopsy demonstrated infiltration by lymphocytes and plasma cells with ectopic germinal centers under the pleural mesothelium. Approximately 50% of IgG-positive plasma cells were IgG4-positive (Fig. 3). Storiform fibrosis and obstructive phlebitis were not found in this small specimen.
Table 1. Laboratory Data on 2nd Admission.
Peripheral blood CRP 0.04 mg/dL Pleural effusion
WBC 8,200 /μL ESR 15 mm/hr Cell count 810 /μL
Neut 87.7 % Ferritin 85 ng/mL poly 0 /μL
Lymp 8.7 % IgG 1,500 mg/dL mono 680 /μL
Mono 3.2 % IgG4 264 mg/dL others 130 /μL
Eosino 0.2 % IgA 226 mg/dL pH 7.5
Baso 0.2 % IgM 70 mg/dL specific gravity 1.016
RBC 5.05 ×106/μL C3 109 mg/dL TP 5.7 g/dL
Hb 15.5 g/dL C4 24 mg/dL Alb 3.3 g/dL
Plt 288 ×103/μL CH50 59.3 U/mL Amy 45 U/L
Cryoglobulin negative Glu 131 mg/dL
Biochemistry/Serology LDH 88 U/L
TP 7.4 g/dL Antibody T-cho 84 mg/dL
Alb 4.2 g/dL ANA negative TG 300 mg/dL
T-Bil 0.5 mg/dL SS-A 3.3 U/mL ADA 25.1 U/L
BUN 24.2 mg/dL SS-B <1.0 U/mL Hyaluronic Acid 6,670 ng/mL
Cre 1.25 mg/dL ds-DNA 3.8 U/mL CEA 1.8 ng/mL
UA 9.2 mg/dL RNP <2.0 U/mL
Na 139.5 mEq/L MPO-ANCA <1.0 U/mL
K 3.8 mEq/L PR3-ANCA <1.0 U/mL
Cl 100 mEq/L
AST 13 U/L Tumor marker
ALT 10 U/L sIL-2R 394 U/mL
LDH 163 U/L CEA 1.6 ng/mL
ALP 235 U/L CYFRA 1.7 ng/mL
γ-GTP 55 U/L SCC 0.7 ng/mL
Amy 62 U/L proGRP 41.5 ng/mL
CK 70 U/L
T-cho 192 mg/dL Infection marker
HbA1c 7.0 % procalcitonin <0.03 ng/mL
KL-6 193 U/mL T-SPOT negative
BNP 8.0 pg/mL GPLcore-IgA negative
fT3 2.9 ng/dL CMV-Ag negative
fT4 1.7 ng/dL β-D <6.0 pg/mL
TSH 1.67 μIU/mL
TP: total protein, Alb: albumin, T-Bil: total bilirubin, BUN: blood urea nitrogen, Cre: creatinine, UA: uric acid, Amy: amylase, T-cho: total cholesterol, KL-6: Krebs von den Lungen-6, BNP: brain natriuretic peptide, fT3: free triiodothyronine, fT4: free thyroxine, TSH: thyroid-stimulating hormone, CRP: C-reactive protein, ESR: erythrocyte sedimentation rate, ANA: antinuclear antibody, SS-A: anti-SS-A/Ro antibody, SS-B: anti-SS-B/La antibody, ds-DNA: anti-double-stranded DNA antibody, RNP: anti-RNP antibody, MPO-ANCA: myeloperoxidase-anti-neutrophil cytoplasmic antibody, PR3-ANCA: proteinase3-anti-neutrophil antibody, sIL-2R: soluble interleukin-2 receptor, GPLcore-IgA: glycopeptidolipid core IgA antibody, CMV-Ag: cytomegalovirus antigenemia, β-D: (1-3-)β-D-glucan, ADA: adenosine deaminase
Figure 1. Pleural effusion and CT images before and after treatment. The right pleural effusion appeared as turbid yellow fluid (A). Bilateral pleural effusion and pericardial effusion were seen at the second admission (B). After treatment with a combination of high-dose corticosteroids and rituximab, the pleural and pericardial effusion was significantly decreased (C).
Figure 2. Lymphangiography images. Lymphangiography showed the intact structure of the thoracic duct (yellow arrows) and revealed no leakage or obstruction of the duct.
Figure 3. Histopathological images from the pleural biopsy. A pleural biopsy showed the infiltration of lymphocytes and plasma cells with ectopic germinal centers under the pleural mesothelium, and more than 50% of IgG-positive plasma cells were IgG4-positive. HE: Hematoxylin and Eosin staining, LPF: low-power field, HPF: high-power field
We performed another lip biopsy, and the specimen showed excessive IgG4-positive plasma cell infiltration [48 cells/high-power field (HPF)] with >50% IgG4/IgG (Fig. 4). According to the diagnostic criteria of IgG4-related respiratory disease (13), the patient met the following: i) pleural involvement with CT, ii) elevated serum IgG4 level, iii) pleural biopsy findings (lymphoplasmacytic infiltration and increased IgG4 positive cells), and iv) IgG4-related sialadenitis confirmed with a lip biopsy. Thus, we diagnosed him with “definite” IgG4-related disease.
Figure 4. Histopathological images from the lip biopsy. A lip biopsy revealed focal IgG4-positive plasma cell infiltration, with up to 48 cells/HPF and an IgG4/IgG ratio exceeding 50%. HE: Hematoxylin and Eosin staining, LPF: low-power field, HPF: high-power field
Regarding mimickers of IgG4-RD, sarcoidosis was considered unlikely because of the lack of any elevation in the level of angiotensin-converting enzyme (ACE) or hypercalcemia on blood tests and no findings of granulomas in the biopsy specimens. The pleural specimens did not show angiocentricity or granuloma formation, so lymphomatoid granulomatosis was also deemed unlikely in this case. No fever or high CRP levels were observed in this patient, which made Multicentric Castleman disease unlikely.
The treatment and clinical course of this patient are shown in Fig. 5. We first performed continuous drainage of the pleural fluid with fasting, intravenous hyperalimentation, and octreotide for two weeks. The octreotide was used in an off-label manner with the patient's consent to reduce lymphatic flow in the thoracic duct (14). The pleural drainage decreased the effusion temporarily, but the production of new fluid did not cease, resulting in the marked loss of serum levels of albumin, IgG, and IgG4. We started high-dose PSL 70 mg (1 mg/kg/day) with RTX (375 mg/m2, weekly, 4 times). The off-label use of RTX for IgG4-RD was approved by the authorized committee in our hospital [approval number: 2020-012] with informed consent from the patient. The pleural effusion gradually decreased. Later, we switched from PSL to methylprednisolone (mPSL) due to the latter's lower mineralocorticoid activity and better transferability to the lung (15,16). Six months from induction therapy, the pleural effusion had significantly improved (Fig. 1C).
Figure 5. Summary of clinical course of this patient. The pleuritis showed an insufficient response to the first induction therapy with moderate-dose PSL and diuretics. However, the second induction therapy with high-dose PSL and RTX resulted in the significant improvement of pleuritis and a reduction in the serum IgG4 levels. PSL: prednisolone, mPSL: methylprednisolone, RTX: rituximab, Tx: treatment
Discussion
The present patient developed refractory chylothorax due to IgG4-RD diagnosed histopathologically with a pleural specimen. The response to a moderate dose of PSL was poor. High-dose PSL and additional RTX resulted in marked improvement. Chylothorax presenting as IgG4-related pleuritis is quite rare, and to our knowledge, this is the first report of the successful treatment of IgG4-related pleuritis with RTX.
Pleural involvement is reportedly rare; indeed, Fei et al. found that 87 of 248 patients with IgG4-RD in a prospective cohort (35.1%) had intrathoracic involvement (17), although the involvement was mainly in the lungs and lymph nodes, including hilar and mediastinal lymphadenopathy, in 52.9%, solid nodules in the lungs in 25.3%, alveolointerstitial opacities in 20.7%, round ground-glass opacities in 9.2%, and bronchovascular opacities in 20.7%. Pleural nodules and thickening were observed in 16.1%, but pleural effusion was seen in only 4.6%.
We summarized 37 previous case reports with IgG4-RD related pleuritis in Table 2 (18-48). Patients with IgG4-related pleuritis were predominantly men (78%), and the mean age was 63.5±14.7 years old. Bilateral pleural effusion was seen in 21 cases, while 11 cases (right, n=7 cases; left, n=4) had unilateral effusion. In the 24 cases with pleural effusion findings available, 22 showed an exudative pattern, while bloody effusion was seen in 2 cases and transudative effusion in 1 case. Pleural effusion cytometry revealed predominantly lymphocytes among total cases, with a high concentration of IgG4 revealed in 10 cases. Our present findings were consistent with those of previous cases with regard to the age, percentage of men, and rate of bilateral exudative pleural effusion.
Table 2. A Summary of 37 Previous Case Reports with IgG4-RD Related Pleuritis.
Case No. Reference Age Gender Side Pleural effusion test Pleural biopsy Serum Associated diseases Initial
PSL dose
(/day) Immunosuppressant PSL effect for pleuritis
Cell count (/μL) Lymph
(%) IgG (mg/dL) IgG4 (mg/dL) ADA (IU/L) IgG4-positive plasma cells (/HPF) IgG4/IgG IgG
(mg/dL) IgG4
(mg/dL)
Non-chylothorax cases
1 18 74 M Right N/D N/D N/D N/D N/D N/D N/D 46 N/D N/D none none - Good response
2 19 65 M Left Exudative N/D lymp 32%, Plasma 32% 3,005 1,510 N/D N/D N/D 3,142 1194% Mikulicz’s disease 30 mg - Good response
3-7 (5 cases) 20 62 (49-76) M (all) N/D N/D N/D N/D N/D N/D N/D N/D N/D high in 3/3 cases (100%) high in 2/4 cases (50%) 3/5 cases N/D N/D N/D
8 21 63 F Bilateral bloody N/D lymphocyte and plasma cells dominant N/D N/D N/D N/D N/D 2,450 420 history of autoimmune pancreatitis dose unknown - Good response
9 22 78 M Bilateral Exudative N/D mononuclear cell dominant N/D 590 34.1-46.7 17.6 85.4 1,604 483 - none - Partial response
10 23 85 M Bilateral (Left dominant) Exudative 2,600 87% 3,403 2,090 122 N/D N/D 4,121 2,740 salivary glands, lymph nodes, orbital lesion, bile duct, gastric glands 30 mg - Good response
11 24 73 M Right Exudative (bloody) 741 69% 3,358 907 59.8 N/D N/D 4,219 1,500 pericarditis, retroperitoneal fibrosis 30 mg - Good response
12 68 M Left Exudative 4,800 92% 2,809 571 104.4 N/D N/D 1,471 372 Mikulicz’s disease 30 mg - Good response
13 25 29 F Bilateral Exudative N/D 93% N/D N/D N/D >30 92% N/D 136 pericardium 40 mg - Good response
14 26 57 M Bilateral N/D N/D N/D N/D N/D N/D N/D >40% N/D 970 none N/D - Good response
15 27 69 M Right Exudative N/D dominant 4,276 N/D 70.6 N/D 50% 3,570 2,380 lymph node 0.5 mg/kg - Good response
16 28 71 F Right N/D N/D N/D N/D N/D N/D 27.3 84% 1,756 684 periaortitis 40 mg - Good response
17 29 74 F Bilateral Exudative N/D N/D N/D N/D normal 91 91% N/D 740 interstitital pneumonia 25 mg (0.5mg/kg) - Good response
18 30 48 M Bilateral Exudative N/D lymphocyte dominant N/D N/D N/D N/D 24% N/D 248 lymph node 0.6 mg/kg - Good response
19 31 63 M Right Exudative N/D N/D N/D N/D N/D 73 >40% N/D 284 none 40 mg MTX
(for PsA) Good response
20 32 74 M Left Transudative N/D N/D N/D N/D N/D N/D 30% 1,300 217 lymph node, neuromyopathy 40 mg - Good response
21 33 68 F Bilateral Exudative N/D N/D N/D N/D N/D N/D N/D N/D 307 uterine enlargement 0.6 mg/kg - Good response
22 34 58 M Bilateral N/D N/D N/D N/D N/D N/D 52 50% 1,200 141 none 37.5 mg AZP→
MTX Good response
23 35 32 M Biateral N/D N/D N/D N/D N/D N/D N/D N/D N/D 550 pericarditis 30 mg - Good response
24 36 78 M Bilateral N/D N/D N/D N/D N/D N/D 100 70% N/D 760 Sclerosing cholangitis, constrictive pericarditis N/D - Good response
25 37 70 M Bilateral N/D N/D N/D N/D N/D N/D none (after treatment) none (after treatment) normal 437 pericarditis, Aortitis high dose mPSL 3days→PSL 1mg/kg CYC Good response
26 70 M Right Exudative N/D dominant N/D N/D N/D N/D >50% N/D 224 mediastinitis 0.6 mg/kg - Good response
27 38 70 M Bilateral (Right dominant) Exudative 5,400 93.80% 4,409 1,070 75.6 >10 >40% 2,518 1,030 none 40 mg - Good response
28 39 84 M Bilateral N/D 448 Plasma 53% N/D N/D N/D 45 N/D N/D 306 none 40 mg - Good response
29 40 43 F Right Exudative N/D 80-97% N/D N/D 4.6-7.0 80 >40% normal 125 Pericardial effusion, abdominal effusion 30 mg - Good response
30 41 55 M Bilateral Exudative 1,952 52% N/D N/D N/D N/D N/D 3,260 534 pericarditis, lacrimal gland, 80 mg MMF N/D
31 42 65 M Bilateral Exudative 2,700/7,160 90%/97% N/D 124/125 23.0/20.5 50 40% 1,490 164 none 30 mg AZP Partial response
32 43 81 M Bilateral Exudative 3,450 69% N/D N/D 85.0 >50 <40% 2,807 233 none 30 mg - Partial response
33 44 70 F Bilateral Exudative N/D N/D 3,269 1,280 75.4 N/D N/D 3,877 >1,500 pericarditis N/D N/D Good response
34 45 72 F Left Exudative 5,483 99% N/D N/D 80.2 >50 >40% 5,310 >1,500 lymph node none - (naturally dissappered)
35 46 46 M Bilateral Exudative N/D 68% N/D 256 36.4 (normal) 22 42% N/D 142 N/D 30 mg - Good response
Cylorhorax cases
36 47 69 M Bilateral Exudative (Chylothorax) 3980/5,870 92%/88.5% 2,696/2,647 571/653 40.8/39.9 N/D 90% 1,539 277 none 30 mg - Partial response
37 48 16 M Bilateral Exudative (Chylothorax) N/D N/D N/D N/D 15 62 40% (mediastinal biopsy) N/D 1,650 none 1 mg/kg AZP Poor response (surgical obliteration)
present case Sakata et al. 66 M Bilateral Exudative (Chylothorax) 810 84% N/D N/D 25.1 50% 1500 264 lacrimal and salivery gland, pericarditis 70mg RTX Poor response
M: male, F: female, N/D: not determined, MTX: methotrexate, AZP: azathioprine, CYC: 381 cyclophosphamide, MMF: mycophenolate mofetil, RTX: rituximab
Interestingly, in previously reported cases of IgG4-related pleuritis, 10 out of 15 cases showed high levels of ADA in the pleural fluid (>40 U/L), which is usually measured as an auxiliary tool for the diagnosis of tuberculous pleuritis (49). Although careful ruling out of tuberculous pleuritis is necessary using other examinations, such as Ziehl-Neelsen staining (50), elevated ADA levels in pleural fluid may be useful for identifying IgG4-RD pleuritis because such a condition reflects the strong activation of lymphocytes. The levels of ADA in the pleural fluid of the present case were within normal limits.
Only two previous cases of IgG4-related pleuritis presenting as chylothorax have been reported (47,48). Kato et al. reported a 69-year-old man with IgG4-related pleuritis, demonstrating right-sided chylothorax and left-sided non-chylothorax pleuritis (47). The right-side chylothorax persisted while the left-side pleuritis improved with corticosteroids. Another case, reported by Goag et al., was a young man with bilateral chylothorax (48) unresponsive to high-dose PSL with azathioprine or octreotide and a limited low-fat diet with medium-chain triglyceride supplementation. He ultimately had to undergo exploratory thoracotomy and surgical obliteration. In contrast to most non-chylothorax IgG4-pleuritis patients, who tend to show a good response to treatment, IgG4-related pleuritis with chylothorax is likely to have a poor response to PSL. The pathogenesis of chylothorax in IgG4-RD is unclear. Lymphangiography in our case did not reveal any leakage from the thoracic duct, suggesting potential micro-damage to the lymphatic channels hampering centripetal lymph propulsion from the periphery of the pleural surface. However, we lacked histological evidence of this, so more cases need to be accumulated to clarify the mechanism involved.
Many kinds of immunosuppressant drugs, such as azathioprine, methotrexate, cyclophosphamide, and mycophenolate mofetil, have been used to try to treat refractory IgG4-RD, but the optimal drug in combination with PSL is still unclear (51). Reports of the effectiveness of RTX in IgG4-RD have been increasing (51-54). Regarding the mechanisms underlying IgG4-RD, RTX, which depletes peripheral B cells, is a reasonable addition to therapy not only to prevent the repletion of short-lived plasmablasts and plasma cells but also to interfere with the maintenance of CD4+ T cell memory (55). Furthermore, a French nationwide study demonstrated the efficacy of RTX for both induction therapy and the maintenance of remission (56). Therefore, we selected RTX in our refractory case, and his pleural effusion gradually disappeared with a steroid-sparing effect. To our knowledge, this is the first case report suggesting the effectiveness of RTX in IgG4-related pleuritis.
In conclusion, we experienced a case of refractory IgG4-related pleuritis with chylothorax that was improved with high-dose PSL and RTX. More cases need to be accumulated in order to clarify the clinical manifestations of IgG4-RD pleuritis and its appropriate treatment.
We declare that we have obtained written informed consent from this patient to publish this case report.
The authors state that they have no Conflict of Interest (COI). | Recovering | ReactionOutcome | CC BY-NC-ND | 33518567 | 20,058,618 | 2021-07-01 |
Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Condition aggravated'. | An Autopsy Case of Primary Biliary Cholangitis with Histological Submassive Hepatic Necrosis Caused by Acute Hepatitis E Virus Infection.
A 59-year-old woman who had been diagnosed with cirrhotic primary biliary cholangitis (PBC) 5 years earlier was admitted for severe jaundice (total bilirubin: 30.1 mg/dL). We suspected that her cirrhotic PBC had deteriorated acutely for some reason. Her general condition deteriorated quickly, and she passed away on day 18 of admission. Hepatitis E virus (HEV)-IgA antibodies were positive, and Genotype 3b HEV involvement was confirmed from a blood sample taken on admission. Histopathological findings revealed cirrhosis and submassive loss and necrosis of hepatocytes. Clinicians should consider the possibility of acute HEV infection as a trigger for acute PBC exacerbation.
Introduction
Primary biliary cholangitis (PBC) is a chronic and slowly progressive cholestatic autoimmune liver disease that is histopathologically characterized by an attack on the small intralobular bile duct by T lymphocytes (1). The precise etiology of PBC remains unknown but is related to genetic susceptibility environmental factors (2-4). Although most patients with PBC are asymptomatic and have a normal life expectancy, clinicians sometimes encounter symptomatic PBC cases with severe jaundice or liver failure as a result of the sustained loss of intralobular bile ducts in spite of ursodeoxycholic acid (UDCA) therapy (5,6). Patients with concomitant acute liver injury from autoimmune hepatitis show particularly rapid disease progression (7). The acute exacerbation of PBC from hepatitis virus co-infection is rare in the clinical setting.
The hepatitis E virus (HEV) is a quasi-enveloped, single-stranded RNA virus that causes acute or chronic hepatitis (8,9). With the increase in the number of hepatitis E cases, HEV antibody is now positive in approximately 5% of the general population in Japan (10,11). Among HEV-associated acute hepatitis cases, 0.5-4% of patients progress to fulminant hepatitis (12), leading to high mortality when intensive care and liver transplantation are unavailable. Rare cases of severe acute HEV hepatitis underlying such chronic liver diseases as alcoholic liver disease, nonalcoholic fatty liver disease, chronic viral hepatitis, and PBC have been documented as well (13-15). No autopsy PBC cases displaying acute exacerbation due to superimposed acute HEV infection have been reported to date.
We herein report the autopsy findings of a PBC case in the cirrhotic stage with histological submassive hepatic necrosis caused by acute HEV infection.
Case Report
A 59-year-old woman who had been serologically diagnosed with PBC after the detection of liver dysfunction 26 years earlier was admitted to our hospital for severe jaundice, brown urine, and leg edema. She had suffered from cold-like symptoms and skin jaundice for a month and had received antitussives and antibiotics (levofloxacin 500 mg/day) from her attending physician 2 weeks before admission. She had no symptoms of diarrhea, vomiting, or a history of eating raw meat. She reported no regular ethanol consumption or travel to a foreign country. Although she had been prescribed 600 mg/day UDCA and 400 mg/day bezafibrate for PBC, her medication compliance was extremely poor. She had persistent liver dysfunction [alanine aminotransferase (ALT) at around 100 U/L] and jaundice (total bilirubin at around 3 mg/dL). Eight years before admission, the histological findings of a liver biopsy specimen showed lymphocyte infiltration in the portal area and severe bile duct loss that were consistent with Nakanuma stage 3 (16) and Scheuer stage III (17) classifications (Fig. 1). Three years later, she was clinically diagnosed with cirrhosis-stage PBC. She had also undergone endoscopic gastric varices treatment one year before admission.
Figure 1. Histological findings of a liver biopsy specimen obtained eight years before admission. a, b) Lymphocyte infiltration in the portal area and severe bile duct loss were observed (Hematoxylin and Eosin staining). c) Azan-Mallory staining showed moderate fibrosis in the liver that was consistent with Nakanuma stage 3 and Scheuer stage III classifications.
On an examination at the time of admission, the patient was 165 cm tall, weighed 68 kg, and had a body mass index of 25.0 kg/m2. Her vital signs included Glasgow Coma Scale score E4V5M6, body temperature 37.3 °C, and blood pressure 111/54 mmHg. She exhibited conjunctival and systemic jaundice and front chest vascular spider but no flapping tremor. Laboratory tests on admission revealed elevated serum aspartate aminotransferase (78 U/L), ALT (100 U/L), gamma-glutamyl transpeptidase (105 U/L), alkaline phosphatase (702 U/L), total bilirubin (30.1 mg/dL), and Mac-2-binding protein glycan isomer (M2BPGi) (7.4 C・O・I) but a reduced platelet count (7.2×104/μL), albumin (2.7 g/dL), and prothrombin time activity (67.7%) (Table 1). Testing for hepatitis A virus antibody (immunoglobulin M), hepatitis B virus surface antigen, and anti-hepatitis C virus (HCV) antibody was negative. Serum antibodies to the Epstein-Barr virus and cytomegalovirus both showed a historical infection pattern. Although serum alpha fetoprotein levels were within normal range, levels of protein induced by vitamin K absence or antagonist II were mildly elevated (152 mAU/mL). Among the autoantibodies tested, fluorescent anti-nuclear antibody (× 640) and anti-mitochondrial M2 antibody (168.1 Index) were positive.
Table 1. Laboratory Findings on Admission.
Blood Chemistry / Serology Viral markers
White blood cell count 5,760 /μL Total protein 5.9 g/dL IgM-HAV Ab (-)
Neutrophils 71.2 % Albumin 2.7 g/dL HBs-Ag 0.001 (-) U/mL
Lymphocytes 19.8 % AST 78 U/L HBs-Ab 0.4 (-) mIU/mL
Monocytes 5.7 % ALT 100 U/L HBc-Ab 0.2 (-) C·O·I
Eosinophils 3.0 % Total bilirubin 30.14 mg/dL IgM-HBc Ab (-)
Basophils 0.3 % GGT 105 U/L HCV-Ab 0.1 (-) C·O·I
Red blood cell count 418 ×104/μL ALP 702 U/L IgM-EBV VCA Ab <10 (-) ×
Hemoglobin 13.1 g/dL BUN 12 mg/dL IgG-EBV VCA Ab 40 (+)
Hematocrit 37.4 % Creatinine 0.59 mg/dL EBV EBNA Ab <10 (-) ×
Platelet count 7.2 ×104/μL NH3 29 μg/dL IgM-CMV Ab 0.29 (-) Index
CRP 1.61 mg/dL IgG-CMV Ab 133.6 (+) AU/mL
Coagulation HbA1c 4.2 % IgA-HEV Ab (+)
PT 67.7 % IgM 139 mg/dL
APTT 29.0 sec IgA 292 mg/dL Autoimmune antibodies
Fibrinogen 192.0 mg/dL IgG 1,156 mg/dL FANA 640 ×
D-dimer 2.3 μg/mL M2BPGi 7.4 C·O·I AMA2 168.1 Index
Anti-centromere antibody (-)
Tumor markers LKM-1 (-)
AFP 7.0 ng/mL ASMA (-)
PIVKA II 152 mAU/mL
PT: prothrombin time, APTT: activated partial thromboplastin time, AST: aspartate aminotransferase, ALT: alanine aminotransferase, GGT: gamma-glutamyl transpeptidase, ALP: alkaline phosphatase, BUN: blood urea nitrogen, CRP: C-reactive protein, HbA1c: hemoglobin A1c, M2BPGi: Mac 2-Binding Protein Gylcan Isomer, AFP: alpha fetoprotein, PIVKA II: protein induced by vitamin K absence or antagonist II, FANA: fluorescent anti-nuclear antibody, AMA2: anti-mitochondrial M2 antibody, LKM-1: anti-liver/kidney microsome type 1 antibody, ASMA: anti-smooth muscle antibody, C·O·I: cut off index
Abdominal ultrasonography showed surface irregularity and a coarse parenchyma echotexture of the liver, suggesting cirrhosis (Fig. 2a). Abdominal contrast-enhanced computed tomography portal phase images showed surface undulation of the liver, collateral circulation around the stomach and splenic hilum, and ascites on the surface of the liver and spleen (Fig. 2b). No evidence suggestive of acute hepatitis, such as periportal collar sign, gallbladder atrophy, or wall thickening, was observed, nor were any space-occupying lesions present in the liver.
Figure 2. a) Abdominal ultrasonography showed liver surface irregularity (arrowheads) and a coarse parenchyma echotexture. b) Abdominal contrast-enhanced computed tomography portal phase images revealed surface undulation of the liver, collateral circulation around the stomach and splenic hilum (arrows), and ascites on the surface of the liver and spleen.
Based on the patient’s clinical findings, we suspected that her cirrhotic PBC had deteriorated acutely for some reason. Although she did not meet the criteria for acute liver failure, the presence of severe jaundice and ascites indicated the need for liver transplantation. After being refused for this treatment, we provided supportive care, including bed rest, lactulose administration, and albumin replacement. On day 13 of admission, HEV-IgA antibody was found to be positive in an admission blood sample, suggesting an association between the exacerbation of her PBC and acute HEV infection. However, the patient’s liver atrophy and renal failure were beyond treatment. Her general condition progressively worsened, and she passed away on day 18 of admission. The entire clinical course is summarized in Fig. 3.
Figure 3. Clinical course of the patient. ALT: alanine aminotransferase, PT: prothrombin time, T-Bil: Total bilirubin, Cre: Creatinine, HEV: Hepatitis E virus
A pathological autopsy was performed after obtaining informed consent from her family. Macroscopically, the surface of the liver was atrophied in a nodular manner, indicating complete cirrhosis (Fig. 4a). Microscopic observation of the liver showed severe atrophy with submassive loss and necrosis of hepatocytes from Zone 3 to Zone 2 of the hepatic lobule (Fig. 4b). However, the distribution did not match the centrilobular necrosis typically observed in hepatic ischemia. In some areas, hepatocytes around the central vein were intact (Fig. 4c). In addition, there was no remarkable steatosis inside hepatocytes indicative of hypoxia (Fig. 4c). Based on these findings, hepatic ischemia was not considered as the main cause of submassive loss and necrosis in this case. Although cholestasis was prominent in the lobules, inflammatory cell infiltration related to acute hepatitis was not evident (Fig. 4b, c). Regenerated nodules and highly fibrous septum formation were found in the liver, which were histologically consistent with cirrhosis (Fig. 4d). In the portal area, the infiltration of mononuclear cells and disappearance of bile ducts suggested advanced PBC (Fig. 4e). Extensive bile duct loss was confirmed between the interlobular and septal bile duct levels.
Figure 4. Autopsy findings. a) Macroscopically, the surface of the liver was atrophied in a nodular manner, indicating complete cirrhosis. b) Severe atrophy with submassive loss and necrosis of hepatocytes (red dotted lines) from Zone 3 to Zone 2 of the hepatic lobule were evident (Hematoxylin and Eosin staining). P: portal vein, C: central vein. c) In some areas, hepatocytes around the central vein were relatively intact, with no steatosis inside hepatocytes suggestive of hypoxia. Cholestasis was prominent in the lobules. Inflammatory cell infiltration indicative of acute hepatitis was not detected. d) On Elastica-Goldner staining, regenerated nodules and highly fibrous septum formation were found in the liver, findings that were histologically consistent with cirrhosis. e) In the portal area, infiltration of mononuclear cells and the disappearance of bile ducts were observed, suggesting advanced PBC. P: portal vein
HEV antibodies (IgG, IgM, and IgA) were measured by an enzyme-linked immunosorbent assay using frozen serum samples according to a previously described method (18). The testing results are shown in Table 2 along with the corresponding hepatobiliary enzymes at each time point. HEV RNA was detected by the nested reverse-transcription polymerase chain reaction with primers targeting the open reading frame 2 (ORF2) region of the HEV genome (nucleotide position 5944-6355, excluding primer sequences at both ends: M73218), as described previously (19). HEV RNA, which had been negative at the last visit before admission, had become positive at admission along with increases in all classes of HEV antibodies. HEV RNA became undetectable during the deterioration of her condition, although a high antibody titer persisted. We determined her 412-nucleotide ORF2 sequence and constructed a molecular phylogenetic tree according to a previously described method (20) (Fig. 5). The HEV strain (HE-JA19-0280: DDBJ/EMBL/GenBank accession number LC581383) derived from this case belonged to genotype 3 (subgenotype 3b) and was closest to those of patients recovering from acute hepatitis E in Tokyo and Gunma Prefectures of Japan.
Figure 5. Phylogenetic tree constructed by the neighbor-joining method based on the partial nucleotide sequence (412 nucleotides) of the open reading frame 2 region of hepatitis E virus (HEV) isolates. In addition to the HEV isolate (HE-JA19-0280) obtained in the present study (highlighted with a closed box), 33 representative genotype 3 isolates (subgenotype 3a: n=8, subgenotype 3b: n=22, and subgenotype 3e: n=3), whose entire genomic sequence is known, are included in the tree using the prototype HEV sequences of genotype 1 (M73218), genotype 2 (M74506), and genotype 4 (AJ272108) as outgroups. Three HEV isolates sharing the highest identity of 97.1-97.8% with the HE-JA19-0280 isolate are also included. Each reference sequence is shown with the genotype/subgenotype followed by the accession number, isolate name, and country in which it was isolated. The bootstrap values (>70%) are indicated for nodes as the percentage of data among 1,000 resampling procedures. The scale bar is in units of nuceotide substitutions per site.
Table 2. Transition of Hepatobiliary Enzymes, HEV Antibodies, and HEV RNA.
Day Laboratory data HEV antibodies HEV RNA
AST
(U/L) ALT
(U/L) GGT
(U/L) ALP
(U/L) T-Bil
(mg/dL) IgG (OD450) IgM (OD450) IgA (OD450)
X - 80 137 111 413 940 3.4 0.010 (-) 0.046 (-) 0.020 (-) Negative
X (admission) 78 100 105 702 30.1 1.661 (+) >3.000 (+) 2.374 (+) +: 1.0×101 copies/mL
X+1 69 80 87 588 26.6 1.578 (+) >3.000 (+) 2.346 (+) +: 1.2×101 copies/mL
X+11 43 44 64 568 39.7 1.850 (+) >3.000 (+) 2.002 (+) Negative
X+14 61 66 78 631 46.7 1.970 (+) >3.000 (+) 1.768 (+) Negative
HEV: hepatitis E virus, AST: aspartate aminotransferase, ALT: alanine aminotransferase, GGT: gamma-glutamyl transpeptidase, ALP: alkaline phosphatase, T-Bil: total bilirubin
Discussion
The present autopsy case displayed histological evidence of submassive necrosis in the liver caused by acute HEV infection. The patient was presumed to have been at the liver cirrhosis stage of PBC but suddenly developed severe jaundice due to superimposed HEV infection and succumbed one month later to hepatic failure. The histopathological findings of severe liver atrophy with submassive loss and necrosis of hepatocytes could not be explained by ischemia only, strongly suggesting the involvement of genotype 3b HEV infection in her histopathological findings.
Although PBC patients generally have a normal life expectancy, they sometimes show rapid disease exacerbation due to concomitant autoimmune hepatitis (7,21) or simultaneous HCV infection (22) as a trigger of PBC deterioration. One rare instance of PBC with acute HEV infection has been reported to date (15). To our knowledge, however, an autopsy case of rapid deterioration triggered by HEV infection has not yet been described. As the mechanism underlying PBC exacerbation due to viral hepatitis infection remains unknown, the present case may contribute to the body of knowledge concerning this condition.
HEV is one of the most common causes of acute viral hepatitis (23). In addition to contaminated water, raw meat from pigs, boars, and deer is another common infection source (24-26). Recently, the prevalence of HEV cases without clinical symptoms as well as those of unknown transmission route has been increasing (27). The infection route in the present case could not be identified based on our medical interview. According to previous reports, pregnancy, old age, alcohol intake, and fatty liver are host factors associated with the aggravation of HEV, and co-infection with chronic liver disease is related to the risk of liver failure (13,14). Regarding the HEV genotype, HEV genotype 4 infection is reportedly associated with aggravation (26,28,29). Genotype 3 HEV, as detected in this case, is generally associated with a low tendency of severe clinical manifestations, although a rare case of progressive genotype 3 HEV infection has been reported (28). A mutation of V239A in the helicase region of the genotype 3 HEV genome has been associated with HEV infection aggravation (30). That mutant was absent in this case (data not shown). The patient had no other apparent host or viral factors associated with HEV severity. However, Wang et al. reported that the cirrhosis stage itself carries a potential risk of liver failure due to HEV infection, regardless of etiology; they further described the potentiation of the cirrhotic liver upon HEV infection and more aggressive immune- or inflammatory-mediated activation of cell death in a cirrhotic liver status as possible mechanisms of exacerbation (15). The above results suggested that even if patients have no documented risk factors of HEV aggravation, clinicians should bear in mind that HEV infection at a cirrhotic liver disease stage can become severe.
This patient had been diagnosed with PBC 26 years earlier based on serological criteria. Eight years before admission, she was already at an advanced stage of PBC, with Nakanuma stage 3 and Scheuer stage III classifications according to a liver biopsy. An autopsy specimen of the liver revealed obvious cirrhosis, which was consistent with the natural history of PBC as suggested by elevated serum surrogate markers of M2BPGi (31,32). However, the submassive loss and necrosis of hepatocytes could not solely be explained by the natural PBC history. Inflammatory cell infiltration suggesting acute hepatitis E (33) was not observed, which suggested a post-inflammatory status. Other general clinical features of acute hepatitis, including markedly elevated levels of liver enzymes, were absent as well. Her liver enzymes were only mildly elevated at day X-80, suggesting that asymptomatic hepatitis may have started at that point, followed by further increases in transaminase levels. Thus, one explanation as to why this case showed mild hepatitis was that the hepatitis had occurred after day X-80 and already peaked and ameliorated by the time of admission, such that jaundice represented the major feature. However, no clinical data were available between the patient’s last outpatient visit at day X-80 and her hospitalization. Another hypothesis was that this case had already reached the complete cirrhosis stage, as shown by the pathological findings, which could have induced mild liver enzyme elevations (34).
Patients with hepatitis E sometimes show severe jaundice (35). Although the underlying mechanism is uncertain, HEV has been reported to exhibit not only hepatocytic but also biliary tropism and replicate within bile duct epithelial cells (36,37). The severe jaundice and cholestasis in this case might have been the result of HEV infection complicating the chronic cholestatic liver disease of PBC. The fact that jaundice was more pronounced than elevated liver enzyme levels may support this notion. Although drug-induced liver injury (levofloxacin 500 mg/day) cannot be ruled out, we suspected that HEV infection likely triggered the exacerbation of PBC due to her awareness of jaundice prior to drug administration and the histological considerations described above.
In conclusion, clinicians should consider the possibility of acute HEV infection as a trigger for the acute exacerbation of PBC. In such cases, it may be necessary to treat the patient with the anticipation of severe aggravation.
The authors state that they have no Conflict of Interest (COI).
Acknowledgement
We thank Trevor Ralph for his English editorial assistance. | BEZAFIBRATE, LEVOFLOXACIN, URSODIOL | DrugsGivenReaction | CC BY-NC-ND | 33518570 | 19,677,427 | 2021-06-15 |
Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Drug-induced liver injury'. | An Autopsy Case of Primary Biliary Cholangitis with Histological Submassive Hepatic Necrosis Caused by Acute Hepatitis E Virus Infection.
A 59-year-old woman who had been diagnosed with cirrhotic primary biliary cholangitis (PBC) 5 years earlier was admitted for severe jaundice (total bilirubin: 30.1 mg/dL). We suspected that her cirrhotic PBC had deteriorated acutely for some reason. Her general condition deteriorated quickly, and she passed away on day 18 of admission. Hepatitis E virus (HEV)-IgA antibodies were positive, and Genotype 3b HEV involvement was confirmed from a blood sample taken on admission. Histopathological findings revealed cirrhosis and submassive loss and necrosis of hepatocytes. Clinicians should consider the possibility of acute HEV infection as a trigger for acute PBC exacerbation.
Introduction
Primary biliary cholangitis (PBC) is a chronic and slowly progressive cholestatic autoimmune liver disease that is histopathologically characterized by an attack on the small intralobular bile duct by T lymphocytes (1). The precise etiology of PBC remains unknown but is related to genetic susceptibility environmental factors (2-4). Although most patients with PBC are asymptomatic and have a normal life expectancy, clinicians sometimes encounter symptomatic PBC cases with severe jaundice or liver failure as a result of the sustained loss of intralobular bile ducts in spite of ursodeoxycholic acid (UDCA) therapy (5,6). Patients with concomitant acute liver injury from autoimmune hepatitis show particularly rapid disease progression (7). The acute exacerbation of PBC from hepatitis virus co-infection is rare in the clinical setting.
The hepatitis E virus (HEV) is a quasi-enveloped, single-stranded RNA virus that causes acute or chronic hepatitis (8,9). With the increase in the number of hepatitis E cases, HEV antibody is now positive in approximately 5% of the general population in Japan (10,11). Among HEV-associated acute hepatitis cases, 0.5-4% of patients progress to fulminant hepatitis (12), leading to high mortality when intensive care and liver transplantation are unavailable. Rare cases of severe acute HEV hepatitis underlying such chronic liver diseases as alcoholic liver disease, nonalcoholic fatty liver disease, chronic viral hepatitis, and PBC have been documented as well (13-15). No autopsy PBC cases displaying acute exacerbation due to superimposed acute HEV infection have been reported to date.
We herein report the autopsy findings of a PBC case in the cirrhotic stage with histological submassive hepatic necrosis caused by acute HEV infection.
Case Report
A 59-year-old woman who had been serologically diagnosed with PBC after the detection of liver dysfunction 26 years earlier was admitted to our hospital for severe jaundice, brown urine, and leg edema. She had suffered from cold-like symptoms and skin jaundice for a month and had received antitussives and antibiotics (levofloxacin 500 mg/day) from her attending physician 2 weeks before admission. She had no symptoms of diarrhea, vomiting, or a history of eating raw meat. She reported no regular ethanol consumption or travel to a foreign country. Although she had been prescribed 600 mg/day UDCA and 400 mg/day bezafibrate for PBC, her medication compliance was extremely poor. She had persistent liver dysfunction [alanine aminotransferase (ALT) at around 100 U/L] and jaundice (total bilirubin at around 3 mg/dL). Eight years before admission, the histological findings of a liver biopsy specimen showed lymphocyte infiltration in the portal area and severe bile duct loss that were consistent with Nakanuma stage 3 (16) and Scheuer stage III (17) classifications (Fig. 1). Three years later, she was clinically diagnosed with cirrhosis-stage PBC. She had also undergone endoscopic gastric varices treatment one year before admission.
Figure 1. Histological findings of a liver biopsy specimen obtained eight years before admission. a, b) Lymphocyte infiltration in the portal area and severe bile duct loss were observed (Hematoxylin and Eosin staining). c) Azan-Mallory staining showed moderate fibrosis in the liver that was consistent with Nakanuma stage 3 and Scheuer stage III classifications.
On an examination at the time of admission, the patient was 165 cm tall, weighed 68 kg, and had a body mass index of 25.0 kg/m2. Her vital signs included Glasgow Coma Scale score E4V5M6, body temperature 37.3 °C, and blood pressure 111/54 mmHg. She exhibited conjunctival and systemic jaundice and front chest vascular spider but no flapping tremor. Laboratory tests on admission revealed elevated serum aspartate aminotransferase (78 U/L), ALT (100 U/L), gamma-glutamyl transpeptidase (105 U/L), alkaline phosphatase (702 U/L), total bilirubin (30.1 mg/dL), and Mac-2-binding protein glycan isomer (M2BPGi) (7.4 C・O・I) but a reduced platelet count (7.2×104/μL), albumin (2.7 g/dL), and prothrombin time activity (67.7%) (Table 1). Testing for hepatitis A virus antibody (immunoglobulin M), hepatitis B virus surface antigen, and anti-hepatitis C virus (HCV) antibody was negative. Serum antibodies to the Epstein-Barr virus and cytomegalovirus both showed a historical infection pattern. Although serum alpha fetoprotein levels were within normal range, levels of protein induced by vitamin K absence or antagonist II were mildly elevated (152 mAU/mL). Among the autoantibodies tested, fluorescent anti-nuclear antibody (× 640) and anti-mitochondrial M2 antibody (168.1 Index) were positive.
Table 1. Laboratory Findings on Admission.
Blood Chemistry / Serology Viral markers
White blood cell count 5,760 /μL Total protein 5.9 g/dL IgM-HAV Ab (-)
Neutrophils 71.2 % Albumin 2.7 g/dL HBs-Ag 0.001 (-) U/mL
Lymphocytes 19.8 % AST 78 U/L HBs-Ab 0.4 (-) mIU/mL
Monocytes 5.7 % ALT 100 U/L HBc-Ab 0.2 (-) C·O·I
Eosinophils 3.0 % Total bilirubin 30.14 mg/dL IgM-HBc Ab (-)
Basophils 0.3 % GGT 105 U/L HCV-Ab 0.1 (-) C·O·I
Red blood cell count 418 ×104/μL ALP 702 U/L IgM-EBV VCA Ab <10 (-) ×
Hemoglobin 13.1 g/dL BUN 12 mg/dL IgG-EBV VCA Ab 40 (+)
Hematocrit 37.4 % Creatinine 0.59 mg/dL EBV EBNA Ab <10 (-) ×
Platelet count 7.2 ×104/μL NH3 29 μg/dL IgM-CMV Ab 0.29 (-) Index
CRP 1.61 mg/dL IgG-CMV Ab 133.6 (+) AU/mL
Coagulation HbA1c 4.2 % IgA-HEV Ab (+)
PT 67.7 % IgM 139 mg/dL
APTT 29.0 sec IgA 292 mg/dL Autoimmune antibodies
Fibrinogen 192.0 mg/dL IgG 1,156 mg/dL FANA 640 ×
D-dimer 2.3 μg/mL M2BPGi 7.4 C·O·I AMA2 168.1 Index
Anti-centromere antibody (-)
Tumor markers LKM-1 (-)
AFP 7.0 ng/mL ASMA (-)
PIVKA II 152 mAU/mL
PT: prothrombin time, APTT: activated partial thromboplastin time, AST: aspartate aminotransferase, ALT: alanine aminotransferase, GGT: gamma-glutamyl transpeptidase, ALP: alkaline phosphatase, BUN: blood urea nitrogen, CRP: C-reactive protein, HbA1c: hemoglobin A1c, M2BPGi: Mac 2-Binding Protein Gylcan Isomer, AFP: alpha fetoprotein, PIVKA II: protein induced by vitamin K absence or antagonist II, FANA: fluorescent anti-nuclear antibody, AMA2: anti-mitochondrial M2 antibody, LKM-1: anti-liver/kidney microsome type 1 antibody, ASMA: anti-smooth muscle antibody, C·O·I: cut off index
Abdominal ultrasonography showed surface irregularity and a coarse parenchyma echotexture of the liver, suggesting cirrhosis (Fig. 2a). Abdominal contrast-enhanced computed tomography portal phase images showed surface undulation of the liver, collateral circulation around the stomach and splenic hilum, and ascites on the surface of the liver and spleen (Fig. 2b). No evidence suggestive of acute hepatitis, such as periportal collar sign, gallbladder atrophy, or wall thickening, was observed, nor were any space-occupying lesions present in the liver.
Figure 2. a) Abdominal ultrasonography showed liver surface irregularity (arrowheads) and a coarse parenchyma echotexture. b) Abdominal contrast-enhanced computed tomography portal phase images revealed surface undulation of the liver, collateral circulation around the stomach and splenic hilum (arrows), and ascites on the surface of the liver and spleen.
Based on the patient’s clinical findings, we suspected that her cirrhotic PBC had deteriorated acutely for some reason. Although she did not meet the criteria for acute liver failure, the presence of severe jaundice and ascites indicated the need for liver transplantation. After being refused for this treatment, we provided supportive care, including bed rest, lactulose administration, and albumin replacement. On day 13 of admission, HEV-IgA antibody was found to be positive in an admission blood sample, suggesting an association between the exacerbation of her PBC and acute HEV infection. However, the patient’s liver atrophy and renal failure were beyond treatment. Her general condition progressively worsened, and she passed away on day 18 of admission. The entire clinical course is summarized in Fig. 3.
Figure 3. Clinical course of the patient. ALT: alanine aminotransferase, PT: prothrombin time, T-Bil: Total bilirubin, Cre: Creatinine, HEV: Hepatitis E virus
A pathological autopsy was performed after obtaining informed consent from her family. Macroscopically, the surface of the liver was atrophied in a nodular manner, indicating complete cirrhosis (Fig. 4a). Microscopic observation of the liver showed severe atrophy with submassive loss and necrosis of hepatocytes from Zone 3 to Zone 2 of the hepatic lobule (Fig. 4b). However, the distribution did not match the centrilobular necrosis typically observed in hepatic ischemia. In some areas, hepatocytes around the central vein were intact (Fig. 4c). In addition, there was no remarkable steatosis inside hepatocytes indicative of hypoxia (Fig. 4c). Based on these findings, hepatic ischemia was not considered as the main cause of submassive loss and necrosis in this case. Although cholestasis was prominent in the lobules, inflammatory cell infiltration related to acute hepatitis was not evident (Fig. 4b, c). Regenerated nodules and highly fibrous septum formation were found in the liver, which were histologically consistent with cirrhosis (Fig. 4d). In the portal area, the infiltration of mononuclear cells and disappearance of bile ducts suggested advanced PBC (Fig. 4e). Extensive bile duct loss was confirmed between the interlobular and septal bile duct levels.
Figure 4. Autopsy findings. a) Macroscopically, the surface of the liver was atrophied in a nodular manner, indicating complete cirrhosis. b) Severe atrophy with submassive loss and necrosis of hepatocytes (red dotted lines) from Zone 3 to Zone 2 of the hepatic lobule were evident (Hematoxylin and Eosin staining). P: portal vein, C: central vein. c) In some areas, hepatocytes around the central vein were relatively intact, with no steatosis inside hepatocytes suggestive of hypoxia. Cholestasis was prominent in the lobules. Inflammatory cell infiltration indicative of acute hepatitis was not detected. d) On Elastica-Goldner staining, regenerated nodules and highly fibrous septum formation were found in the liver, findings that were histologically consistent with cirrhosis. e) In the portal area, infiltration of mononuclear cells and the disappearance of bile ducts were observed, suggesting advanced PBC. P: portal vein
HEV antibodies (IgG, IgM, and IgA) were measured by an enzyme-linked immunosorbent assay using frozen serum samples according to a previously described method (18). The testing results are shown in Table 2 along with the corresponding hepatobiliary enzymes at each time point. HEV RNA was detected by the nested reverse-transcription polymerase chain reaction with primers targeting the open reading frame 2 (ORF2) region of the HEV genome (nucleotide position 5944-6355, excluding primer sequences at both ends: M73218), as described previously (19). HEV RNA, which had been negative at the last visit before admission, had become positive at admission along with increases in all classes of HEV antibodies. HEV RNA became undetectable during the deterioration of her condition, although a high antibody titer persisted. We determined her 412-nucleotide ORF2 sequence and constructed a molecular phylogenetic tree according to a previously described method (20) (Fig. 5). The HEV strain (HE-JA19-0280: DDBJ/EMBL/GenBank accession number LC581383) derived from this case belonged to genotype 3 (subgenotype 3b) and was closest to those of patients recovering from acute hepatitis E in Tokyo and Gunma Prefectures of Japan.
Figure 5. Phylogenetic tree constructed by the neighbor-joining method based on the partial nucleotide sequence (412 nucleotides) of the open reading frame 2 region of hepatitis E virus (HEV) isolates. In addition to the HEV isolate (HE-JA19-0280) obtained in the present study (highlighted with a closed box), 33 representative genotype 3 isolates (subgenotype 3a: n=8, subgenotype 3b: n=22, and subgenotype 3e: n=3), whose entire genomic sequence is known, are included in the tree using the prototype HEV sequences of genotype 1 (M73218), genotype 2 (M74506), and genotype 4 (AJ272108) as outgroups. Three HEV isolates sharing the highest identity of 97.1-97.8% with the HE-JA19-0280 isolate are also included. Each reference sequence is shown with the genotype/subgenotype followed by the accession number, isolate name, and country in which it was isolated. The bootstrap values (>70%) are indicated for nodes as the percentage of data among 1,000 resampling procedures. The scale bar is in units of nuceotide substitutions per site.
Table 2. Transition of Hepatobiliary Enzymes, HEV Antibodies, and HEV RNA.
Day Laboratory data HEV antibodies HEV RNA
AST
(U/L) ALT
(U/L) GGT
(U/L) ALP
(U/L) T-Bil
(mg/dL) IgG (OD450) IgM (OD450) IgA (OD450)
X - 80 137 111 413 940 3.4 0.010 (-) 0.046 (-) 0.020 (-) Negative
X (admission) 78 100 105 702 30.1 1.661 (+) >3.000 (+) 2.374 (+) +: 1.0×101 copies/mL
X+1 69 80 87 588 26.6 1.578 (+) >3.000 (+) 2.346 (+) +: 1.2×101 copies/mL
X+11 43 44 64 568 39.7 1.850 (+) >3.000 (+) 2.002 (+) Negative
X+14 61 66 78 631 46.7 1.970 (+) >3.000 (+) 1.768 (+) Negative
HEV: hepatitis E virus, AST: aspartate aminotransferase, ALT: alanine aminotransferase, GGT: gamma-glutamyl transpeptidase, ALP: alkaline phosphatase, T-Bil: total bilirubin
Discussion
The present autopsy case displayed histological evidence of submassive necrosis in the liver caused by acute HEV infection. The patient was presumed to have been at the liver cirrhosis stage of PBC but suddenly developed severe jaundice due to superimposed HEV infection and succumbed one month later to hepatic failure. The histopathological findings of severe liver atrophy with submassive loss and necrosis of hepatocytes could not be explained by ischemia only, strongly suggesting the involvement of genotype 3b HEV infection in her histopathological findings.
Although PBC patients generally have a normal life expectancy, they sometimes show rapid disease exacerbation due to concomitant autoimmune hepatitis (7,21) or simultaneous HCV infection (22) as a trigger of PBC deterioration. One rare instance of PBC with acute HEV infection has been reported to date (15). To our knowledge, however, an autopsy case of rapid deterioration triggered by HEV infection has not yet been described. As the mechanism underlying PBC exacerbation due to viral hepatitis infection remains unknown, the present case may contribute to the body of knowledge concerning this condition.
HEV is one of the most common causes of acute viral hepatitis (23). In addition to contaminated water, raw meat from pigs, boars, and deer is another common infection source (24-26). Recently, the prevalence of HEV cases without clinical symptoms as well as those of unknown transmission route has been increasing (27). The infection route in the present case could not be identified based on our medical interview. According to previous reports, pregnancy, old age, alcohol intake, and fatty liver are host factors associated with the aggravation of HEV, and co-infection with chronic liver disease is related to the risk of liver failure (13,14). Regarding the HEV genotype, HEV genotype 4 infection is reportedly associated with aggravation (26,28,29). Genotype 3 HEV, as detected in this case, is generally associated with a low tendency of severe clinical manifestations, although a rare case of progressive genotype 3 HEV infection has been reported (28). A mutation of V239A in the helicase region of the genotype 3 HEV genome has been associated with HEV infection aggravation (30). That mutant was absent in this case (data not shown). The patient had no other apparent host or viral factors associated with HEV severity. However, Wang et al. reported that the cirrhosis stage itself carries a potential risk of liver failure due to HEV infection, regardless of etiology; they further described the potentiation of the cirrhotic liver upon HEV infection and more aggressive immune- or inflammatory-mediated activation of cell death in a cirrhotic liver status as possible mechanisms of exacerbation (15). The above results suggested that even if patients have no documented risk factors of HEV aggravation, clinicians should bear in mind that HEV infection at a cirrhotic liver disease stage can become severe.
This patient had been diagnosed with PBC 26 years earlier based on serological criteria. Eight years before admission, she was already at an advanced stage of PBC, with Nakanuma stage 3 and Scheuer stage III classifications according to a liver biopsy. An autopsy specimen of the liver revealed obvious cirrhosis, which was consistent with the natural history of PBC as suggested by elevated serum surrogate markers of M2BPGi (31,32). However, the submassive loss and necrosis of hepatocytes could not solely be explained by the natural PBC history. Inflammatory cell infiltration suggesting acute hepatitis E (33) was not observed, which suggested a post-inflammatory status. Other general clinical features of acute hepatitis, including markedly elevated levels of liver enzymes, were absent as well. Her liver enzymes were only mildly elevated at day X-80, suggesting that asymptomatic hepatitis may have started at that point, followed by further increases in transaminase levels. Thus, one explanation as to why this case showed mild hepatitis was that the hepatitis had occurred after day X-80 and already peaked and ameliorated by the time of admission, such that jaundice represented the major feature. However, no clinical data were available between the patient’s last outpatient visit at day X-80 and her hospitalization. Another hypothesis was that this case had already reached the complete cirrhosis stage, as shown by the pathological findings, which could have induced mild liver enzyme elevations (34).
Patients with hepatitis E sometimes show severe jaundice (35). Although the underlying mechanism is uncertain, HEV has been reported to exhibit not only hepatocytic but also biliary tropism and replicate within bile duct epithelial cells (36,37). The severe jaundice and cholestasis in this case might have been the result of HEV infection complicating the chronic cholestatic liver disease of PBC. The fact that jaundice was more pronounced than elevated liver enzyme levels may support this notion. Although drug-induced liver injury (levofloxacin 500 mg/day) cannot be ruled out, we suspected that HEV infection likely triggered the exacerbation of PBC due to her awareness of jaundice prior to drug administration and the histological considerations described above.
In conclusion, clinicians should consider the possibility of acute HEV infection as a trigger for the acute exacerbation of PBC. In such cases, it may be necessary to treat the patient with the anticipation of severe aggravation.
The authors state that they have no Conflict of Interest (COI).
Acknowledgement
We thank Trevor Ralph for his English editorial assistance. | BEZAFIBRATE, LEVOFLOXACIN, URSODIOL | DrugsGivenReaction | CC BY-NC-ND | 33518570 | 19,677,427 | 2021-06-15 |
Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Hepatic cirrhosis'. | An Autopsy Case of Primary Biliary Cholangitis with Histological Submassive Hepatic Necrosis Caused by Acute Hepatitis E Virus Infection.
A 59-year-old woman who had been diagnosed with cirrhotic primary biliary cholangitis (PBC) 5 years earlier was admitted for severe jaundice (total bilirubin: 30.1 mg/dL). We suspected that her cirrhotic PBC had deteriorated acutely for some reason. Her general condition deteriorated quickly, and she passed away on day 18 of admission. Hepatitis E virus (HEV)-IgA antibodies were positive, and Genotype 3b HEV involvement was confirmed from a blood sample taken on admission. Histopathological findings revealed cirrhosis and submassive loss and necrosis of hepatocytes. Clinicians should consider the possibility of acute HEV infection as a trigger for acute PBC exacerbation.
Introduction
Primary biliary cholangitis (PBC) is a chronic and slowly progressive cholestatic autoimmune liver disease that is histopathologically characterized by an attack on the small intralobular bile duct by T lymphocytes (1). The precise etiology of PBC remains unknown but is related to genetic susceptibility environmental factors (2-4). Although most patients with PBC are asymptomatic and have a normal life expectancy, clinicians sometimes encounter symptomatic PBC cases with severe jaundice or liver failure as a result of the sustained loss of intralobular bile ducts in spite of ursodeoxycholic acid (UDCA) therapy (5,6). Patients with concomitant acute liver injury from autoimmune hepatitis show particularly rapid disease progression (7). The acute exacerbation of PBC from hepatitis virus co-infection is rare in the clinical setting.
The hepatitis E virus (HEV) is a quasi-enveloped, single-stranded RNA virus that causes acute or chronic hepatitis (8,9). With the increase in the number of hepatitis E cases, HEV antibody is now positive in approximately 5% of the general population in Japan (10,11). Among HEV-associated acute hepatitis cases, 0.5-4% of patients progress to fulminant hepatitis (12), leading to high mortality when intensive care and liver transplantation are unavailable. Rare cases of severe acute HEV hepatitis underlying such chronic liver diseases as alcoholic liver disease, nonalcoholic fatty liver disease, chronic viral hepatitis, and PBC have been documented as well (13-15). No autopsy PBC cases displaying acute exacerbation due to superimposed acute HEV infection have been reported to date.
We herein report the autopsy findings of a PBC case in the cirrhotic stage with histological submassive hepatic necrosis caused by acute HEV infection.
Case Report
A 59-year-old woman who had been serologically diagnosed with PBC after the detection of liver dysfunction 26 years earlier was admitted to our hospital for severe jaundice, brown urine, and leg edema. She had suffered from cold-like symptoms and skin jaundice for a month and had received antitussives and antibiotics (levofloxacin 500 mg/day) from her attending physician 2 weeks before admission. She had no symptoms of diarrhea, vomiting, or a history of eating raw meat. She reported no regular ethanol consumption or travel to a foreign country. Although she had been prescribed 600 mg/day UDCA and 400 mg/day bezafibrate for PBC, her medication compliance was extremely poor. She had persistent liver dysfunction [alanine aminotransferase (ALT) at around 100 U/L] and jaundice (total bilirubin at around 3 mg/dL). Eight years before admission, the histological findings of a liver biopsy specimen showed lymphocyte infiltration in the portal area and severe bile duct loss that were consistent with Nakanuma stage 3 (16) and Scheuer stage III (17) classifications (Fig. 1). Three years later, she was clinically diagnosed with cirrhosis-stage PBC. She had also undergone endoscopic gastric varices treatment one year before admission.
Figure 1. Histological findings of a liver biopsy specimen obtained eight years before admission. a, b) Lymphocyte infiltration in the portal area and severe bile duct loss were observed (Hematoxylin and Eosin staining). c) Azan-Mallory staining showed moderate fibrosis in the liver that was consistent with Nakanuma stage 3 and Scheuer stage III classifications.
On an examination at the time of admission, the patient was 165 cm tall, weighed 68 kg, and had a body mass index of 25.0 kg/m2. Her vital signs included Glasgow Coma Scale score E4V5M6, body temperature 37.3 °C, and blood pressure 111/54 mmHg. She exhibited conjunctival and systemic jaundice and front chest vascular spider but no flapping tremor. Laboratory tests on admission revealed elevated serum aspartate aminotransferase (78 U/L), ALT (100 U/L), gamma-glutamyl transpeptidase (105 U/L), alkaline phosphatase (702 U/L), total bilirubin (30.1 mg/dL), and Mac-2-binding protein glycan isomer (M2BPGi) (7.4 C・O・I) but a reduced platelet count (7.2×104/μL), albumin (2.7 g/dL), and prothrombin time activity (67.7%) (Table 1). Testing for hepatitis A virus antibody (immunoglobulin M), hepatitis B virus surface antigen, and anti-hepatitis C virus (HCV) antibody was negative. Serum antibodies to the Epstein-Barr virus and cytomegalovirus both showed a historical infection pattern. Although serum alpha fetoprotein levels were within normal range, levels of protein induced by vitamin K absence or antagonist II were mildly elevated (152 mAU/mL). Among the autoantibodies tested, fluorescent anti-nuclear antibody (× 640) and anti-mitochondrial M2 antibody (168.1 Index) were positive.
Table 1. Laboratory Findings on Admission.
Blood Chemistry / Serology Viral markers
White blood cell count 5,760 /μL Total protein 5.9 g/dL IgM-HAV Ab (-)
Neutrophils 71.2 % Albumin 2.7 g/dL HBs-Ag 0.001 (-) U/mL
Lymphocytes 19.8 % AST 78 U/L HBs-Ab 0.4 (-) mIU/mL
Monocytes 5.7 % ALT 100 U/L HBc-Ab 0.2 (-) C·O·I
Eosinophils 3.0 % Total bilirubin 30.14 mg/dL IgM-HBc Ab (-)
Basophils 0.3 % GGT 105 U/L HCV-Ab 0.1 (-) C·O·I
Red blood cell count 418 ×104/μL ALP 702 U/L IgM-EBV VCA Ab <10 (-) ×
Hemoglobin 13.1 g/dL BUN 12 mg/dL IgG-EBV VCA Ab 40 (+)
Hematocrit 37.4 % Creatinine 0.59 mg/dL EBV EBNA Ab <10 (-) ×
Platelet count 7.2 ×104/μL NH3 29 μg/dL IgM-CMV Ab 0.29 (-) Index
CRP 1.61 mg/dL IgG-CMV Ab 133.6 (+) AU/mL
Coagulation HbA1c 4.2 % IgA-HEV Ab (+)
PT 67.7 % IgM 139 mg/dL
APTT 29.0 sec IgA 292 mg/dL Autoimmune antibodies
Fibrinogen 192.0 mg/dL IgG 1,156 mg/dL FANA 640 ×
D-dimer 2.3 μg/mL M2BPGi 7.4 C·O·I AMA2 168.1 Index
Anti-centromere antibody (-)
Tumor markers LKM-1 (-)
AFP 7.0 ng/mL ASMA (-)
PIVKA II 152 mAU/mL
PT: prothrombin time, APTT: activated partial thromboplastin time, AST: aspartate aminotransferase, ALT: alanine aminotransferase, GGT: gamma-glutamyl transpeptidase, ALP: alkaline phosphatase, BUN: blood urea nitrogen, CRP: C-reactive protein, HbA1c: hemoglobin A1c, M2BPGi: Mac 2-Binding Protein Gylcan Isomer, AFP: alpha fetoprotein, PIVKA II: protein induced by vitamin K absence or antagonist II, FANA: fluorescent anti-nuclear antibody, AMA2: anti-mitochondrial M2 antibody, LKM-1: anti-liver/kidney microsome type 1 antibody, ASMA: anti-smooth muscle antibody, C·O·I: cut off index
Abdominal ultrasonography showed surface irregularity and a coarse parenchyma echotexture of the liver, suggesting cirrhosis (Fig. 2a). Abdominal contrast-enhanced computed tomography portal phase images showed surface undulation of the liver, collateral circulation around the stomach and splenic hilum, and ascites on the surface of the liver and spleen (Fig. 2b). No evidence suggestive of acute hepatitis, such as periportal collar sign, gallbladder atrophy, or wall thickening, was observed, nor were any space-occupying lesions present in the liver.
Figure 2. a) Abdominal ultrasonography showed liver surface irregularity (arrowheads) and a coarse parenchyma echotexture. b) Abdominal contrast-enhanced computed tomography portal phase images revealed surface undulation of the liver, collateral circulation around the stomach and splenic hilum (arrows), and ascites on the surface of the liver and spleen.
Based on the patient’s clinical findings, we suspected that her cirrhotic PBC had deteriorated acutely for some reason. Although she did not meet the criteria for acute liver failure, the presence of severe jaundice and ascites indicated the need for liver transplantation. After being refused for this treatment, we provided supportive care, including bed rest, lactulose administration, and albumin replacement. On day 13 of admission, HEV-IgA antibody was found to be positive in an admission blood sample, suggesting an association between the exacerbation of her PBC and acute HEV infection. However, the patient’s liver atrophy and renal failure were beyond treatment. Her general condition progressively worsened, and she passed away on day 18 of admission. The entire clinical course is summarized in Fig. 3.
Figure 3. Clinical course of the patient. ALT: alanine aminotransferase, PT: prothrombin time, T-Bil: Total bilirubin, Cre: Creatinine, HEV: Hepatitis E virus
A pathological autopsy was performed after obtaining informed consent from her family. Macroscopically, the surface of the liver was atrophied in a nodular manner, indicating complete cirrhosis (Fig. 4a). Microscopic observation of the liver showed severe atrophy with submassive loss and necrosis of hepatocytes from Zone 3 to Zone 2 of the hepatic lobule (Fig. 4b). However, the distribution did not match the centrilobular necrosis typically observed in hepatic ischemia. In some areas, hepatocytes around the central vein were intact (Fig. 4c). In addition, there was no remarkable steatosis inside hepatocytes indicative of hypoxia (Fig. 4c). Based on these findings, hepatic ischemia was not considered as the main cause of submassive loss and necrosis in this case. Although cholestasis was prominent in the lobules, inflammatory cell infiltration related to acute hepatitis was not evident (Fig. 4b, c). Regenerated nodules and highly fibrous septum formation were found in the liver, which were histologically consistent with cirrhosis (Fig. 4d). In the portal area, the infiltration of mononuclear cells and disappearance of bile ducts suggested advanced PBC (Fig. 4e). Extensive bile duct loss was confirmed between the interlobular and septal bile duct levels.
Figure 4. Autopsy findings. a) Macroscopically, the surface of the liver was atrophied in a nodular manner, indicating complete cirrhosis. b) Severe atrophy with submassive loss and necrosis of hepatocytes (red dotted lines) from Zone 3 to Zone 2 of the hepatic lobule were evident (Hematoxylin and Eosin staining). P: portal vein, C: central vein. c) In some areas, hepatocytes around the central vein were relatively intact, with no steatosis inside hepatocytes suggestive of hypoxia. Cholestasis was prominent in the lobules. Inflammatory cell infiltration indicative of acute hepatitis was not detected. d) On Elastica-Goldner staining, regenerated nodules and highly fibrous septum formation were found in the liver, findings that were histologically consistent with cirrhosis. e) In the portal area, infiltration of mononuclear cells and the disappearance of bile ducts were observed, suggesting advanced PBC. P: portal vein
HEV antibodies (IgG, IgM, and IgA) were measured by an enzyme-linked immunosorbent assay using frozen serum samples according to a previously described method (18). The testing results are shown in Table 2 along with the corresponding hepatobiliary enzymes at each time point. HEV RNA was detected by the nested reverse-transcription polymerase chain reaction with primers targeting the open reading frame 2 (ORF2) region of the HEV genome (nucleotide position 5944-6355, excluding primer sequences at both ends: M73218), as described previously (19). HEV RNA, which had been negative at the last visit before admission, had become positive at admission along with increases in all classes of HEV antibodies. HEV RNA became undetectable during the deterioration of her condition, although a high antibody titer persisted. We determined her 412-nucleotide ORF2 sequence and constructed a molecular phylogenetic tree according to a previously described method (20) (Fig. 5). The HEV strain (HE-JA19-0280: DDBJ/EMBL/GenBank accession number LC581383) derived from this case belonged to genotype 3 (subgenotype 3b) and was closest to those of patients recovering from acute hepatitis E in Tokyo and Gunma Prefectures of Japan.
Figure 5. Phylogenetic tree constructed by the neighbor-joining method based on the partial nucleotide sequence (412 nucleotides) of the open reading frame 2 region of hepatitis E virus (HEV) isolates. In addition to the HEV isolate (HE-JA19-0280) obtained in the present study (highlighted with a closed box), 33 representative genotype 3 isolates (subgenotype 3a: n=8, subgenotype 3b: n=22, and subgenotype 3e: n=3), whose entire genomic sequence is known, are included in the tree using the prototype HEV sequences of genotype 1 (M73218), genotype 2 (M74506), and genotype 4 (AJ272108) as outgroups. Three HEV isolates sharing the highest identity of 97.1-97.8% with the HE-JA19-0280 isolate are also included. Each reference sequence is shown with the genotype/subgenotype followed by the accession number, isolate name, and country in which it was isolated. The bootstrap values (>70%) are indicated for nodes as the percentage of data among 1,000 resampling procedures. The scale bar is in units of nuceotide substitutions per site.
Table 2. Transition of Hepatobiliary Enzymes, HEV Antibodies, and HEV RNA.
Day Laboratory data HEV antibodies HEV RNA
AST
(U/L) ALT
(U/L) GGT
(U/L) ALP
(U/L) T-Bil
(mg/dL) IgG (OD450) IgM (OD450) IgA (OD450)
X - 80 137 111 413 940 3.4 0.010 (-) 0.046 (-) 0.020 (-) Negative
X (admission) 78 100 105 702 30.1 1.661 (+) >3.000 (+) 2.374 (+) +: 1.0×101 copies/mL
X+1 69 80 87 588 26.6 1.578 (+) >3.000 (+) 2.346 (+) +: 1.2×101 copies/mL
X+11 43 44 64 568 39.7 1.850 (+) >3.000 (+) 2.002 (+) Negative
X+14 61 66 78 631 46.7 1.970 (+) >3.000 (+) 1.768 (+) Negative
HEV: hepatitis E virus, AST: aspartate aminotransferase, ALT: alanine aminotransferase, GGT: gamma-glutamyl transpeptidase, ALP: alkaline phosphatase, T-Bil: total bilirubin
Discussion
The present autopsy case displayed histological evidence of submassive necrosis in the liver caused by acute HEV infection. The patient was presumed to have been at the liver cirrhosis stage of PBC but suddenly developed severe jaundice due to superimposed HEV infection and succumbed one month later to hepatic failure. The histopathological findings of severe liver atrophy with submassive loss and necrosis of hepatocytes could not be explained by ischemia only, strongly suggesting the involvement of genotype 3b HEV infection in her histopathological findings.
Although PBC patients generally have a normal life expectancy, they sometimes show rapid disease exacerbation due to concomitant autoimmune hepatitis (7,21) or simultaneous HCV infection (22) as a trigger of PBC deterioration. One rare instance of PBC with acute HEV infection has been reported to date (15). To our knowledge, however, an autopsy case of rapid deterioration triggered by HEV infection has not yet been described. As the mechanism underlying PBC exacerbation due to viral hepatitis infection remains unknown, the present case may contribute to the body of knowledge concerning this condition.
HEV is one of the most common causes of acute viral hepatitis (23). In addition to contaminated water, raw meat from pigs, boars, and deer is another common infection source (24-26). Recently, the prevalence of HEV cases without clinical symptoms as well as those of unknown transmission route has been increasing (27). The infection route in the present case could not be identified based on our medical interview. According to previous reports, pregnancy, old age, alcohol intake, and fatty liver are host factors associated with the aggravation of HEV, and co-infection with chronic liver disease is related to the risk of liver failure (13,14). Regarding the HEV genotype, HEV genotype 4 infection is reportedly associated with aggravation (26,28,29). Genotype 3 HEV, as detected in this case, is generally associated with a low tendency of severe clinical manifestations, although a rare case of progressive genotype 3 HEV infection has been reported (28). A mutation of V239A in the helicase region of the genotype 3 HEV genome has been associated with HEV infection aggravation (30). That mutant was absent in this case (data not shown). The patient had no other apparent host or viral factors associated with HEV severity. However, Wang et al. reported that the cirrhosis stage itself carries a potential risk of liver failure due to HEV infection, regardless of etiology; they further described the potentiation of the cirrhotic liver upon HEV infection and more aggressive immune- or inflammatory-mediated activation of cell death in a cirrhotic liver status as possible mechanisms of exacerbation (15). The above results suggested that even if patients have no documented risk factors of HEV aggravation, clinicians should bear in mind that HEV infection at a cirrhotic liver disease stage can become severe.
This patient had been diagnosed with PBC 26 years earlier based on serological criteria. Eight years before admission, she was already at an advanced stage of PBC, with Nakanuma stage 3 and Scheuer stage III classifications according to a liver biopsy. An autopsy specimen of the liver revealed obvious cirrhosis, which was consistent with the natural history of PBC as suggested by elevated serum surrogate markers of M2BPGi (31,32). However, the submassive loss and necrosis of hepatocytes could not solely be explained by the natural PBC history. Inflammatory cell infiltration suggesting acute hepatitis E (33) was not observed, which suggested a post-inflammatory status. Other general clinical features of acute hepatitis, including markedly elevated levels of liver enzymes, were absent as well. Her liver enzymes were only mildly elevated at day X-80, suggesting that asymptomatic hepatitis may have started at that point, followed by further increases in transaminase levels. Thus, one explanation as to why this case showed mild hepatitis was that the hepatitis had occurred after day X-80 and already peaked and ameliorated by the time of admission, such that jaundice represented the major feature. However, no clinical data were available between the patient’s last outpatient visit at day X-80 and her hospitalization. Another hypothesis was that this case had already reached the complete cirrhosis stage, as shown by the pathological findings, which could have induced mild liver enzyme elevations (34).
Patients with hepatitis E sometimes show severe jaundice (35). Although the underlying mechanism is uncertain, HEV has been reported to exhibit not only hepatocytic but also biliary tropism and replicate within bile duct epithelial cells (36,37). The severe jaundice and cholestasis in this case might have been the result of HEV infection complicating the chronic cholestatic liver disease of PBC. The fact that jaundice was more pronounced than elevated liver enzyme levels may support this notion. Although drug-induced liver injury (levofloxacin 500 mg/day) cannot be ruled out, we suspected that HEV infection likely triggered the exacerbation of PBC due to her awareness of jaundice prior to drug administration and the histological considerations described above.
In conclusion, clinicians should consider the possibility of acute HEV infection as a trigger for the acute exacerbation of PBC. In such cases, it may be necessary to treat the patient with the anticipation of severe aggravation.
The authors state that they have no Conflict of Interest (COI).
Acknowledgement
We thank Trevor Ralph for his English editorial assistance. | BEZAFIBRATE, LEVOFLOXACIN, URSODIOL | DrugsGivenReaction | CC BY-NC-ND | 33518570 | 19,677,427 | 2021-06-15 |
Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Hepatic failure'. | An Autopsy Case of Primary Biliary Cholangitis with Histological Submassive Hepatic Necrosis Caused by Acute Hepatitis E Virus Infection.
A 59-year-old woman who had been diagnosed with cirrhotic primary biliary cholangitis (PBC) 5 years earlier was admitted for severe jaundice (total bilirubin: 30.1 mg/dL). We suspected that her cirrhotic PBC had deteriorated acutely for some reason. Her general condition deteriorated quickly, and she passed away on day 18 of admission. Hepatitis E virus (HEV)-IgA antibodies were positive, and Genotype 3b HEV involvement was confirmed from a blood sample taken on admission. Histopathological findings revealed cirrhosis and submassive loss and necrosis of hepatocytes. Clinicians should consider the possibility of acute HEV infection as a trigger for acute PBC exacerbation.
Introduction
Primary biliary cholangitis (PBC) is a chronic and slowly progressive cholestatic autoimmune liver disease that is histopathologically characterized by an attack on the small intralobular bile duct by T lymphocytes (1). The precise etiology of PBC remains unknown but is related to genetic susceptibility environmental factors (2-4). Although most patients with PBC are asymptomatic and have a normal life expectancy, clinicians sometimes encounter symptomatic PBC cases with severe jaundice or liver failure as a result of the sustained loss of intralobular bile ducts in spite of ursodeoxycholic acid (UDCA) therapy (5,6). Patients with concomitant acute liver injury from autoimmune hepatitis show particularly rapid disease progression (7). The acute exacerbation of PBC from hepatitis virus co-infection is rare in the clinical setting.
The hepatitis E virus (HEV) is a quasi-enveloped, single-stranded RNA virus that causes acute or chronic hepatitis (8,9). With the increase in the number of hepatitis E cases, HEV antibody is now positive in approximately 5% of the general population in Japan (10,11). Among HEV-associated acute hepatitis cases, 0.5-4% of patients progress to fulminant hepatitis (12), leading to high mortality when intensive care and liver transplantation are unavailable. Rare cases of severe acute HEV hepatitis underlying such chronic liver diseases as alcoholic liver disease, nonalcoholic fatty liver disease, chronic viral hepatitis, and PBC have been documented as well (13-15). No autopsy PBC cases displaying acute exacerbation due to superimposed acute HEV infection have been reported to date.
We herein report the autopsy findings of a PBC case in the cirrhotic stage with histological submassive hepatic necrosis caused by acute HEV infection.
Case Report
A 59-year-old woman who had been serologically diagnosed with PBC after the detection of liver dysfunction 26 years earlier was admitted to our hospital for severe jaundice, brown urine, and leg edema. She had suffered from cold-like symptoms and skin jaundice for a month and had received antitussives and antibiotics (levofloxacin 500 mg/day) from her attending physician 2 weeks before admission. She had no symptoms of diarrhea, vomiting, or a history of eating raw meat. She reported no regular ethanol consumption or travel to a foreign country. Although she had been prescribed 600 mg/day UDCA and 400 mg/day bezafibrate for PBC, her medication compliance was extremely poor. She had persistent liver dysfunction [alanine aminotransferase (ALT) at around 100 U/L] and jaundice (total bilirubin at around 3 mg/dL). Eight years before admission, the histological findings of a liver biopsy specimen showed lymphocyte infiltration in the portal area and severe bile duct loss that were consistent with Nakanuma stage 3 (16) and Scheuer stage III (17) classifications (Fig. 1). Three years later, she was clinically diagnosed with cirrhosis-stage PBC. She had also undergone endoscopic gastric varices treatment one year before admission.
Figure 1. Histological findings of a liver biopsy specimen obtained eight years before admission. a, b) Lymphocyte infiltration in the portal area and severe bile duct loss were observed (Hematoxylin and Eosin staining). c) Azan-Mallory staining showed moderate fibrosis in the liver that was consistent with Nakanuma stage 3 and Scheuer stage III classifications.
On an examination at the time of admission, the patient was 165 cm tall, weighed 68 kg, and had a body mass index of 25.0 kg/m2. Her vital signs included Glasgow Coma Scale score E4V5M6, body temperature 37.3 °C, and blood pressure 111/54 mmHg. She exhibited conjunctival and systemic jaundice and front chest vascular spider but no flapping tremor. Laboratory tests on admission revealed elevated serum aspartate aminotransferase (78 U/L), ALT (100 U/L), gamma-glutamyl transpeptidase (105 U/L), alkaline phosphatase (702 U/L), total bilirubin (30.1 mg/dL), and Mac-2-binding protein glycan isomer (M2BPGi) (7.4 C・O・I) but a reduced platelet count (7.2×104/μL), albumin (2.7 g/dL), and prothrombin time activity (67.7%) (Table 1). Testing for hepatitis A virus antibody (immunoglobulin M), hepatitis B virus surface antigen, and anti-hepatitis C virus (HCV) antibody was negative. Serum antibodies to the Epstein-Barr virus and cytomegalovirus both showed a historical infection pattern. Although serum alpha fetoprotein levels were within normal range, levels of protein induced by vitamin K absence or antagonist II were mildly elevated (152 mAU/mL). Among the autoantibodies tested, fluorescent anti-nuclear antibody (× 640) and anti-mitochondrial M2 antibody (168.1 Index) were positive.
Table 1. Laboratory Findings on Admission.
Blood Chemistry / Serology Viral markers
White blood cell count 5,760 /μL Total protein 5.9 g/dL IgM-HAV Ab (-)
Neutrophils 71.2 % Albumin 2.7 g/dL HBs-Ag 0.001 (-) U/mL
Lymphocytes 19.8 % AST 78 U/L HBs-Ab 0.4 (-) mIU/mL
Monocytes 5.7 % ALT 100 U/L HBc-Ab 0.2 (-) C·O·I
Eosinophils 3.0 % Total bilirubin 30.14 mg/dL IgM-HBc Ab (-)
Basophils 0.3 % GGT 105 U/L HCV-Ab 0.1 (-) C·O·I
Red blood cell count 418 ×104/μL ALP 702 U/L IgM-EBV VCA Ab <10 (-) ×
Hemoglobin 13.1 g/dL BUN 12 mg/dL IgG-EBV VCA Ab 40 (+)
Hematocrit 37.4 % Creatinine 0.59 mg/dL EBV EBNA Ab <10 (-) ×
Platelet count 7.2 ×104/μL NH3 29 μg/dL IgM-CMV Ab 0.29 (-) Index
CRP 1.61 mg/dL IgG-CMV Ab 133.6 (+) AU/mL
Coagulation HbA1c 4.2 % IgA-HEV Ab (+)
PT 67.7 % IgM 139 mg/dL
APTT 29.0 sec IgA 292 mg/dL Autoimmune antibodies
Fibrinogen 192.0 mg/dL IgG 1,156 mg/dL FANA 640 ×
D-dimer 2.3 μg/mL M2BPGi 7.4 C·O·I AMA2 168.1 Index
Anti-centromere antibody (-)
Tumor markers LKM-1 (-)
AFP 7.0 ng/mL ASMA (-)
PIVKA II 152 mAU/mL
PT: prothrombin time, APTT: activated partial thromboplastin time, AST: aspartate aminotransferase, ALT: alanine aminotransferase, GGT: gamma-glutamyl transpeptidase, ALP: alkaline phosphatase, BUN: blood urea nitrogen, CRP: C-reactive protein, HbA1c: hemoglobin A1c, M2BPGi: Mac 2-Binding Protein Gylcan Isomer, AFP: alpha fetoprotein, PIVKA II: protein induced by vitamin K absence or antagonist II, FANA: fluorescent anti-nuclear antibody, AMA2: anti-mitochondrial M2 antibody, LKM-1: anti-liver/kidney microsome type 1 antibody, ASMA: anti-smooth muscle antibody, C·O·I: cut off index
Abdominal ultrasonography showed surface irregularity and a coarse parenchyma echotexture of the liver, suggesting cirrhosis (Fig. 2a). Abdominal contrast-enhanced computed tomography portal phase images showed surface undulation of the liver, collateral circulation around the stomach and splenic hilum, and ascites on the surface of the liver and spleen (Fig. 2b). No evidence suggestive of acute hepatitis, such as periportal collar sign, gallbladder atrophy, or wall thickening, was observed, nor were any space-occupying lesions present in the liver.
Figure 2. a) Abdominal ultrasonography showed liver surface irregularity (arrowheads) and a coarse parenchyma echotexture. b) Abdominal contrast-enhanced computed tomography portal phase images revealed surface undulation of the liver, collateral circulation around the stomach and splenic hilum (arrows), and ascites on the surface of the liver and spleen.
Based on the patient’s clinical findings, we suspected that her cirrhotic PBC had deteriorated acutely for some reason. Although she did not meet the criteria for acute liver failure, the presence of severe jaundice and ascites indicated the need for liver transplantation. After being refused for this treatment, we provided supportive care, including bed rest, lactulose administration, and albumin replacement. On day 13 of admission, HEV-IgA antibody was found to be positive in an admission blood sample, suggesting an association between the exacerbation of her PBC and acute HEV infection. However, the patient’s liver atrophy and renal failure were beyond treatment. Her general condition progressively worsened, and she passed away on day 18 of admission. The entire clinical course is summarized in Fig. 3.
Figure 3. Clinical course of the patient. ALT: alanine aminotransferase, PT: prothrombin time, T-Bil: Total bilirubin, Cre: Creatinine, HEV: Hepatitis E virus
A pathological autopsy was performed after obtaining informed consent from her family. Macroscopically, the surface of the liver was atrophied in a nodular manner, indicating complete cirrhosis (Fig. 4a). Microscopic observation of the liver showed severe atrophy with submassive loss and necrosis of hepatocytes from Zone 3 to Zone 2 of the hepatic lobule (Fig. 4b). However, the distribution did not match the centrilobular necrosis typically observed in hepatic ischemia. In some areas, hepatocytes around the central vein were intact (Fig. 4c). In addition, there was no remarkable steatosis inside hepatocytes indicative of hypoxia (Fig. 4c). Based on these findings, hepatic ischemia was not considered as the main cause of submassive loss and necrosis in this case. Although cholestasis was prominent in the lobules, inflammatory cell infiltration related to acute hepatitis was not evident (Fig. 4b, c). Regenerated nodules and highly fibrous septum formation were found in the liver, which were histologically consistent with cirrhosis (Fig. 4d). In the portal area, the infiltration of mononuclear cells and disappearance of bile ducts suggested advanced PBC (Fig. 4e). Extensive bile duct loss was confirmed between the interlobular and septal bile duct levels.
Figure 4. Autopsy findings. a) Macroscopically, the surface of the liver was atrophied in a nodular manner, indicating complete cirrhosis. b) Severe atrophy with submassive loss and necrosis of hepatocytes (red dotted lines) from Zone 3 to Zone 2 of the hepatic lobule were evident (Hematoxylin and Eosin staining). P: portal vein, C: central vein. c) In some areas, hepatocytes around the central vein were relatively intact, with no steatosis inside hepatocytes suggestive of hypoxia. Cholestasis was prominent in the lobules. Inflammatory cell infiltration indicative of acute hepatitis was not detected. d) On Elastica-Goldner staining, regenerated nodules and highly fibrous septum formation were found in the liver, findings that were histologically consistent with cirrhosis. e) In the portal area, infiltration of mononuclear cells and the disappearance of bile ducts were observed, suggesting advanced PBC. P: portal vein
HEV antibodies (IgG, IgM, and IgA) were measured by an enzyme-linked immunosorbent assay using frozen serum samples according to a previously described method (18). The testing results are shown in Table 2 along with the corresponding hepatobiliary enzymes at each time point. HEV RNA was detected by the nested reverse-transcription polymerase chain reaction with primers targeting the open reading frame 2 (ORF2) region of the HEV genome (nucleotide position 5944-6355, excluding primer sequences at both ends: M73218), as described previously (19). HEV RNA, which had been negative at the last visit before admission, had become positive at admission along with increases in all classes of HEV antibodies. HEV RNA became undetectable during the deterioration of her condition, although a high antibody titer persisted. We determined her 412-nucleotide ORF2 sequence and constructed a molecular phylogenetic tree according to a previously described method (20) (Fig. 5). The HEV strain (HE-JA19-0280: DDBJ/EMBL/GenBank accession number LC581383) derived from this case belonged to genotype 3 (subgenotype 3b) and was closest to those of patients recovering from acute hepatitis E in Tokyo and Gunma Prefectures of Japan.
Figure 5. Phylogenetic tree constructed by the neighbor-joining method based on the partial nucleotide sequence (412 nucleotides) of the open reading frame 2 region of hepatitis E virus (HEV) isolates. In addition to the HEV isolate (HE-JA19-0280) obtained in the present study (highlighted with a closed box), 33 representative genotype 3 isolates (subgenotype 3a: n=8, subgenotype 3b: n=22, and subgenotype 3e: n=3), whose entire genomic sequence is known, are included in the tree using the prototype HEV sequences of genotype 1 (M73218), genotype 2 (M74506), and genotype 4 (AJ272108) as outgroups. Three HEV isolates sharing the highest identity of 97.1-97.8% with the HE-JA19-0280 isolate are also included. Each reference sequence is shown with the genotype/subgenotype followed by the accession number, isolate name, and country in which it was isolated. The bootstrap values (>70%) are indicated for nodes as the percentage of data among 1,000 resampling procedures. The scale bar is in units of nuceotide substitutions per site.
Table 2. Transition of Hepatobiliary Enzymes, HEV Antibodies, and HEV RNA.
Day Laboratory data HEV antibodies HEV RNA
AST
(U/L) ALT
(U/L) GGT
(U/L) ALP
(U/L) T-Bil
(mg/dL) IgG (OD450) IgM (OD450) IgA (OD450)
X - 80 137 111 413 940 3.4 0.010 (-) 0.046 (-) 0.020 (-) Negative
X (admission) 78 100 105 702 30.1 1.661 (+) >3.000 (+) 2.374 (+) +: 1.0×101 copies/mL
X+1 69 80 87 588 26.6 1.578 (+) >3.000 (+) 2.346 (+) +: 1.2×101 copies/mL
X+11 43 44 64 568 39.7 1.850 (+) >3.000 (+) 2.002 (+) Negative
X+14 61 66 78 631 46.7 1.970 (+) >3.000 (+) 1.768 (+) Negative
HEV: hepatitis E virus, AST: aspartate aminotransferase, ALT: alanine aminotransferase, GGT: gamma-glutamyl transpeptidase, ALP: alkaline phosphatase, T-Bil: total bilirubin
Discussion
The present autopsy case displayed histological evidence of submassive necrosis in the liver caused by acute HEV infection. The patient was presumed to have been at the liver cirrhosis stage of PBC but suddenly developed severe jaundice due to superimposed HEV infection and succumbed one month later to hepatic failure. The histopathological findings of severe liver atrophy with submassive loss and necrosis of hepatocytes could not be explained by ischemia only, strongly suggesting the involvement of genotype 3b HEV infection in her histopathological findings.
Although PBC patients generally have a normal life expectancy, they sometimes show rapid disease exacerbation due to concomitant autoimmune hepatitis (7,21) or simultaneous HCV infection (22) as a trigger of PBC deterioration. One rare instance of PBC with acute HEV infection has been reported to date (15). To our knowledge, however, an autopsy case of rapid deterioration triggered by HEV infection has not yet been described. As the mechanism underlying PBC exacerbation due to viral hepatitis infection remains unknown, the present case may contribute to the body of knowledge concerning this condition.
HEV is one of the most common causes of acute viral hepatitis (23). In addition to contaminated water, raw meat from pigs, boars, and deer is another common infection source (24-26). Recently, the prevalence of HEV cases without clinical symptoms as well as those of unknown transmission route has been increasing (27). The infection route in the present case could not be identified based on our medical interview. According to previous reports, pregnancy, old age, alcohol intake, and fatty liver are host factors associated with the aggravation of HEV, and co-infection with chronic liver disease is related to the risk of liver failure (13,14). Regarding the HEV genotype, HEV genotype 4 infection is reportedly associated with aggravation (26,28,29). Genotype 3 HEV, as detected in this case, is generally associated with a low tendency of severe clinical manifestations, although a rare case of progressive genotype 3 HEV infection has been reported (28). A mutation of V239A in the helicase region of the genotype 3 HEV genome has been associated with HEV infection aggravation (30). That mutant was absent in this case (data not shown). The patient had no other apparent host or viral factors associated with HEV severity. However, Wang et al. reported that the cirrhosis stage itself carries a potential risk of liver failure due to HEV infection, regardless of etiology; they further described the potentiation of the cirrhotic liver upon HEV infection and more aggressive immune- or inflammatory-mediated activation of cell death in a cirrhotic liver status as possible mechanisms of exacerbation (15). The above results suggested that even if patients have no documented risk factors of HEV aggravation, clinicians should bear in mind that HEV infection at a cirrhotic liver disease stage can become severe.
This patient had been diagnosed with PBC 26 years earlier based on serological criteria. Eight years before admission, she was already at an advanced stage of PBC, with Nakanuma stage 3 and Scheuer stage III classifications according to a liver biopsy. An autopsy specimen of the liver revealed obvious cirrhosis, which was consistent with the natural history of PBC as suggested by elevated serum surrogate markers of M2BPGi (31,32). However, the submassive loss and necrosis of hepatocytes could not solely be explained by the natural PBC history. Inflammatory cell infiltration suggesting acute hepatitis E (33) was not observed, which suggested a post-inflammatory status. Other general clinical features of acute hepatitis, including markedly elevated levels of liver enzymes, were absent as well. Her liver enzymes were only mildly elevated at day X-80, suggesting that asymptomatic hepatitis may have started at that point, followed by further increases in transaminase levels. Thus, one explanation as to why this case showed mild hepatitis was that the hepatitis had occurred after day X-80 and already peaked and ameliorated by the time of admission, such that jaundice represented the major feature. However, no clinical data were available between the patient’s last outpatient visit at day X-80 and her hospitalization. Another hypothesis was that this case had already reached the complete cirrhosis stage, as shown by the pathological findings, which could have induced mild liver enzyme elevations (34).
Patients with hepatitis E sometimes show severe jaundice (35). Although the underlying mechanism is uncertain, HEV has been reported to exhibit not only hepatocytic but also biliary tropism and replicate within bile duct epithelial cells (36,37). The severe jaundice and cholestasis in this case might have been the result of HEV infection complicating the chronic cholestatic liver disease of PBC. The fact that jaundice was more pronounced than elevated liver enzyme levels may support this notion. Although drug-induced liver injury (levofloxacin 500 mg/day) cannot be ruled out, we suspected that HEV infection likely triggered the exacerbation of PBC due to her awareness of jaundice prior to drug administration and the histological considerations described above.
In conclusion, clinicians should consider the possibility of acute HEV infection as a trigger for the acute exacerbation of PBC. In such cases, it may be necessary to treat the patient with the anticipation of severe aggravation.
The authors state that they have no Conflict of Interest (COI).
Acknowledgement
We thank Trevor Ralph for his English editorial assistance. | BEZAFIBRATE, LEVOFLOXACIN, URSODIOL | DrugsGivenReaction | CC BY-NC-ND | 33518570 | 19,677,427 | 2021-06-15 |
Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Primary biliary cholangitis'. | An Autopsy Case of Primary Biliary Cholangitis with Histological Submassive Hepatic Necrosis Caused by Acute Hepatitis E Virus Infection.
A 59-year-old woman who had been diagnosed with cirrhotic primary biliary cholangitis (PBC) 5 years earlier was admitted for severe jaundice (total bilirubin: 30.1 mg/dL). We suspected that her cirrhotic PBC had deteriorated acutely for some reason. Her general condition deteriorated quickly, and she passed away on day 18 of admission. Hepatitis E virus (HEV)-IgA antibodies were positive, and Genotype 3b HEV involvement was confirmed from a blood sample taken on admission. Histopathological findings revealed cirrhosis and submassive loss and necrosis of hepatocytes. Clinicians should consider the possibility of acute HEV infection as a trigger for acute PBC exacerbation.
Introduction
Primary biliary cholangitis (PBC) is a chronic and slowly progressive cholestatic autoimmune liver disease that is histopathologically characterized by an attack on the small intralobular bile duct by T lymphocytes (1). The precise etiology of PBC remains unknown but is related to genetic susceptibility environmental factors (2-4). Although most patients with PBC are asymptomatic and have a normal life expectancy, clinicians sometimes encounter symptomatic PBC cases with severe jaundice or liver failure as a result of the sustained loss of intralobular bile ducts in spite of ursodeoxycholic acid (UDCA) therapy (5,6). Patients with concomitant acute liver injury from autoimmune hepatitis show particularly rapid disease progression (7). The acute exacerbation of PBC from hepatitis virus co-infection is rare in the clinical setting.
The hepatitis E virus (HEV) is a quasi-enveloped, single-stranded RNA virus that causes acute or chronic hepatitis (8,9). With the increase in the number of hepatitis E cases, HEV antibody is now positive in approximately 5% of the general population in Japan (10,11). Among HEV-associated acute hepatitis cases, 0.5-4% of patients progress to fulminant hepatitis (12), leading to high mortality when intensive care and liver transplantation are unavailable. Rare cases of severe acute HEV hepatitis underlying such chronic liver diseases as alcoholic liver disease, nonalcoholic fatty liver disease, chronic viral hepatitis, and PBC have been documented as well (13-15). No autopsy PBC cases displaying acute exacerbation due to superimposed acute HEV infection have been reported to date.
We herein report the autopsy findings of a PBC case in the cirrhotic stage with histological submassive hepatic necrosis caused by acute HEV infection.
Case Report
A 59-year-old woman who had been serologically diagnosed with PBC after the detection of liver dysfunction 26 years earlier was admitted to our hospital for severe jaundice, brown urine, and leg edema. She had suffered from cold-like symptoms and skin jaundice for a month and had received antitussives and antibiotics (levofloxacin 500 mg/day) from her attending physician 2 weeks before admission. She had no symptoms of diarrhea, vomiting, or a history of eating raw meat. She reported no regular ethanol consumption or travel to a foreign country. Although she had been prescribed 600 mg/day UDCA and 400 mg/day bezafibrate for PBC, her medication compliance was extremely poor. She had persistent liver dysfunction [alanine aminotransferase (ALT) at around 100 U/L] and jaundice (total bilirubin at around 3 mg/dL). Eight years before admission, the histological findings of a liver biopsy specimen showed lymphocyte infiltration in the portal area and severe bile duct loss that were consistent with Nakanuma stage 3 (16) and Scheuer stage III (17) classifications (Fig. 1). Three years later, she was clinically diagnosed with cirrhosis-stage PBC. She had also undergone endoscopic gastric varices treatment one year before admission.
Figure 1. Histological findings of a liver biopsy specimen obtained eight years before admission. a, b) Lymphocyte infiltration in the portal area and severe bile duct loss were observed (Hematoxylin and Eosin staining). c) Azan-Mallory staining showed moderate fibrosis in the liver that was consistent with Nakanuma stage 3 and Scheuer stage III classifications.
On an examination at the time of admission, the patient was 165 cm tall, weighed 68 kg, and had a body mass index of 25.0 kg/m2. Her vital signs included Glasgow Coma Scale score E4V5M6, body temperature 37.3 °C, and blood pressure 111/54 mmHg. She exhibited conjunctival and systemic jaundice and front chest vascular spider but no flapping tremor. Laboratory tests on admission revealed elevated serum aspartate aminotransferase (78 U/L), ALT (100 U/L), gamma-glutamyl transpeptidase (105 U/L), alkaline phosphatase (702 U/L), total bilirubin (30.1 mg/dL), and Mac-2-binding protein glycan isomer (M2BPGi) (7.4 C・O・I) but a reduced platelet count (7.2×104/μL), albumin (2.7 g/dL), and prothrombin time activity (67.7%) (Table 1). Testing for hepatitis A virus antibody (immunoglobulin M), hepatitis B virus surface antigen, and anti-hepatitis C virus (HCV) antibody was negative. Serum antibodies to the Epstein-Barr virus and cytomegalovirus both showed a historical infection pattern. Although serum alpha fetoprotein levels were within normal range, levels of protein induced by vitamin K absence or antagonist II were mildly elevated (152 mAU/mL). Among the autoantibodies tested, fluorescent anti-nuclear antibody (× 640) and anti-mitochondrial M2 antibody (168.1 Index) were positive.
Table 1. Laboratory Findings on Admission.
Blood Chemistry / Serology Viral markers
White blood cell count 5,760 /μL Total protein 5.9 g/dL IgM-HAV Ab (-)
Neutrophils 71.2 % Albumin 2.7 g/dL HBs-Ag 0.001 (-) U/mL
Lymphocytes 19.8 % AST 78 U/L HBs-Ab 0.4 (-) mIU/mL
Monocytes 5.7 % ALT 100 U/L HBc-Ab 0.2 (-) C·O·I
Eosinophils 3.0 % Total bilirubin 30.14 mg/dL IgM-HBc Ab (-)
Basophils 0.3 % GGT 105 U/L HCV-Ab 0.1 (-) C·O·I
Red blood cell count 418 ×104/μL ALP 702 U/L IgM-EBV VCA Ab <10 (-) ×
Hemoglobin 13.1 g/dL BUN 12 mg/dL IgG-EBV VCA Ab 40 (+)
Hematocrit 37.4 % Creatinine 0.59 mg/dL EBV EBNA Ab <10 (-) ×
Platelet count 7.2 ×104/μL NH3 29 μg/dL IgM-CMV Ab 0.29 (-) Index
CRP 1.61 mg/dL IgG-CMV Ab 133.6 (+) AU/mL
Coagulation HbA1c 4.2 % IgA-HEV Ab (+)
PT 67.7 % IgM 139 mg/dL
APTT 29.0 sec IgA 292 mg/dL Autoimmune antibodies
Fibrinogen 192.0 mg/dL IgG 1,156 mg/dL FANA 640 ×
D-dimer 2.3 μg/mL M2BPGi 7.4 C·O·I AMA2 168.1 Index
Anti-centromere antibody (-)
Tumor markers LKM-1 (-)
AFP 7.0 ng/mL ASMA (-)
PIVKA II 152 mAU/mL
PT: prothrombin time, APTT: activated partial thromboplastin time, AST: aspartate aminotransferase, ALT: alanine aminotransferase, GGT: gamma-glutamyl transpeptidase, ALP: alkaline phosphatase, BUN: blood urea nitrogen, CRP: C-reactive protein, HbA1c: hemoglobin A1c, M2BPGi: Mac 2-Binding Protein Gylcan Isomer, AFP: alpha fetoprotein, PIVKA II: protein induced by vitamin K absence or antagonist II, FANA: fluorescent anti-nuclear antibody, AMA2: anti-mitochondrial M2 antibody, LKM-1: anti-liver/kidney microsome type 1 antibody, ASMA: anti-smooth muscle antibody, C·O·I: cut off index
Abdominal ultrasonography showed surface irregularity and a coarse parenchyma echotexture of the liver, suggesting cirrhosis (Fig. 2a). Abdominal contrast-enhanced computed tomography portal phase images showed surface undulation of the liver, collateral circulation around the stomach and splenic hilum, and ascites on the surface of the liver and spleen (Fig. 2b). No evidence suggestive of acute hepatitis, such as periportal collar sign, gallbladder atrophy, or wall thickening, was observed, nor were any space-occupying lesions present in the liver.
Figure 2. a) Abdominal ultrasonography showed liver surface irregularity (arrowheads) and a coarse parenchyma echotexture. b) Abdominal contrast-enhanced computed tomography portal phase images revealed surface undulation of the liver, collateral circulation around the stomach and splenic hilum (arrows), and ascites on the surface of the liver and spleen.
Based on the patient’s clinical findings, we suspected that her cirrhotic PBC had deteriorated acutely for some reason. Although she did not meet the criteria for acute liver failure, the presence of severe jaundice and ascites indicated the need for liver transplantation. After being refused for this treatment, we provided supportive care, including bed rest, lactulose administration, and albumin replacement. On day 13 of admission, HEV-IgA antibody was found to be positive in an admission blood sample, suggesting an association between the exacerbation of her PBC and acute HEV infection. However, the patient’s liver atrophy and renal failure were beyond treatment. Her general condition progressively worsened, and she passed away on day 18 of admission. The entire clinical course is summarized in Fig. 3.
Figure 3. Clinical course of the patient. ALT: alanine aminotransferase, PT: prothrombin time, T-Bil: Total bilirubin, Cre: Creatinine, HEV: Hepatitis E virus
A pathological autopsy was performed after obtaining informed consent from her family. Macroscopically, the surface of the liver was atrophied in a nodular manner, indicating complete cirrhosis (Fig. 4a). Microscopic observation of the liver showed severe atrophy with submassive loss and necrosis of hepatocytes from Zone 3 to Zone 2 of the hepatic lobule (Fig. 4b). However, the distribution did not match the centrilobular necrosis typically observed in hepatic ischemia. In some areas, hepatocytes around the central vein were intact (Fig. 4c). In addition, there was no remarkable steatosis inside hepatocytes indicative of hypoxia (Fig. 4c). Based on these findings, hepatic ischemia was not considered as the main cause of submassive loss and necrosis in this case. Although cholestasis was prominent in the lobules, inflammatory cell infiltration related to acute hepatitis was not evident (Fig. 4b, c). Regenerated nodules and highly fibrous septum formation were found in the liver, which were histologically consistent with cirrhosis (Fig. 4d). In the portal area, the infiltration of mononuclear cells and disappearance of bile ducts suggested advanced PBC (Fig. 4e). Extensive bile duct loss was confirmed between the interlobular and septal bile duct levels.
Figure 4. Autopsy findings. a) Macroscopically, the surface of the liver was atrophied in a nodular manner, indicating complete cirrhosis. b) Severe atrophy with submassive loss and necrosis of hepatocytes (red dotted lines) from Zone 3 to Zone 2 of the hepatic lobule were evident (Hematoxylin and Eosin staining). P: portal vein, C: central vein. c) In some areas, hepatocytes around the central vein were relatively intact, with no steatosis inside hepatocytes suggestive of hypoxia. Cholestasis was prominent in the lobules. Inflammatory cell infiltration indicative of acute hepatitis was not detected. d) On Elastica-Goldner staining, regenerated nodules and highly fibrous septum formation were found in the liver, findings that were histologically consistent with cirrhosis. e) In the portal area, infiltration of mononuclear cells and the disappearance of bile ducts were observed, suggesting advanced PBC. P: portal vein
HEV antibodies (IgG, IgM, and IgA) were measured by an enzyme-linked immunosorbent assay using frozen serum samples according to a previously described method (18). The testing results are shown in Table 2 along with the corresponding hepatobiliary enzymes at each time point. HEV RNA was detected by the nested reverse-transcription polymerase chain reaction with primers targeting the open reading frame 2 (ORF2) region of the HEV genome (nucleotide position 5944-6355, excluding primer sequences at both ends: M73218), as described previously (19). HEV RNA, which had been negative at the last visit before admission, had become positive at admission along with increases in all classes of HEV antibodies. HEV RNA became undetectable during the deterioration of her condition, although a high antibody titer persisted. We determined her 412-nucleotide ORF2 sequence and constructed a molecular phylogenetic tree according to a previously described method (20) (Fig. 5). The HEV strain (HE-JA19-0280: DDBJ/EMBL/GenBank accession number LC581383) derived from this case belonged to genotype 3 (subgenotype 3b) and was closest to those of patients recovering from acute hepatitis E in Tokyo and Gunma Prefectures of Japan.
Figure 5. Phylogenetic tree constructed by the neighbor-joining method based on the partial nucleotide sequence (412 nucleotides) of the open reading frame 2 region of hepatitis E virus (HEV) isolates. In addition to the HEV isolate (HE-JA19-0280) obtained in the present study (highlighted with a closed box), 33 representative genotype 3 isolates (subgenotype 3a: n=8, subgenotype 3b: n=22, and subgenotype 3e: n=3), whose entire genomic sequence is known, are included in the tree using the prototype HEV sequences of genotype 1 (M73218), genotype 2 (M74506), and genotype 4 (AJ272108) as outgroups. Three HEV isolates sharing the highest identity of 97.1-97.8% with the HE-JA19-0280 isolate are also included. Each reference sequence is shown with the genotype/subgenotype followed by the accession number, isolate name, and country in which it was isolated. The bootstrap values (>70%) are indicated for nodes as the percentage of data among 1,000 resampling procedures. The scale bar is in units of nuceotide substitutions per site.
Table 2. Transition of Hepatobiliary Enzymes, HEV Antibodies, and HEV RNA.
Day Laboratory data HEV antibodies HEV RNA
AST
(U/L) ALT
(U/L) GGT
(U/L) ALP
(U/L) T-Bil
(mg/dL) IgG (OD450) IgM (OD450) IgA (OD450)
X - 80 137 111 413 940 3.4 0.010 (-) 0.046 (-) 0.020 (-) Negative
X (admission) 78 100 105 702 30.1 1.661 (+) >3.000 (+) 2.374 (+) +: 1.0×101 copies/mL
X+1 69 80 87 588 26.6 1.578 (+) >3.000 (+) 2.346 (+) +: 1.2×101 copies/mL
X+11 43 44 64 568 39.7 1.850 (+) >3.000 (+) 2.002 (+) Negative
X+14 61 66 78 631 46.7 1.970 (+) >3.000 (+) 1.768 (+) Negative
HEV: hepatitis E virus, AST: aspartate aminotransferase, ALT: alanine aminotransferase, GGT: gamma-glutamyl transpeptidase, ALP: alkaline phosphatase, T-Bil: total bilirubin
Discussion
The present autopsy case displayed histological evidence of submassive necrosis in the liver caused by acute HEV infection. The patient was presumed to have been at the liver cirrhosis stage of PBC but suddenly developed severe jaundice due to superimposed HEV infection and succumbed one month later to hepatic failure. The histopathological findings of severe liver atrophy with submassive loss and necrosis of hepatocytes could not be explained by ischemia only, strongly suggesting the involvement of genotype 3b HEV infection in her histopathological findings.
Although PBC patients generally have a normal life expectancy, they sometimes show rapid disease exacerbation due to concomitant autoimmune hepatitis (7,21) or simultaneous HCV infection (22) as a trigger of PBC deterioration. One rare instance of PBC with acute HEV infection has been reported to date (15). To our knowledge, however, an autopsy case of rapid deterioration triggered by HEV infection has not yet been described. As the mechanism underlying PBC exacerbation due to viral hepatitis infection remains unknown, the present case may contribute to the body of knowledge concerning this condition.
HEV is one of the most common causes of acute viral hepatitis (23). In addition to contaminated water, raw meat from pigs, boars, and deer is another common infection source (24-26). Recently, the prevalence of HEV cases without clinical symptoms as well as those of unknown transmission route has been increasing (27). The infection route in the present case could not be identified based on our medical interview. According to previous reports, pregnancy, old age, alcohol intake, and fatty liver are host factors associated with the aggravation of HEV, and co-infection with chronic liver disease is related to the risk of liver failure (13,14). Regarding the HEV genotype, HEV genotype 4 infection is reportedly associated with aggravation (26,28,29). Genotype 3 HEV, as detected in this case, is generally associated with a low tendency of severe clinical manifestations, although a rare case of progressive genotype 3 HEV infection has been reported (28). A mutation of V239A in the helicase region of the genotype 3 HEV genome has been associated with HEV infection aggravation (30). That mutant was absent in this case (data not shown). The patient had no other apparent host or viral factors associated with HEV severity. However, Wang et al. reported that the cirrhosis stage itself carries a potential risk of liver failure due to HEV infection, regardless of etiology; they further described the potentiation of the cirrhotic liver upon HEV infection and more aggressive immune- or inflammatory-mediated activation of cell death in a cirrhotic liver status as possible mechanisms of exacerbation (15). The above results suggested that even if patients have no documented risk factors of HEV aggravation, clinicians should bear in mind that HEV infection at a cirrhotic liver disease stage can become severe.
This patient had been diagnosed with PBC 26 years earlier based on serological criteria. Eight years before admission, she was already at an advanced stage of PBC, with Nakanuma stage 3 and Scheuer stage III classifications according to a liver biopsy. An autopsy specimen of the liver revealed obvious cirrhosis, which was consistent with the natural history of PBC as suggested by elevated serum surrogate markers of M2BPGi (31,32). However, the submassive loss and necrosis of hepatocytes could not solely be explained by the natural PBC history. Inflammatory cell infiltration suggesting acute hepatitis E (33) was not observed, which suggested a post-inflammatory status. Other general clinical features of acute hepatitis, including markedly elevated levels of liver enzymes, were absent as well. Her liver enzymes were only mildly elevated at day X-80, suggesting that asymptomatic hepatitis may have started at that point, followed by further increases in transaminase levels. Thus, one explanation as to why this case showed mild hepatitis was that the hepatitis had occurred after day X-80 and already peaked and ameliorated by the time of admission, such that jaundice represented the major feature. However, no clinical data were available between the patient’s last outpatient visit at day X-80 and her hospitalization. Another hypothesis was that this case had already reached the complete cirrhosis stage, as shown by the pathological findings, which could have induced mild liver enzyme elevations (34).
Patients with hepatitis E sometimes show severe jaundice (35). Although the underlying mechanism is uncertain, HEV has been reported to exhibit not only hepatocytic but also biliary tropism and replicate within bile duct epithelial cells (36,37). The severe jaundice and cholestasis in this case might have been the result of HEV infection complicating the chronic cholestatic liver disease of PBC. The fact that jaundice was more pronounced than elevated liver enzyme levels may support this notion. Although drug-induced liver injury (levofloxacin 500 mg/day) cannot be ruled out, we suspected that HEV infection likely triggered the exacerbation of PBC due to her awareness of jaundice prior to drug administration and the histological considerations described above.
In conclusion, clinicians should consider the possibility of acute HEV infection as a trigger for the acute exacerbation of PBC. In such cases, it may be necessary to treat the patient with the anticipation of severe aggravation.
The authors state that they have no Conflict of Interest (COI).
Acknowledgement
We thank Trevor Ralph for his English editorial assistance. | BEZAFIBRATE, LEVOFLOXACIN, URSODIOL | DrugsGivenReaction | CC BY-NC-ND | 33518570 | 19,677,427 | 2021-06-15 |
Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Renal failure'. | An Autopsy Case of Primary Biliary Cholangitis with Histological Submassive Hepatic Necrosis Caused by Acute Hepatitis E Virus Infection.
A 59-year-old woman who had been diagnosed with cirrhotic primary biliary cholangitis (PBC) 5 years earlier was admitted for severe jaundice (total bilirubin: 30.1 mg/dL). We suspected that her cirrhotic PBC had deteriorated acutely for some reason. Her general condition deteriorated quickly, and she passed away on day 18 of admission. Hepatitis E virus (HEV)-IgA antibodies were positive, and Genotype 3b HEV involvement was confirmed from a blood sample taken on admission. Histopathological findings revealed cirrhosis and submassive loss and necrosis of hepatocytes. Clinicians should consider the possibility of acute HEV infection as a trigger for acute PBC exacerbation.
Introduction
Primary biliary cholangitis (PBC) is a chronic and slowly progressive cholestatic autoimmune liver disease that is histopathologically characterized by an attack on the small intralobular bile duct by T lymphocytes (1). The precise etiology of PBC remains unknown but is related to genetic susceptibility environmental factors (2-4). Although most patients with PBC are asymptomatic and have a normal life expectancy, clinicians sometimes encounter symptomatic PBC cases with severe jaundice or liver failure as a result of the sustained loss of intralobular bile ducts in spite of ursodeoxycholic acid (UDCA) therapy (5,6). Patients with concomitant acute liver injury from autoimmune hepatitis show particularly rapid disease progression (7). The acute exacerbation of PBC from hepatitis virus co-infection is rare in the clinical setting.
The hepatitis E virus (HEV) is a quasi-enveloped, single-stranded RNA virus that causes acute or chronic hepatitis (8,9). With the increase in the number of hepatitis E cases, HEV antibody is now positive in approximately 5% of the general population in Japan (10,11). Among HEV-associated acute hepatitis cases, 0.5-4% of patients progress to fulminant hepatitis (12), leading to high mortality when intensive care and liver transplantation are unavailable. Rare cases of severe acute HEV hepatitis underlying such chronic liver diseases as alcoholic liver disease, nonalcoholic fatty liver disease, chronic viral hepatitis, and PBC have been documented as well (13-15). No autopsy PBC cases displaying acute exacerbation due to superimposed acute HEV infection have been reported to date.
We herein report the autopsy findings of a PBC case in the cirrhotic stage with histological submassive hepatic necrosis caused by acute HEV infection.
Case Report
A 59-year-old woman who had been serologically diagnosed with PBC after the detection of liver dysfunction 26 years earlier was admitted to our hospital for severe jaundice, brown urine, and leg edema. She had suffered from cold-like symptoms and skin jaundice for a month and had received antitussives and antibiotics (levofloxacin 500 mg/day) from her attending physician 2 weeks before admission. She had no symptoms of diarrhea, vomiting, or a history of eating raw meat. She reported no regular ethanol consumption or travel to a foreign country. Although she had been prescribed 600 mg/day UDCA and 400 mg/day bezafibrate for PBC, her medication compliance was extremely poor. She had persistent liver dysfunction [alanine aminotransferase (ALT) at around 100 U/L] and jaundice (total bilirubin at around 3 mg/dL). Eight years before admission, the histological findings of a liver biopsy specimen showed lymphocyte infiltration in the portal area and severe bile duct loss that were consistent with Nakanuma stage 3 (16) and Scheuer stage III (17) classifications (Fig. 1). Three years later, she was clinically diagnosed with cirrhosis-stage PBC. She had also undergone endoscopic gastric varices treatment one year before admission.
Figure 1. Histological findings of a liver biopsy specimen obtained eight years before admission. a, b) Lymphocyte infiltration in the portal area and severe bile duct loss were observed (Hematoxylin and Eosin staining). c) Azan-Mallory staining showed moderate fibrosis in the liver that was consistent with Nakanuma stage 3 and Scheuer stage III classifications.
On an examination at the time of admission, the patient was 165 cm tall, weighed 68 kg, and had a body mass index of 25.0 kg/m2. Her vital signs included Glasgow Coma Scale score E4V5M6, body temperature 37.3 °C, and blood pressure 111/54 mmHg. She exhibited conjunctival and systemic jaundice and front chest vascular spider but no flapping tremor. Laboratory tests on admission revealed elevated serum aspartate aminotransferase (78 U/L), ALT (100 U/L), gamma-glutamyl transpeptidase (105 U/L), alkaline phosphatase (702 U/L), total bilirubin (30.1 mg/dL), and Mac-2-binding protein glycan isomer (M2BPGi) (7.4 C・O・I) but a reduced platelet count (7.2×104/μL), albumin (2.7 g/dL), and prothrombin time activity (67.7%) (Table 1). Testing for hepatitis A virus antibody (immunoglobulin M), hepatitis B virus surface antigen, and anti-hepatitis C virus (HCV) antibody was negative. Serum antibodies to the Epstein-Barr virus and cytomegalovirus both showed a historical infection pattern. Although serum alpha fetoprotein levels were within normal range, levels of protein induced by vitamin K absence or antagonist II were mildly elevated (152 mAU/mL). Among the autoantibodies tested, fluorescent anti-nuclear antibody (× 640) and anti-mitochondrial M2 antibody (168.1 Index) were positive.
Table 1. Laboratory Findings on Admission.
Blood Chemistry / Serology Viral markers
White blood cell count 5,760 /μL Total protein 5.9 g/dL IgM-HAV Ab (-)
Neutrophils 71.2 % Albumin 2.7 g/dL HBs-Ag 0.001 (-) U/mL
Lymphocytes 19.8 % AST 78 U/L HBs-Ab 0.4 (-) mIU/mL
Monocytes 5.7 % ALT 100 U/L HBc-Ab 0.2 (-) C·O·I
Eosinophils 3.0 % Total bilirubin 30.14 mg/dL IgM-HBc Ab (-)
Basophils 0.3 % GGT 105 U/L HCV-Ab 0.1 (-) C·O·I
Red blood cell count 418 ×104/μL ALP 702 U/L IgM-EBV VCA Ab <10 (-) ×
Hemoglobin 13.1 g/dL BUN 12 mg/dL IgG-EBV VCA Ab 40 (+)
Hematocrit 37.4 % Creatinine 0.59 mg/dL EBV EBNA Ab <10 (-) ×
Platelet count 7.2 ×104/μL NH3 29 μg/dL IgM-CMV Ab 0.29 (-) Index
CRP 1.61 mg/dL IgG-CMV Ab 133.6 (+) AU/mL
Coagulation HbA1c 4.2 % IgA-HEV Ab (+)
PT 67.7 % IgM 139 mg/dL
APTT 29.0 sec IgA 292 mg/dL Autoimmune antibodies
Fibrinogen 192.0 mg/dL IgG 1,156 mg/dL FANA 640 ×
D-dimer 2.3 μg/mL M2BPGi 7.4 C·O·I AMA2 168.1 Index
Anti-centromere antibody (-)
Tumor markers LKM-1 (-)
AFP 7.0 ng/mL ASMA (-)
PIVKA II 152 mAU/mL
PT: prothrombin time, APTT: activated partial thromboplastin time, AST: aspartate aminotransferase, ALT: alanine aminotransferase, GGT: gamma-glutamyl transpeptidase, ALP: alkaline phosphatase, BUN: blood urea nitrogen, CRP: C-reactive protein, HbA1c: hemoglobin A1c, M2BPGi: Mac 2-Binding Protein Gylcan Isomer, AFP: alpha fetoprotein, PIVKA II: protein induced by vitamin K absence or antagonist II, FANA: fluorescent anti-nuclear antibody, AMA2: anti-mitochondrial M2 antibody, LKM-1: anti-liver/kidney microsome type 1 antibody, ASMA: anti-smooth muscle antibody, C·O·I: cut off index
Abdominal ultrasonography showed surface irregularity and a coarse parenchyma echotexture of the liver, suggesting cirrhosis (Fig. 2a). Abdominal contrast-enhanced computed tomography portal phase images showed surface undulation of the liver, collateral circulation around the stomach and splenic hilum, and ascites on the surface of the liver and spleen (Fig. 2b). No evidence suggestive of acute hepatitis, such as periportal collar sign, gallbladder atrophy, or wall thickening, was observed, nor were any space-occupying lesions present in the liver.
Figure 2. a) Abdominal ultrasonography showed liver surface irregularity (arrowheads) and a coarse parenchyma echotexture. b) Abdominal contrast-enhanced computed tomography portal phase images revealed surface undulation of the liver, collateral circulation around the stomach and splenic hilum (arrows), and ascites on the surface of the liver and spleen.
Based on the patient’s clinical findings, we suspected that her cirrhotic PBC had deteriorated acutely for some reason. Although she did not meet the criteria for acute liver failure, the presence of severe jaundice and ascites indicated the need for liver transplantation. After being refused for this treatment, we provided supportive care, including bed rest, lactulose administration, and albumin replacement. On day 13 of admission, HEV-IgA antibody was found to be positive in an admission blood sample, suggesting an association between the exacerbation of her PBC and acute HEV infection. However, the patient’s liver atrophy and renal failure were beyond treatment. Her general condition progressively worsened, and she passed away on day 18 of admission. The entire clinical course is summarized in Fig. 3.
Figure 3. Clinical course of the patient. ALT: alanine aminotransferase, PT: prothrombin time, T-Bil: Total bilirubin, Cre: Creatinine, HEV: Hepatitis E virus
A pathological autopsy was performed after obtaining informed consent from her family. Macroscopically, the surface of the liver was atrophied in a nodular manner, indicating complete cirrhosis (Fig. 4a). Microscopic observation of the liver showed severe atrophy with submassive loss and necrosis of hepatocytes from Zone 3 to Zone 2 of the hepatic lobule (Fig. 4b). However, the distribution did not match the centrilobular necrosis typically observed in hepatic ischemia. In some areas, hepatocytes around the central vein were intact (Fig. 4c). In addition, there was no remarkable steatosis inside hepatocytes indicative of hypoxia (Fig. 4c). Based on these findings, hepatic ischemia was not considered as the main cause of submassive loss and necrosis in this case. Although cholestasis was prominent in the lobules, inflammatory cell infiltration related to acute hepatitis was not evident (Fig. 4b, c). Regenerated nodules and highly fibrous septum formation were found in the liver, which were histologically consistent with cirrhosis (Fig. 4d). In the portal area, the infiltration of mononuclear cells and disappearance of bile ducts suggested advanced PBC (Fig. 4e). Extensive bile duct loss was confirmed between the interlobular and septal bile duct levels.
Figure 4. Autopsy findings. a) Macroscopically, the surface of the liver was atrophied in a nodular manner, indicating complete cirrhosis. b) Severe atrophy with submassive loss and necrosis of hepatocytes (red dotted lines) from Zone 3 to Zone 2 of the hepatic lobule were evident (Hematoxylin and Eosin staining). P: portal vein, C: central vein. c) In some areas, hepatocytes around the central vein were relatively intact, with no steatosis inside hepatocytes suggestive of hypoxia. Cholestasis was prominent in the lobules. Inflammatory cell infiltration indicative of acute hepatitis was not detected. d) On Elastica-Goldner staining, regenerated nodules and highly fibrous septum formation were found in the liver, findings that were histologically consistent with cirrhosis. e) In the portal area, infiltration of mononuclear cells and the disappearance of bile ducts were observed, suggesting advanced PBC. P: portal vein
HEV antibodies (IgG, IgM, and IgA) were measured by an enzyme-linked immunosorbent assay using frozen serum samples according to a previously described method (18). The testing results are shown in Table 2 along with the corresponding hepatobiliary enzymes at each time point. HEV RNA was detected by the nested reverse-transcription polymerase chain reaction with primers targeting the open reading frame 2 (ORF2) region of the HEV genome (nucleotide position 5944-6355, excluding primer sequences at both ends: M73218), as described previously (19). HEV RNA, which had been negative at the last visit before admission, had become positive at admission along with increases in all classes of HEV antibodies. HEV RNA became undetectable during the deterioration of her condition, although a high antibody titer persisted. We determined her 412-nucleotide ORF2 sequence and constructed a molecular phylogenetic tree according to a previously described method (20) (Fig. 5). The HEV strain (HE-JA19-0280: DDBJ/EMBL/GenBank accession number LC581383) derived from this case belonged to genotype 3 (subgenotype 3b) and was closest to those of patients recovering from acute hepatitis E in Tokyo and Gunma Prefectures of Japan.
Figure 5. Phylogenetic tree constructed by the neighbor-joining method based on the partial nucleotide sequence (412 nucleotides) of the open reading frame 2 region of hepatitis E virus (HEV) isolates. In addition to the HEV isolate (HE-JA19-0280) obtained in the present study (highlighted with a closed box), 33 representative genotype 3 isolates (subgenotype 3a: n=8, subgenotype 3b: n=22, and subgenotype 3e: n=3), whose entire genomic sequence is known, are included in the tree using the prototype HEV sequences of genotype 1 (M73218), genotype 2 (M74506), and genotype 4 (AJ272108) as outgroups. Three HEV isolates sharing the highest identity of 97.1-97.8% with the HE-JA19-0280 isolate are also included. Each reference sequence is shown with the genotype/subgenotype followed by the accession number, isolate name, and country in which it was isolated. The bootstrap values (>70%) are indicated for nodes as the percentage of data among 1,000 resampling procedures. The scale bar is in units of nuceotide substitutions per site.
Table 2. Transition of Hepatobiliary Enzymes, HEV Antibodies, and HEV RNA.
Day Laboratory data HEV antibodies HEV RNA
AST
(U/L) ALT
(U/L) GGT
(U/L) ALP
(U/L) T-Bil
(mg/dL) IgG (OD450) IgM (OD450) IgA (OD450)
X - 80 137 111 413 940 3.4 0.010 (-) 0.046 (-) 0.020 (-) Negative
X (admission) 78 100 105 702 30.1 1.661 (+) >3.000 (+) 2.374 (+) +: 1.0×101 copies/mL
X+1 69 80 87 588 26.6 1.578 (+) >3.000 (+) 2.346 (+) +: 1.2×101 copies/mL
X+11 43 44 64 568 39.7 1.850 (+) >3.000 (+) 2.002 (+) Negative
X+14 61 66 78 631 46.7 1.970 (+) >3.000 (+) 1.768 (+) Negative
HEV: hepatitis E virus, AST: aspartate aminotransferase, ALT: alanine aminotransferase, GGT: gamma-glutamyl transpeptidase, ALP: alkaline phosphatase, T-Bil: total bilirubin
Discussion
The present autopsy case displayed histological evidence of submassive necrosis in the liver caused by acute HEV infection. The patient was presumed to have been at the liver cirrhosis stage of PBC but suddenly developed severe jaundice due to superimposed HEV infection and succumbed one month later to hepatic failure. The histopathological findings of severe liver atrophy with submassive loss and necrosis of hepatocytes could not be explained by ischemia only, strongly suggesting the involvement of genotype 3b HEV infection in her histopathological findings.
Although PBC patients generally have a normal life expectancy, they sometimes show rapid disease exacerbation due to concomitant autoimmune hepatitis (7,21) or simultaneous HCV infection (22) as a trigger of PBC deterioration. One rare instance of PBC with acute HEV infection has been reported to date (15). To our knowledge, however, an autopsy case of rapid deterioration triggered by HEV infection has not yet been described. As the mechanism underlying PBC exacerbation due to viral hepatitis infection remains unknown, the present case may contribute to the body of knowledge concerning this condition.
HEV is one of the most common causes of acute viral hepatitis (23). In addition to contaminated water, raw meat from pigs, boars, and deer is another common infection source (24-26). Recently, the prevalence of HEV cases without clinical symptoms as well as those of unknown transmission route has been increasing (27). The infection route in the present case could not be identified based on our medical interview. According to previous reports, pregnancy, old age, alcohol intake, and fatty liver are host factors associated with the aggravation of HEV, and co-infection with chronic liver disease is related to the risk of liver failure (13,14). Regarding the HEV genotype, HEV genotype 4 infection is reportedly associated with aggravation (26,28,29). Genotype 3 HEV, as detected in this case, is generally associated with a low tendency of severe clinical manifestations, although a rare case of progressive genotype 3 HEV infection has been reported (28). A mutation of V239A in the helicase region of the genotype 3 HEV genome has been associated with HEV infection aggravation (30). That mutant was absent in this case (data not shown). The patient had no other apparent host or viral factors associated with HEV severity. However, Wang et al. reported that the cirrhosis stage itself carries a potential risk of liver failure due to HEV infection, regardless of etiology; they further described the potentiation of the cirrhotic liver upon HEV infection and more aggressive immune- or inflammatory-mediated activation of cell death in a cirrhotic liver status as possible mechanisms of exacerbation (15). The above results suggested that even if patients have no documented risk factors of HEV aggravation, clinicians should bear in mind that HEV infection at a cirrhotic liver disease stage can become severe.
This patient had been diagnosed with PBC 26 years earlier based on serological criteria. Eight years before admission, she was already at an advanced stage of PBC, with Nakanuma stage 3 and Scheuer stage III classifications according to a liver biopsy. An autopsy specimen of the liver revealed obvious cirrhosis, which was consistent with the natural history of PBC as suggested by elevated serum surrogate markers of M2BPGi (31,32). However, the submassive loss and necrosis of hepatocytes could not solely be explained by the natural PBC history. Inflammatory cell infiltration suggesting acute hepatitis E (33) was not observed, which suggested a post-inflammatory status. Other general clinical features of acute hepatitis, including markedly elevated levels of liver enzymes, were absent as well. Her liver enzymes were only mildly elevated at day X-80, suggesting that asymptomatic hepatitis may have started at that point, followed by further increases in transaminase levels. Thus, one explanation as to why this case showed mild hepatitis was that the hepatitis had occurred after day X-80 and already peaked and ameliorated by the time of admission, such that jaundice represented the major feature. However, no clinical data were available between the patient’s last outpatient visit at day X-80 and her hospitalization. Another hypothesis was that this case had already reached the complete cirrhosis stage, as shown by the pathological findings, which could have induced mild liver enzyme elevations (34).
Patients with hepatitis E sometimes show severe jaundice (35). Although the underlying mechanism is uncertain, HEV has been reported to exhibit not only hepatocytic but also biliary tropism and replicate within bile duct epithelial cells (36,37). The severe jaundice and cholestasis in this case might have been the result of HEV infection complicating the chronic cholestatic liver disease of PBC. The fact that jaundice was more pronounced than elevated liver enzyme levels may support this notion. Although drug-induced liver injury (levofloxacin 500 mg/day) cannot be ruled out, we suspected that HEV infection likely triggered the exacerbation of PBC due to her awareness of jaundice prior to drug administration and the histological considerations described above.
In conclusion, clinicians should consider the possibility of acute HEV infection as a trigger for the acute exacerbation of PBC. In such cases, it may be necessary to treat the patient with the anticipation of severe aggravation.
The authors state that they have no Conflict of Interest (COI).
Acknowledgement
We thank Trevor Ralph for his English editorial assistance. | BEZAFIBRATE, LEVOFLOXACIN, URSODIOL | DrugsGivenReaction | CC BY-NC-ND | 33518570 | 19,677,427 | 2021-06-15 |
What is the weight of the patient? | An Autopsy Case of Primary Biliary Cholangitis with Histological Submassive Hepatic Necrosis Caused by Acute Hepatitis E Virus Infection.
A 59-year-old woman who had been diagnosed with cirrhotic primary biliary cholangitis (PBC) 5 years earlier was admitted for severe jaundice (total bilirubin: 30.1 mg/dL). We suspected that her cirrhotic PBC had deteriorated acutely for some reason. Her general condition deteriorated quickly, and she passed away on day 18 of admission. Hepatitis E virus (HEV)-IgA antibodies were positive, and Genotype 3b HEV involvement was confirmed from a blood sample taken on admission. Histopathological findings revealed cirrhosis and submassive loss and necrosis of hepatocytes. Clinicians should consider the possibility of acute HEV infection as a trigger for acute PBC exacerbation.
Introduction
Primary biliary cholangitis (PBC) is a chronic and slowly progressive cholestatic autoimmune liver disease that is histopathologically characterized by an attack on the small intralobular bile duct by T lymphocytes (1). The precise etiology of PBC remains unknown but is related to genetic susceptibility environmental factors (2-4). Although most patients with PBC are asymptomatic and have a normal life expectancy, clinicians sometimes encounter symptomatic PBC cases with severe jaundice or liver failure as a result of the sustained loss of intralobular bile ducts in spite of ursodeoxycholic acid (UDCA) therapy (5,6). Patients with concomitant acute liver injury from autoimmune hepatitis show particularly rapid disease progression (7). The acute exacerbation of PBC from hepatitis virus co-infection is rare in the clinical setting.
The hepatitis E virus (HEV) is a quasi-enveloped, single-stranded RNA virus that causes acute or chronic hepatitis (8,9). With the increase in the number of hepatitis E cases, HEV antibody is now positive in approximately 5% of the general population in Japan (10,11). Among HEV-associated acute hepatitis cases, 0.5-4% of patients progress to fulminant hepatitis (12), leading to high mortality when intensive care and liver transplantation are unavailable. Rare cases of severe acute HEV hepatitis underlying such chronic liver diseases as alcoholic liver disease, nonalcoholic fatty liver disease, chronic viral hepatitis, and PBC have been documented as well (13-15). No autopsy PBC cases displaying acute exacerbation due to superimposed acute HEV infection have been reported to date.
We herein report the autopsy findings of a PBC case in the cirrhotic stage with histological submassive hepatic necrosis caused by acute HEV infection.
Case Report
A 59-year-old woman who had been serologically diagnosed with PBC after the detection of liver dysfunction 26 years earlier was admitted to our hospital for severe jaundice, brown urine, and leg edema. She had suffered from cold-like symptoms and skin jaundice for a month and had received antitussives and antibiotics (levofloxacin 500 mg/day) from her attending physician 2 weeks before admission. She had no symptoms of diarrhea, vomiting, or a history of eating raw meat. She reported no regular ethanol consumption or travel to a foreign country. Although she had been prescribed 600 mg/day UDCA and 400 mg/day bezafibrate for PBC, her medication compliance was extremely poor. She had persistent liver dysfunction [alanine aminotransferase (ALT) at around 100 U/L] and jaundice (total bilirubin at around 3 mg/dL). Eight years before admission, the histological findings of a liver biopsy specimen showed lymphocyte infiltration in the portal area and severe bile duct loss that were consistent with Nakanuma stage 3 (16) and Scheuer stage III (17) classifications (Fig. 1). Three years later, she was clinically diagnosed with cirrhosis-stage PBC. She had also undergone endoscopic gastric varices treatment one year before admission.
Figure 1. Histological findings of a liver biopsy specimen obtained eight years before admission. a, b) Lymphocyte infiltration in the portal area and severe bile duct loss were observed (Hematoxylin and Eosin staining). c) Azan-Mallory staining showed moderate fibrosis in the liver that was consistent with Nakanuma stage 3 and Scheuer stage III classifications.
On an examination at the time of admission, the patient was 165 cm tall, weighed 68 kg, and had a body mass index of 25.0 kg/m2. Her vital signs included Glasgow Coma Scale score E4V5M6, body temperature 37.3 °C, and blood pressure 111/54 mmHg. She exhibited conjunctival and systemic jaundice and front chest vascular spider but no flapping tremor. Laboratory tests on admission revealed elevated serum aspartate aminotransferase (78 U/L), ALT (100 U/L), gamma-glutamyl transpeptidase (105 U/L), alkaline phosphatase (702 U/L), total bilirubin (30.1 mg/dL), and Mac-2-binding protein glycan isomer (M2BPGi) (7.4 C・O・I) but a reduced platelet count (7.2×104/μL), albumin (2.7 g/dL), and prothrombin time activity (67.7%) (Table 1). Testing for hepatitis A virus antibody (immunoglobulin M), hepatitis B virus surface antigen, and anti-hepatitis C virus (HCV) antibody was negative. Serum antibodies to the Epstein-Barr virus and cytomegalovirus both showed a historical infection pattern. Although serum alpha fetoprotein levels were within normal range, levels of protein induced by vitamin K absence or antagonist II were mildly elevated (152 mAU/mL). Among the autoantibodies tested, fluorescent anti-nuclear antibody (× 640) and anti-mitochondrial M2 antibody (168.1 Index) were positive.
Table 1. Laboratory Findings on Admission.
Blood Chemistry / Serology Viral markers
White blood cell count 5,760 /μL Total protein 5.9 g/dL IgM-HAV Ab (-)
Neutrophils 71.2 % Albumin 2.7 g/dL HBs-Ag 0.001 (-) U/mL
Lymphocytes 19.8 % AST 78 U/L HBs-Ab 0.4 (-) mIU/mL
Monocytes 5.7 % ALT 100 U/L HBc-Ab 0.2 (-) C·O·I
Eosinophils 3.0 % Total bilirubin 30.14 mg/dL IgM-HBc Ab (-)
Basophils 0.3 % GGT 105 U/L HCV-Ab 0.1 (-) C·O·I
Red blood cell count 418 ×104/μL ALP 702 U/L IgM-EBV VCA Ab <10 (-) ×
Hemoglobin 13.1 g/dL BUN 12 mg/dL IgG-EBV VCA Ab 40 (+)
Hematocrit 37.4 % Creatinine 0.59 mg/dL EBV EBNA Ab <10 (-) ×
Platelet count 7.2 ×104/μL NH3 29 μg/dL IgM-CMV Ab 0.29 (-) Index
CRP 1.61 mg/dL IgG-CMV Ab 133.6 (+) AU/mL
Coagulation HbA1c 4.2 % IgA-HEV Ab (+)
PT 67.7 % IgM 139 mg/dL
APTT 29.0 sec IgA 292 mg/dL Autoimmune antibodies
Fibrinogen 192.0 mg/dL IgG 1,156 mg/dL FANA 640 ×
D-dimer 2.3 μg/mL M2BPGi 7.4 C·O·I AMA2 168.1 Index
Anti-centromere antibody (-)
Tumor markers LKM-1 (-)
AFP 7.0 ng/mL ASMA (-)
PIVKA II 152 mAU/mL
PT: prothrombin time, APTT: activated partial thromboplastin time, AST: aspartate aminotransferase, ALT: alanine aminotransferase, GGT: gamma-glutamyl transpeptidase, ALP: alkaline phosphatase, BUN: blood urea nitrogen, CRP: C-reactive protein, HbA1c: hemoglobin A1c, M2BPGi: Mac 2-Binding Protein Gylcan Isomer, AFP: alpha fetoprotein, PIVKA II: protein induced by vitamin K absence or antagonist II, FANA: fluorescent anti-nuclear antibody, AMA2: anti-mitochondrial M2 antibody, LKM-1: anti-liver/kidney microsome type 1 antibody, ASMA: anti-smooth muscle antibody, C·O·I: cut off index
Abdominal ultrasonography showed surface irregularity and a coarse parenchyma echotexture of the liver, suggesting cirrhosis (Fig. 2a). Abdominal contrast-enhanced computed tomography portal phase images showed surface undulation of the liver, collateral circulation around the stomach and splenic hilum, and ascites on the surface of the liver and spleen (Fig. 2b). No evidence suggestive of acute hepatitis, such as periportal collar sign, gallbladder atrophy, or wall thickening, was observed, nor were any space-occupying lesions present in the liver.
Figure 2. a) Abdominal ultrasonography showed liver surface irregularity (arrowheads) and a coarse parenchyma echotexture. b) Abdominal contrast-enhanced computed tomography portal phase images revealed surface undulation of the liver, collateral circulation around the stomach and splenic hilum (arrows), and ascites on the surface of the liver and spleen.
Based on the patient’s clinical findings, we suspected that her cirrhotic PBC had deteriorated acutely for some reason. Although she did not meet the criteria for acute liver failure, the presence of severe jaundice and ascites indicated the need for liver transplantation. After being refused for this treatment, we provided supportive care, including bed rest, lactulose administration, and albumin replacement. On day 13 of admission, HEV-IgA antibody was found to be positive in an admission blood sample, suggesting an association between the exacerbation of her PBC and acute HEV infection. However, the patient’s liver atrophy and renal failure were beyond treatment. Her general condition progressively worsened, and she passed away on day 18 of admission. The entire clinical course is summarized in Fig. 3.
Figure 3. Clinical course of the patient. ALT: alanine aminotransferase, PT: prothrombin time, T-Bil: Total bilirubin, Cre: Creatinine, HEV: Hepatitis E virus
A pathological autopsy was performed after obtaining informed consent from her family. Macroscopically, the surface of the liver was atrophied in a nodular manner, indicating complete cirrhosis (Fig. 4a). Microscopic observation of the liver showed severe atrophy with submassive loss and necrosis of hepatocytes from Zone 3 to Zone 2 of the hepatic lobule (Fig. 4b). However, the distribution did not match the centrilobular necrosis typically observed in hepatic ischemia. In some areas, hepatocytes around the central vein were intact (Fig. 4c). In addition, there was no remarkable steatosis inside hepatocytes indicative of hypoxia (Fig. 4c). Based on these findings, hepatic ischemia was not considered as the main cause of submassive loss and necrosis in this case. Although cholestasis was prominent in the lobules, inflammatory cell infiltration related to acute hepatitis was not evident (Fig. 4b, c). Regenerated nodules and highly fibrous septum formation were found in the liver, which were histologically consistent with cirrhosis (Fig. 4d). In the portal area, the infiltration of mononuclear cells and disappearance of bile ducts suggested advanced PBC (Fig. 4e). Extensive bile duct loss was confirmed between the interlobular and septal bile duct levels.
Figure 4. Autopsy findings. a) Macroscopically, the surface of the liver was atrophied in a nodular manner, indicating complete cirrhosis. b) Severe atrophy with submassive loss and necrosis of hepatocytes (red dotted lines) from Zone 3 to Zone 2 of the hepatic lobule were evident (Hematoxylin and Eosin staining). P: portal vein, C: central vein. c) In some areas, hepatocytes around the central vein were relatively intact, with no steatosis inside hepatocytes suggestive of hypoxia. Cholestasis was prominent in the lobules. Inflammatory cell infiltration indicative of acute hepatitis was not detected. d) On Elastica-Goldner staining, regenerated nodules and highly fibrous septum formation were found in the liver, findings that were histologically consistent with cirrhosis. e) In the portal area, infiltration of mononuclear cells and the disappearance of bile ducts were observed, suggesting advanced PBC. P: portal vein
HEV antibodies (IgG, IgM, and IgA) were measured by an enzyme-linked immunosorbent assay using frozen serum samples according to a previously described method (18). The testing results are shown in Table 2 along with the corresponding hepatobiliary enzymes at each time point. HEV RNA was detected by the nested reverse-transcription polymerase chain reaction with primers targeting the open reading frame 2 (ORF2) region of the HEV genome (nucleotide position 5944-6355, excluding primer sequences at both ends: M73218), as described previously (19). HEV RNA, which had been negative at the last visit before admission, had become positive at admission along with increases in all classes of HEV antibodies. HEV RNA became undetectable during the deterioration of her condition, although a high antibody titer persisted. We determined her 412-nucleotide ORF2 sequence and constructed a molecular phylogenetic tree according to a previously described method (20) (Fig. 5). The HEV strain (HE-JA19-0280: DDBJ/EMBL/GenBank accession number LC581383) derived from this case belonged to genotype 3 (subgenotype 3b) and was closest to those of patients recovering from acute hepatitis E in Tokyo and Gunma Prefectures of Japan.
Figure 5. Phylogenetic tree constructed by the neighbor-joining method based on the partial nucleotide sequence (412 nucleotides) of the open reading frame 2 region of hepatitis E virus (HEV) isolates. In addition to the HEV isolate (HE-JA19-0280) obtained in the present study (highlighted with a closed box), 33 representative genotype 3 isolates (subgenotype 3a: n=8, subgenotype 3b: n=22, and subgenotype 3e: n=3), whose entire genomic sequence is known, are included in the tree using the prototype HEV sequences of genotype 1 (M73218), genotype 2 (M74506), and genotype 4 (AJ272108) as outgroups. Three HEV isolates sharing the highest identity of 97.1-97.8% with the HE-JA19-0280 isolate are also included. Each reference sequence is shown with the genotype/subgenotype followed by the accession number, isolate name, and country in which it was isolated. The bootstrap values (>70%) are indicated for nodes as the percentage of data among 1,000 resampling procedures. The scale bar is in units of nuceotide substitutions per site.
Table 2. Transition of Hepatobiliary Enzymes, HEV Antibodies, and HEV RNA.
Day Laboratory data HEV antibodies HEV RNA
AST
(U/L) ALT
(U/L) GGT
(U/L) ALP
(U/L) T-Bil
(mg/dL) IgG (OD450) IgM (OD450) IgA (OD450)
X - 80 137 111 413 940 3.4 0.010 (-) 0.046 (-) 0.020 (-) Negative
X (admission) 78 100 105 702 30.1 1.661 (+) >3.000 (+) 2.374 (+) +: 1.0×101 copies/mL
X+1 69 80 87 588 26.6 1.578 (+) >3.000 (+) 2.346 (+) +: 1.2×101 copies/mL
X+11 43 44 64 568 39.7 1.850 (+) >3.000 (+) 2.002 (+) Negative
X+14 61 66 78 631 46.7 1.970 (+) >3.000 (+) 1.768 (+) Negative
HEV: hepatitis E virus, AST: aspartate aminotransferase, ALT: alanine aminotransferase, GGT: gamma-glutamyl transpeptidase, ALP: alkaline phosphatase, T-Bil: total bilirubin
Discussion
The present autopsy case displayed histological evidence of submassive necrosis in the liver caused by acute HEV infection. The patient was presumed to have been at the liver cirrhosis stage of PBC but suddenly developed severe jaundice due to superimposed HEV infection and succumbed one month later to hepatic failure. The histopathological findings of severe liver atrophy with submassive loss and necrosis of hepatocytes could not be explained by ischemia only, strongly suggesting the involvement of genotype 3b HEV infection in her histopathological findings.
Although PBC patients generally have a normal life expectancy, they sometimes show rapid disease exacerbation due to concomitant autoimmune hepatitis (7,21) or simultaneous HCV infection (22) as a trigger of PBC deterioration. One rare instance of PBC with acute HEV infection has been reported to date (15). To our knowledge, however, an autopsy case of rapid deterioration triggered by HEV infection has not yet been described. As the mechanism underlying PBC exacerbation due to viral hepatitis infection remains unknown, the present case may contribute to the body of knowledge concerning this condition.
HEV is one of the most common causes of acute viral hepatitis (23). In addition to contaminated water, raw meat from pigs, boars, and deer is another common infection source (24-26). Recently, the prevalence of HEV cases without clinical symptoms as well as those of unknown transmission route has been increasing (27). The infection route in the present case could not be identified based on our medical interview. According to previous reports, pregnancy, old age, alcohol intake, and fatty liver are host factors associated with the aggravation of HEV, and co-infection with chronic liver disease is related to the risk of liver failure (13,14). Regarding the HEV genotype, HEV genotype 4 infection is reportedly associated with aggravation (26,28,29). Genotype 3 HEV, as detected in this case, is generally associated with a low tendency of severe clinical manifestations, although a rare case of progressive genotype 3 HEV infection has been reported (28). A mutation of V239A in the helicase region of the genotype 3 HEV genome has been associated with HEV infection aggravation (30). That mutant was absent in this case (data not shown). The patient had no other apparent host or viral factors associated with HEV severity. However, Wang et al. reported that the cirrhosis stage itself carries a potential risk of liver failure due to HEV infection, regardless of etiology; they further described the potentiation of the cirrhotic liver upon HEV infection and more aggressive immune- or inflammatory-mediated activation of cell death in a cirrhotic liver status as possible mechanisms of exacerbation (15). The above results suggested that even if patients have no documented risk factors of HEV aggravation, clinicians should bear in mind that HEV infection at a cirrhotic liver disease stage can become severe.
This patient had been diagnosed with PBC 26 years earlier based on serological criteria. Eight years before admission, she was already at an advanced stage of PBC, with Nakanuma stage 3 and Scheuer stage III classifications according to a liver biopsy. An autopsy specimen of the liver revealed obvious cirrhosis, which was consistent with the natural history of PBC as suggested by elevated serum surrogate markers of M2BPGi (31,32). However, the submassive loss and necrosis of hepatocytes could not solely be explained by the natural PBC history. Inflammatory cell infiltration suggesting acute hepatitis E (33) was not observed, which suggested a post-inflammatory status. Other general clinical features of acute hepatitis, including markedly elevated levels of liver enzymes, were absent as well. Her liver enzymes were only mildly elevated at day X-80, suggesting that asymptomatic hepatitis may have started at that point, followed by further increases in transaminase levels. Thus, one explanation as to why this case showed mild hepatitis was that the hepatitis had occurred after day X-80 and already peaked and ameliorated by the time of admission, such that jaundice represented the major feature. However, no clinical data were available between the patient’s last outpatient visit at day X-80 and her hospitalization. Another hypothesis was that this case had already reached the complete cirrhosis stage, as shown by the pathological findings, which could have induced mild liver enzyme elevations (34).
Patients with hepatitis E sometimes show severe jaundice (35). Although the underlying mechanism is uncertain, HEV has been reported to exhibit not only hepatocytic but also biliary tropism and replicate within bile duct epithelial cells (36,37). The severe jaundice and cholestasis in this case might have been the result of HEV infection complicating the chronic cholestatic liver disease of PBC. The fact that jaundice was more pronounced than elevated liver enzyme levels may support this notion. Although drug-induced liver injury (levofloxacin 500 mg/day) cannot be ruled out, we suspected that HEV infection likely triggered the exacerbation of PBC due to her awareness of jaundice prior to drug administration and the histological considerations described above.
In conclusion, clinicians should consider the possibility of acute HEV infection as a trigger for the acute exacerbation of PBC. In such cases, it may be necessary to treat the patient with the anticipation of severe aggravation.
The authors state that they have no Conflict of Interest (COI).
Acknowledgement
We thank Trevor Ralph for his English editorial assistance. | 68 kg. | Weight | CC BY-NC-ND | 33518570 | 19,677,427 | 2021-06-15 |
What was the outcome of reaction 'Condition aggravated'? | An Autopsy Case of Primary Biliary Cholangitis with Histological Submassive Hepatic Necrosis Caused by Acute Hepatitis E Virus Infection.
A 59-year-old woman who had been diagnosed with cirrhotic primary biliary cholangitis (PBC) 5 years earlier was admitted for severe jaundice (total bilirubin: 30.1 mg/dL). We suspected that her cirrhotic PBC had deteriorated acutely for some reason. Her general condition deteriorated quickly, and she passed away on day 18 of admission. Hepatitis E virus (HEV)-IgA antibodies were positive, and Genotype 3b HEV involvement was confirmed from a blood sample taken on admission. Histopathological findings revealed cirrhosis and submassive loss and necrosis of hepatocytes. Clinicians should consider the possibility of acute HEV infection as a trigger for acute PBC exacerbation.
Introduction
Primary biliary cholangitis (PBC) is a chronic and slowly progressive cholestatic autoimmune liver disease that is histopathologically characterized by an attack on the small intralobular bile duct by T lymphocytes (1). The precise etiology of PBC remains unknown but is related to genetic susceptibility environmental factors (2-4). Although most patients with PBC are asymptomatic and have a normal life expectancy, clinicians sometimes encounter symptomatic PBC cases with severe jaundice or liver failure as a result of the sustained loss of intralobular bile ducts in spite of ursodeoxycholic acid (UDCA) therapy (5,6). Patients with concomitant acute liver injury from autoimmune hepatitis show particularly rapid disease progression (7). The acute exacerbation of PBC from hepatitis virus co-infection is rare in the clinical setting.
The hepatitis E virus (HEV) is a quasi-enveloped, single-stranded RNA virus that causes acute or chronic hepatitis (8,9). With the increase in the number of hepatitis E cases, HEV antibody is now positive in approximately 5% of the general population in Japan (10,11). Among HEV-associated acute hepatitis cases, 0.5-4% of patients progress to fulminant hepatitis (12), leading to high mortality when intensive care and liver transplantation are unavailable. Rare cases of severe acute HEV hepatitis underlying such chronic liver diseases as alcoholic liver disease, nonalcoholic fatty liver disease, chronic viral hepatitis, and PBC have been documented as well (13-15). No autopsy PBC cases displaying acute exacerbation due to superimposed acute HEV infection have been reported to date.
We herein report the autopsy findings of a PBC case in the cirrhotic stage with histological submassive hepatic necrosis caused by acute HEV infection.
Case Report
A 59-year-old woman who had been serologically diagnosed with PBC after the detection of liver dysfunction 26 years earlier was admitted to our hospital for severe jaundice, brown urine, and leg edema. She had suffered from cold-like symptoms and skin jaundice for a month and had received antitussives and antibiotics (levofloxacin 500 mg/day) from her attending physician 2 weeks before admission. She had no symptoms of diarrhea, vomiting, or a history of eating raw meat. She reported no regular ethanol consumption or travel to a foreign country. Although she had been prescribed 600 mg/day UDCA and 400 mg/day bezafibrate for PBC, her medication compliance was extremely poor. She had persistent liver dysfunction [alanine aminotransferase (ALT) at around 100 U/L] and jaundice (total bilirubin at around 3 mg/dL). Eight years before admission, the histological findings of a liver biopsy specimen showed lymphocyte infiltration in the portal area and severe bile duct loss that were consistent with Nakanuma stage 3 (16) and Scheuer stage III (17) classifications (Fig. 1). Three years later, she was clinically diagnosed with cirrhosis-stage PBC. She had also undergone endoscopic gastric varices treatment one year before admission.
Figure 1. Histological findings of a liver biopsy specimen obtained eight years before admission. a, b) Lymphocyte infiltration in the portal area and severe bile duct loss were observed (Hematoxylin and Eosin staining). c) Azan-Mallory staining showed moderate fibrosis in the liver that was consistent with Nakanuma stage 3 and Scheuer stage III classifications.
On an examination at the time of admission, the patient was 165 cm tall, weighed 68 kg, and had a body mass index of 25.0 kg/m2. Her vital signs included Glasgow Coma Scale score E4V5M6, body temperature 37.3 °C, and blood pressure 111/54 mmHg. She exhibited conjunctival and systemic jaundice and front chest vascular spider but no flapping tremor. Laboratory tests on admission revealed elevated serum aspartate aminotransferase (78 U/L), ALT (100 U/L), gamma-glutamyl transpeptidase (105 U/L), alkaline phosphatase (702 U/L), total bilirubin (30.1 mg/dL), and Mac-2-binding protein glycan isomer (M2BPGi) (7.4 C・O・I) but a reduced platelet count (7.2×104/μL), albumin (2.7 g/dL), and prothrombin time activity (67.7%) (Table 1). Testing for hepatitis A virus antibody (immunoglobulin M), hepatitis B virus surface antigen, and anti-hepatitis C virus (HCV) antibody was negative. Serum antibodies to the Epstein-Barr virus and cytomegalovirus both showed a historical infection pattern. Although serum alpha fetoprotein levels were within normal range, levels of protein induced by vitamin K absence or antagonist II were mildly elevated (152 mAU/mL). Among the autoantibodies tested, fluorescent anti-nuclear antibody (× 640) and anti-mitochondrial M2 antibody (168.1 Index) were positive.
Table 1. Laboratory Findings on Admission.
Blood Chemistry / Serology Viral markers
White blood cell count 5,760 /μL Total protein 5.9 g/dL IgM-HAV Ab (-)
Neutrophils 71.2 % Albumin 2.7 g/dL HBs-Ag 0.001 (-) U/mL
Lymphocytes 19.8 % AST 78 U/L HBs-Ab 0.4 (-) mIU/mL
Monocytes 5.7 % ALT 100 U/L HBc-Ab 0.2 (-) C·O·I
Eosinophils 3.0 % Total bilirubin 30.14 mg/dL IgM-HBc Ab (-)
Basophils 0.3 % GGT 105 U/L HCV-Ab 0.1 (-) C·O·I
Red blood cell count 418 ×104/μL ALP 702 U/L IgM-EBV VCA Ab <10 (-) ×
Hemoglobin 13.1 g/dL BUN 12 mg/dL IgG-EBV VCA Ab 40 (+)
Hematocrit 37.4 % Creatinine 0.59 mg/dL EBV EBNA Ab <10 (-) ×
Platelet count 7.2 ×104/μL NH3 29 μg/dL IgM-CMV Ab 0.29 (-) Index
CRP 1.61 mg/dL IgG-CMV Ab 133.6 (+) AU/mL
Coagulation HbA1c 4.2 % IgA-HEV Ab (+)
PT 67.7 % IgM 139 mg/dL
APTT 29.0 sec IgA 292 mg/dL Autoimmune antibodies
Fibrinogen 192.0 mg/dL IgG 1,156 mg/dL FANA 640 ×
D-dimer 2.3 μg/mL M2BPGi 7.4 C·O·I AMA2 168.1 Index
Anti-centromere antibody (-)
Tumor markers LKM-1 (-)
AFP 7.0 ng/mL ASMA (-)
PIVKA II 152 mAU/mL
PT: prothrombin time, APTT: activated partial thromboplastin time, AST: aspartate aminotransferase, ALT: alanine aminotransferase, GGT: gamma-glutamyl transpeptidase, ALP: alkaline phosphatase, BUN: blood urea nitrogen, CRP: C-reactive protein, HbA1c: hemoglobin A1c, M2BPGi: Mac 2-Binding Protein Gylcan Isomer, AFP: alpha fetoprotein, PIVKA II: protein induced by vitamin K absence or antagonist II, FANA: fluorescent anti-nuclear antibody, AMA2: anti-mitochondrial M2 antibody, LKM-1: anti-liver/kidney microsome type 1 antibody, ASMA: anti-smooth muscle antibody, C·O·I: cut off index
Abdominal ultrasonography showed surface irregularity and a coarse parenchyma echotexture of the liver, suggesting cirrhosis (Fig. 2a). Abdominal contrast-enhanced computed tomography portal phase images showed surface undulation of the liver, collateral circulation around the stomach and splenic hilum, and ascites on the surface of the liver and spleen (Fig. 2b). No evidence suggestive of acute hepatitis, such as periportal collar sign, gallbladder atrophy, or wall thickening, was observed, nor were any space-occupying lesions present in the liver.
Figure 2. a) Abdominal ultrasonography showed liver surface irregularity (arrowheads) and a coarse parenchyma echotexture. b) Abdominal contrast-enhanced computed tomography portal phase images revealed surface undulation of the liver, collateral circulation around the stomach and splenic hilum (arrows), and ascites on the surface of the liver and spleen.
Based on the patient’s clinical findings, we suspected that her cirrhotic PBC had deteriorated acutely for some reason. Although she did not meet the criteria for acute liver failure, the presence of severe jaundice and ascites indicated the need for liver transplantation. After being refused for this treatment, we provided supportive care, including bed rest, lactulose administration, and albumin replacement. On day 13 of admission, HEV-IgA antibody was found to be positive in an admission blood sample, suggesting an association between the exacerbation of her PBC and acute HEV infection. However, the patient’s liver atrophy and renal failure were beyond treatment. Her general condition progressively worsened, and she passed away on day 18 of admission. The entire clinical course is summarized in Fig. 3.
Figure 3. Clinical course of the patient. ALT: alanine aminotransferase, PT: prothrombin time, T-Bil: Total bilirubin, Cre: Creatinine, HEV: Hepatitis E virus
A pathological autopsy was performed after obtaining informed consent from her family. Macroscopically, the surface of the liver was atrophied in a nodular manner, indicating complete cirrhosis (Fig. 4a). Microscopic observation of the liver showed severe atrophy with submassive loss and necrosis of hepatocytes from Zone 3 to Zone 2 of the hepatic lobule (Fig. 4b). However, the distribution did not match the centrilobular necrosis typically observed in hepatic ischemia. In some areas, hepatocytes around the central vein were intact (Fig. 4c). In addition, there was no remarkable steatosis inside hepatocytes indicative of hypoxia (Fig. 4c). Based on these findings, hepatic ischemia was not considered as the main cause of submassive loss and necrosis in this case. Although cholestasis was prominent in the lobules, inflammatory cell infiltration related to acute hepatitis was not evident (Fig. 4b, c). Regenerated nodules and highly fibrous septum formation were found in the liver, which were histologically consistent with cirrhosis (Fig. 4d). In the portal area, the infiltration of mononuclear cells and disappearance of bile ducts suggested advanced PBC (Fig. 4e). Extensive bile duct loss was confirmed between the interlobular and septal bile duct levels.
Figure 4. Autopsy findings. a) Macroscopically, the surface of the liver was atrophied in a nodular manner, indicating complete cirrhosis. b) Severe atrophy with submassive loss and necrosis of hepatocytes (red dotted lines) from Zone 3 to Zone 2 of the hepatic lobule were evident (Hematoxylin and Eosin staining). P: portal vein, C: central vein. c) In some areas, hepatocytes around the central vein were relatively intact, with no steatosis inside hepatocytes suggestive of hypoxia. Cholestasis was prominent in the lobules. Inflammatory cell infiltration indicative of acute hepatitis was not detected. d) On Elastica-Goldner staining, regenerated nodules and highly fibrous septum formation were found in the liver, findings that were histologically consistent with cirrhosis. e) In the portal area, infiltration of mononuclear cells and the disappearance of bile ducts were observed, suggesting advanced PBC. P: portal vein
HEV antibodies (IgG, IgM, and IgA) were measured by an enzyme-linked immunosorbent assay using frozen serum samples according to a previously described method (18). The testing results are shown in Table 2 along with the corresponding hepatobiliary enzymes at each time point. HEV RNA was detected by the nested reverse-transcription polymerase chain reaction with primers targeting the open reading frame 2 (ORF2) region of the HEV genome (nucleotide position 5944-6355, excluding primer sequences at both ends: M73218), as described previously (19). HEV RNA, which had been negative at the last visit before admission, had become positive at admission along with increases in all classes of HEV antibodies. HEV RNA became undetectable during the deterioration of her condition, although a high antibody titer persisted. We determined her 412-nucleotide ORF2 sequence and constructed a molecular phylogenetic tree according to a previously described method (20) (Fig. 5). The HEV strain (HE-JA19-0280: DDBJ/EMBL/GenBank accession number LC581383) derived from this case belonged to genotype 3 (subgenotype 3b) and was closest to those of patients recovering from acute hepatitis E in Tokyo and Gunma Prefectures of Japan.
Figure 5. Phylogenetic tree constructed by the neighbor-joining method based on the partial nucleotide sequence (412 nucleotides) of the open reading frame 2 region of hepatitis E virus (HEV) isolates. In addition to the HEV isolate (HE-JA19-0280) obtained in the present study (highlighted with a closed box), 33 representative genotype 3 isolates (subgenotype 3a: n=8, subgenotype 3b: n=22, and subgenotype 3e: n=3), whose entire genomic sequence is known, are included in the tree using the prototype HEV sequences of genotype 1 (M73218), genotype 2 (M74506), and genotype 4 (AJ272108) as outgroups. Three HEV isolates sharing the highest identity of 97.1-97.8% with the HE-JA19-0280 isolate are also included. Each reference sequence is shown with the genotype/subgenotype followed by the accession number, isolate name, and country in which it was isolated. The bootstrap values (>70%) are indicated for nodes as the percentage of data among 1,000 resampling procedures. The scale bar is in units of nuceotide substitutions per site.
Table 2. Transition of Hepatobiliary Enzymes, HEV Antibodies, and HEV RNA.
Day Laboratory data HEV antibodies HEV RNA
AST
(U/L) ALT
(U/L) GGT
(U/L) ALP
(U/L) T-Bil
(mg/dL) IgG (OD450) IgM (OD450) IgA (OD450)
X - 80 137 111 413 940 3.4 0.010 (-) 0.046 (-) 0.020 (-) Negative
X (admission) 78 100 105 702 30.1 1.661 (+) >3.000 (+) 2.374 (+) +: 1.0×101 copies/mL
X+1 69 80 87 588 26.6 1.578 (+) >3.000 (+) 2.346 (+) +: 1.2×101 copies/mL
X+11 43 44 64 568 39.7 1.850 (+) >3.000 (+) 2.002 (+) Negative
X+14 61 66 78 631 46.7 1.970 (+) >3.000 (+) 1.768 (+) Negative
HEV: hepatitis E virus, AST: aspartate aminotransferase, ALT: alanine aminotransferase, GGT: gamma-glutamyl transpeptidase, ALP: alkaline phosphatase, T-Bil: total bilirubin
Discussion
The present autopsy case displayed histological evidence of submassive necrosis in the liver caused by acute HEV infection. The patient was presumed to have been at the liver cirrhosis stage of PBC but suddenly developed severe jaundice due to superimposed HEV infection and succumbed one month later to hepatic failure. The histopathological findings of severe liver atrophy with submassive loss and necrosis of hepatocytes could not be explained by ischemia only, strongly suggesting the involvement of genotype 3b HEV infection in her histopathological findings.
Although PBC patients generally have a normal life expectancy, they sometimes show rapid disease exacerbation due to concomitant autoimmune hepatitis (7,21) or simultaneous HCV infection (22) as a trigger of PBC deterioration. One rare instance of PBC with acute HEV infection has been reported to date (15). To our knowledge, however, an autopsy case of rapid deterioration triggered by HEV infection has not yet been described. As the mechanism underlying PBC exacerbation due to viral hepatitis infection remains unknown, the present case may contribute to the body of knowledge concerning this condition.
HEV is one of the most common causes of acute viral hepatitis (23). In addition to contaminated water, raw meat from pigs, boars, and deer is another common infection source (24-26). Recently, the prevalence of HEV cases without clinical symptoms as well as those of unknown transmission route has been increasing (27). The infection route in the present case could not be identified based on our medical interview. According to previous reports, pregnancy, old age, alcohol intake, and fatty liver are host factors associated with the aggravation of HEV, and co-infection with chronic liver disease is related to the risk of liver failure (13,14). Regarding the HEV genotype, HEV genotype 4 infection is reportedly associated with aggravation (26,28,29). Genotype 3 HEV, as detected in this case, is generally associated with a low tendency of severe clinical manifestations, although a rare case of progressive genotype 3 HEV infection has been reported (28). A mutation of V239A in the helicase region of the genotype 3 HEV genome has been associated with HEV infection aggravation (30). That mutant was absent in this case (data not shown). The patient had no other apparent host or viral factors associated with HEV severity. However, Wang et al. reported that the cirrhosis stage itself carries a potential risk of liver failure due to HEV infection, regardless of etiology; they further described the potentiation of the cirrhotic liver upon HEV infection and more aggressive immune- or inflammatory-mediated activation of cell death in a cirrhotic liver status as possible mechanisms of exacerbation (15). The above results suggested that even if patients have no documented risk factors of HEV aggravation, clinicians should bear in mind that HEV infection at a cirrhotic liver disease stage can become severe.
This patient had been diagnosed with PBC 26 years earlier based on serological criteria. Eight years before admission, she was already at an advanced stage of PBC, with Nakanuma stage 3 and Scheuer stage III classifications according to a liver biopsy. An autopsy specimen of the liver revealed obvious cirrhosis, which was consistent with the natural history of PBC as suggested by elevated serum surrogate markers of M2BPGi (31,32). However, the submassive loss and necrosis of hepatocytes could not solely be explained by the natural PBC history. Inflammatory cell infiltration suggesting acute hepatitis E (33) was not observed, which suggested a post-inflammatory status. Other general clinical features of acute hepatitis, including markedly elevated levels of liver enzymes, were absent as well. Her liver enzymes were only mildly elevated at day X-80, suggesting that asymptomatic hepatitis may have started at that point, followed by further increases in transaminase levels. Thus, one explanation as to why this case showed mild hepatitis was that the hepatitis had occurred after day X-80 and already peaked and ameliorated by the time of admission, such that jaundice represented the major feature. However, no clinical data were available between the patient’s last outpatient visit at day X-80 and her hospitalization. Another hypothesis was that this case had already reached the complete cirrhosis stage, as shown by the pathological findings, which could have induced mild liver enzyme elevations (34).
Patients with hepatitis E sometimes show severe jaundice (35). Although the underlying mechanism is uncertain, HEV has been reported to exhibit not only hepatocytic but also biliary tropism and replicate within bile duct epithelial cells (36,37). The severe jaundice and cholestasis in this case might have been the result of HEV infection complicating the chronic cholestatic liver disease of PBC. The fact that jaundice was more pronounced than elevated liver enzyme levels may support this notion. Although drug-induced liver injury (levofloxacin 500 mg/day) cannot be ruled out, we suspected that HEV infection likely triggered the exacerbation of PBC due to her awareness of jaundice prior to drug administration and the histological considerations described above.
In conclusion, clinicians should consider the possibility of acute HEV infection as a trigger for the acute exacerbation of PBC. In such cases, it may be necessary to treat the patient with the anticipation of severe aggravation.
The authors state that they have no Conflict of Interest (COI).
Acknowledgement
We thank Trevor Ralph for his English editorial assistance. | Not recovered | ReactionOutcome | CC BY-NC-ND | 33518570 | 19,677,427 | 2021-06-15 |
What was the outcome of reaction 'Drug-induced liver injury'? | An Autopsy Case of Primary Biliary Cholangitis with Histological Submassive Hepatic Necrosis Caused by Acute Hepatitis E Virus Infection.
A 59-year-old woman who had been diagnosed with cirrhotic primary biliary cholangitis (PBC) 5 years earlier was admitted for severe jaundice (total bilirubin: 30.1 mg/dL). We suspected that her cirrhotic PBC had deteriorated acutely for some reason. Her general condition deteriorated quickly, and she passed away on day 18 of admission. Hepatitis E virus (HEV)-IgA antibodies were positive, and Genotype 3b HEV involvement was confirmed from a blood sample taken on admission. Histopathological findings revealed cirrhosis and submassive loss and necrosis of hepatocytes. Clinicians should consider the possibility of acute HEV infection as a trigger for acute PBC exacerbation.
Introduction
Primary biliary cholangitis (PBC) is a chronic and slowly progressive cholestatic autoimmune liver disease that is histopathologically characterized by an attack on the small intralobular bile duct by T lymphocytes (1). The precise etiology of PBC remains unknown but is related to genetic susceptibility environmental factors (2-4). Although most patients with PBC are asymptomatic and have a normal life expectancy, clinicians sometimes encounter symptomatic PBC cases with severe jaundice or liver failure as a result of the sustained loss of intralobular bile ducts in spite of ursodeoxycholic acid (UDCA) therapy (5,6). Patients with concomitant acute liver injury from autoimmune hepatitis show particularly rapid disease progression (7). The acute exacerbation of PBC from hepatitis virus co-infection is rare in the clinical setting.
The hepatitis E virus (HEV) is a quasi-enveloped, single-stranded RNA virus that causes acute or chronic hepatitis (8,9). With the increase in the number of hepatitis E cases, HEV antibody is now positive in approximately 5% of the general population in Japan (10,11). Among HEV-associated acute hepatitis cases, 0.5-4% of patients progress to fulminant hepatitis (12), leading to high mortality when intensive care and liver transplantation are unavailable. Rare cases of severe acute HEV hepatitis underlying such chronic liver diseases as alcoholic liver disease, nonalcoholic fatty liver disease, chronic viral hepatitis, and PBC have been documented as well (13-15). No autopsy PBC cases displaying acute exacerbation due to superimposed acute HEV infection have been reported to date.
We herein report the autopsy findings of a PBC case in the cirrhotic stage with histological submassive hepatic necrosis caused by acute HEV infection.
Case Report
A 59-year-old woman who had been serologically diagnosed with PBC after the detection of liver dysfunction 26 years earlier was admitted to our hospital for severe jaundice, brown urine, and leg edema. She had suffered from cold-like symptoms and skin jaundice for a month and had received antitussives and antibiotics (levofloxacin 500 mg/day) from her attending physician 2 weeks before admission. She had no symptoms of diarrhea, vomiting, or a history of eating raw meat. She reported no regular ethanol consumption or travel to a foreign country. Although she had been prescribed 600 mg/day UDCA and 400 mg/day bezafibrate for PBC, her medication compliance was extremely poor. She had persistent liver dysfunction [alanine aminotransferase (ALT) at around 100 U/L] and jaundice (total bilirubin at around 3 mg/dL). Eight years before admission, the histological findings of a liver biopsy specimen showed lymphocyte infiltration in the portal area and severe bile duct loss that were consistent with Nakanuma stage 3 (16) and Scheuer stage III (17) classifications (Fig. 1). Three years later, she was clinically diagnosed with cirrhosis-stage PBC. She had also undergone endoscopic gastric varices treatment one year before admission.
Figure 1. Histological findings of a liver biopsy specimen obtained eight years before admission. a, b) Lymphocyte infiltration in the portal area and severe bile duct loss were observed (Hematoxylin and Eosin staining). c) Azan-Mallory staining showed moderate fibrosis in the liver that was consistent with Nakanuma stage 3 and Scheuer stage III classifications.
On an examination at the time of admission, the patient was 165 cm tall, weighed 68 kg, and had a body mass index of 25.0 kg/m2. Her vital signs included Glasgow Coma Scale score E4V5M6, body temperature 37.3 °C, and blood pressure 111/54 mmHg. She exhibited conjunctival and systemic jaundice and front chest vascular spider but no flapping tremor. Laboratory tests on admission revealed elevated serum aspartate aminotransferase (78 U/L), ALT (100 U/L), gamma-glutamyl transpeptidase (105 U/L), alkaline phosphatase (702 U/L), total bilirubin (30.1 mg/dL), and Mac-2-binding protein glycan isomer (M2BPGi) (7.4 C・O・I) but a reduced platelet count (7.2×104/μL), albumin (2.7 g/dL), and prothrombin time activity (67.7%) (Table 1). Testing for hepatitis A virus antibody (immunoglobulin M), hepatitis B virus surface antigen, and anti-hepatitis C virus (HCV) antibody was negative. Serum antibodies to the Epstein-Barr virus and cytomegalovirus both showed a historical infection pattern. Although serum alpha fetoprotein levels were within normal range, levels of protein induced by vitamin K absence or antagonist II were mildly elevated (152 mAU/mL). Among the autoantibodies tested, fluorescent anti-nuclear antibody (× 640) and anti-mitochondrial M2 antibody (168.1 Index) were positive.
Table 1. Laboratory Findings on Admission.
Blood Chemistry / Serology Viral markers
White blood cell count 5,760 /μL Total protein 5.9 g/dL IgM-HAV Ab (-)
Neutrophils 71.2 % Albumin 2.7 g/dL HBs-Ag 0.001 (-) U/mL
Lymphocytes 19.8 % AST 78 U/L HBs-Ab 0.4 (-) mIU/mL
Monocytes 5.7 % ALT 100 U/L HBc-Ab 0.2 (-) C·O·I
Eosinophils 3.0 % Total bilirubin 30.14 mg/dL IgM-HBc Ab (-)
Basophils 0.3 % GGT 105 U/L HCV-Ab 0.1 (-) C·O·I
Red blood cell count 418 ×104/μL ALP 702 U/L IgM-EBV VCA Ab <10 (-) ×
Hemoglobin 13.1 g/dL BUN 12 mg/dL IgG-EBV VCA Ab 40 (+)
Hematocrit 37.4 % Creatinine 0.59 mg/dL EBV EBNA Ab <10 (-) ×
Platelet count 7.2 ×104/μL NH3 29 μg/dL IgM-CMV Ab 0.29 (-) Index
CRP 1.61 mg/dL IgG-CMV Ab 133.6 (+) AU/mL
Coagulation HbA1c 4.2 % IgA-HEV Ab (+)
PT 67.7 % IgM 139 mg/dL
APTT 29.0 sec IgA 292 mg/dL Autoimmune antibodies
Fibrinogen 192.0 mg/dL IgG 1,156 mg/dL FANA 640 ×
D-dimer 2.3 μg/mL M2BPGi 7.4 C·O·I AMA2 168.1 Index
Anti-centromere antibody (-)
Tumor markers LKM-1 (-)
AFP 7.0 ng/mL ASMA (-)
PIVKA II 152 mAU/mL
PT: prothrombin time, APTT: activated partial thromboplastin time, AST: aspartate aminotransferase, ALT: alanine aminotransferase, GGT: gamma-glutamyl transpeptidase, ALP: alkaline phosphatase, BUN: blood urea nitrogen, CRP: C-reactive protein, HbA1c: hemoglobin A1c, M2BPGi: Mac 2-Binding Protein Gylcan Isomer, AFP: alpha fetoprotein, PIVKA II: protein induced by vitamin K absence or antagonist II, FANA: fluorescent anti-nuclear antibody, AMA2: anti-mitochondrial M2 antibody, LKM-1: anti-liver/kidney microsome type 1 antibody, ASMA: anti-smooth muscle antibody, C·O·I: cut off index
Abdominal ultrasonography showed surface irregularity and a coarse parenchyma echotexture of the liver, suggesting cirrhosis (Fig. 2a). Abdominal contrast-enhanced computed tomography portal phase images showed surface undulation of the liver, collateral circulation around the stomach and splenic hilum, and ascites on the surface of the liver and spleen (Fig. 2b). No evidence suggestive of acute hepatitis, such as periportal collar sign, gallbladder atrophy, or wall thickening, was observed, nor were any space-occupying lesions present in the liver.
Figure 2. a) Abdominal ultrasonography showed liver surface irregularity (arrowheads) and a coarse parenchyma echotexture. b) Abdominal contrast-enhanced computed tomography portal phase images revealed surface undulation of the liver, collateral circulation around the stomach and splenic hilum (arrows), and ascites on the surface of the liver and spleen.
Based on the patient’s clinical findings, we suspected that her cirrhotic PBC had deteriorated acutely for some reason. Although she did not meet the criteria for acute liver failure, the presence of severe jaundice and ascites indicated the need for liver transplantation. After being refused for this treatment, we provided supportive care, including bed rest, lactulose administration, and albumin replacement. On day 13 of admission, HEV-IgA antibody was found to be positive in an admission blood sample, suggesting an association between the exacerbation of her PBC and acute HEV infection. However, the patient’s liver atrophy and renal failure were beyond treatment. Her general condition progressively worsened, and she passed away on day 18 of admission. The entire clinical course is summarized in Fig. 3.
Figure 3. Clinical course of the patient. ALT: alanine aminotransferase, PT: prothrombin time, T-Bil: Total bilirubin, Cre: Creatinine, HEV: Hepatitis E virus
A pathological autopsy was performed after obtaining informed consent from her family. Macroscopically, the surface of the liver was atrophied in a nodular manner, indicating complete cirrhosis (Fig. 4a). Microscopic observation of the liver showed severe atrophy with submassive loss and necrosis of hepatocytes from Zone 3 to Zone 2 of the hepatic lobule (Fig. 4b). However, the distribution did not match the centrilobular necrosis typically observed in hepatic ischemia. In some areas, hepatocytes around the central vein were intact (Fig. 4c). In addition, there was no remarkable steatosis inside hepatocytes indicative of hypoxia (Fig. 4c). Based on these findings, hepatic ischemia was not considered as the main cause of submassive loss and necrosis in this case. Although cholestasis was prominent in the lobules, inflammatory cell infiltration related to acute hepatitis was not evident (Fig. 4b, c). Regenerated nodules and highly fibrous septum formation were found in the liver, which were histologically consistent with cirrhosis (Fig. 4d). In the portal area, the infiltration of mononuclear cells and disappearance of bile ducts suggested advanced PBC (Fig. 4e). Extensive bile duct loss was confirmed between the interlobular and septal bile duct levels.
Figure 4. Autopsy findings. a) Macroscopically, the surface of the liver was atrophied in a nodular manner, indicating complete cirrhosis. b) Severe atrophy with submassive loss and necrosis of hepatocytes (red dotted lines) from Zone 3 to Zone 2 of the hepatic lobule were evident (Hematoxylin and Eosin staining). P: portal vein, C: central vein. c) In some areas, hepatocytes around the central vein were relatively intact, with no steatosis inside hepatocytes suggestive of hypoxia. Cholestasis was prominent in the lobules. Inflammatory cell infiltration indicative of acute hepatitis was not detected. d) On Elastica-Goldner staining, regenerated nodules and highly fibrous septum formation were found in the liver, findings that were histologically consistent with cirrhosis. e) In the portal area, infiltration of mononuclear cells and the disappearance of bile ducts were observed, suggesting advanced PBC. P: portal vein
HEV antibodies (IgG, IgM, and IgA) were measured by an enzyme-linked immunosorbent assay using frozen serum samples according to a previously described method (18). The testing results are shown in Table 2 along with the corresponding hepatobiliary enzymes at each time point. HEV RNA was detected by the nested reverse-transcription polymerase chain reaction with primers targeting the open reading frame 2 (ORF2) region of the HEV genome (nucleotide position 5944-6355, excluding primer sequences at both ends: M73218), as described previously (19). HEV RNA, which had been negative at the last visit before admission, had become positive at admission along with increases in all classes of HEV antibodies. HEV RNA became undetectable during the deterioration of her condition, although a high antibody titer persisted. We determined her 412-nucleotide ORF2 sequence and constructed a molecular phylogenetic tree according to a previously described method (20) (Fig. 5). The HEV strain (HE-JA19-0280: DDBJ/EMBL/GenBank accession number LC581383) derived from this case belonged to genotype 3 (subgenotype 3b) and was closest to those of patients recovering from acute hepatitis E in Tokyo and Gunma Prefectures of Japan.
Figure 5. Phylogenetic tree constructed by the neighbor-joining method based on the partial nucleotide sequence (412 nucleotides) of the open reading frame 2 region of hepatitis E virus (HEV) isolates. In addition to the HEV isolate (HE-JA19-0280) obtained in the present study (highlighted with a closed box), 33 representative genotype 3 isolates (subgenotype 3a: n=8, subgenotype 3b: n=22, and subgenotype 3e: n=3), whose entire genomic sequence is known, are included in the tree using the prototype HEV sequences of genotype 1 (M73218), genotype 2 (M74506), and genotype 4 (AJ272108) as outgroups. Three HEV isolates sharing the highest identity of 97.1-97.8% with the HE-JA19-0280 isolate are also included. Each reference sequence is shown with the genotype/subgenotype followed by the accession number, isolate name, and country in which it was isolated. The bootstrap values (>70%) are indicated for nodes as the percentage of data among 1,000 resampling procedures. The scale bar is in units of nuceotide substitutions per site.
Table 2. Transition of Hepatobiliary Enzymes, HEV Antibodies, and HEV RNA.
Day Laboratory data HEV antibodies HEV RNA
AST
(U/L) ALT
(U/L) GGT
(U/L) ALP
(U/L) T-Bil
(mg/dL) IgG (OD450) IgM (OD450) IgA (OD450)
X - 80 137 111 413 940 3.4 0.010 (-) 0.046 (-) 0.020 (-) Negative
X (admission) 78 100 105 702 30.1 1.661 (+) >3.000 (+) 2.374 (+) +: 1.0×101 copies/mL
X+1 69 80 87 588 26.6 1.578 (+) >3.000 (+) 2.346 (+) +: 1.2×101 copies/mL
X+11 43 44 64 568 39.7 1.850 (+) >3.000 (+) 2.002 (+) Negative
X+14 61 66 78 631 46.7 1.970 (+) >3.000 (+) 1.768 (+) Negative
HEV: hepatitis E virus, AST: aspartate aminotransferase, ALT: alanine aminotransferase, GGT: gamma-glutamyl transpeptidase, ALP: alkaline phosphatase, T-Bil: total bilirubin
Discussion
The present autopsy case displayed histological evidence of submassive necrosis in the liver caused by acute HEV infection. The patient was presumed to have been at the liver cirrhosis stage of PBC but suddenly developed severe jaundice due to superimposed HEV infection and succumbed one month later to hepatic failure. The histopathological findings of severe liver atrophy with submassive loss and necrosis of hepatocytes could not be explained by ischemia only, strongly suggesting the involvement of genotype 3b HEV infection in her histopathological findings.
Although PBC patients generally have a normal life expectancy, they sometimes show rapid disease exacerbation due to concomitant autoimmune hepatitis (7,21) or simultaneous HCV infection (22) as a trigger of PBC deterioration. One rare instance of PBC with acute HEV infection has been reported to date (15). To our knowledge, however, an autopsy case of rapid deterioration triggered by HEV infection has not yet been described. As the mechanism underlying PBC exacerbation due to viral hepatitis infection remains unknown, the present case may contribute to the body of knowledge concerning this condition.
HEV is one of the most common causes of acute viral hepatitis (23). In addition to contaminated water, raw meat from pigs, boars, and deer is another common infection source (24-26). Recently, the prevalence of HEV cases without clinical symptoms as well as those of unknown transmission route has been increasing (27). The infection route in the present case could not be identified based on our medical interview. According to previous reports, pregnancy, old age, alcohol intake, and fatty liver are host factors associated with the aggravation of HEV, and co-infection with chronic liver disease is related to the risk of liver failure (13,14). Regarding the HEV genotype, HEV genotype 4 infection is reportedly associated with aggravation (26,28,29). Genotype 3 HEV, as detected in this case, is generally associated with a low tendency of severe clinical manifestations, although a rare case of progressive genotype 3 HEV infection has been reported (28). A mutation of V239A in the helicase region of the genotype 3 HEV genome has been associated with HEV infection aggravation (30). That mutant was absent in this case (data not shown). The patient had no other apparent host or viral factors associated with HEV severity. However, Wang et al. reported that the cirrhosis stage itself carries a potential risk of liver failure due to HEV infection, regardless of etiology; they further described the potentiation of the cirrhotic liver upon HEV infection and more aggressive immune- or inflammatory-mediated activation of cell death in a cirrhotic liver status as possible mechanisms of exacerbation (15). The above results suggested that even if patients have no documented risk factors of HEV aggravation, clinicians should bear in mind that HEV infection at a cirrhotic liver disease stage can become severe.
This patient had been diagnosed with PBC 26 years earlier based on serological criteria. Eight years before admission, she was already at an advanced stage of PBC, with Nakanuma stage 3 and Scheuer stage III classifications according to a liver biopsy. An autopsy specimen of the liver revealed obvious cirrhosis, which was consistent with the natural history of PBC as suggested by elevated serum surrogate markers of M2BPGi (31,32). However, the submassive loss and necrosis of hepatocytes could not solely be explained by the natural PBC history. Inflammatory cell infiltration suggesting acute hepatitis E (33) was not observed, which suggested a post-inflammatory status. Other general clinical features of acute hepatitis, including markedly elevated levels of liver enzymes, were absent as well. Her liver enzymes were only mildly elevated at day X-80, suggesting that asymptomatic hepatitis may have started at that point, followed by further increases in transaminase levels. Thus, one explanation as to why this case showed mild hepatitis was that the hepatitis had occurred after day X-80 and already peaked and ameliorated by the time of admission, such that jaundice represented the major feature. However, no clinical data were available between the patient’s last outpatient visit at day X-80 and her hospitalization. Another hypothesis was that this case had already reached the complete cirrhosis stage, as shown by the pathological findings, which could have induced mild liver enzyme elevations (34).
Patients with hepatitis E sometimes show severe jaundice (35). Although the underlying mechanism is uncertain, HEV has been reported to exhibit not only hepatocytic but also biliary tropism and replicate within bile duct epithelial cells (36,37). The severe jaundice and cholestasis in this case might have been the result of HEV infection complicating the chronic cholestatic liver disease of PBC. The fact that jaundice was more pronounced than elevated liver enzyme levels may support this notion. Although drug-induced liver injury (levofloxacin 500 mg/day) cannot be ruled out, we suspected that HEV infection likely triggered the exacerbation of PBC due to her awareness of jaundice prior to drug administration and the histological considerations described above.
In conclusion, clinicians should consider the possibility of acute HEV infection as a trigger for the acute exacerbation of PBC. In such cases, it may be necessary to treat the patient with the anticipation of severe aggravation.
The authors state that they have no Conflict of Interest (COI).
Acknowledgement
We thank Trevor Ralph for his English editorial assistance. | Not recovered | ReactionOutcome | CC BY-NC-ND | 33518570 | 19,677,427 | 2021-06-15 |
What was the outcome of reaction 'Hepatic cirrhosis'? | An Autopsy Case of Primary Biliary Cholangitis with Histological Submassive Hepatic Necrosis Caused by Acute Hepatitis E Virus Infection.
A 59-year-old woman who had been diagnosed with cirrhotic primary biliary cholangitis (PBC) 5 years earlier was admitted for severe jaundice (total bilirubin: 30.1 mg/dL). We suspected that her cirrhotic PBC had deteriorated acutely for some reason. Her general condition deteriorated quickly, and she passed away on day 18 of admission. Hepatitis E virus (HEV)-IgA antibodies were positive, and Genotype 3b HEV involvement was confirmed from a blood sample taken on admission. Histopathological findings revealed cirrhosis and submassive loss and necrosis of hepatocytes. Clinicians should consider the possibility of acute HEV infection as a trigger for acute PBC exacerbation.
Introduction
Primary biliary cholangitis (PBC) is a chronic and slowly progressive cholestatic autoimmune liver disease that is histopathologically characterized by an attack on the small intralobular bile duct by T lymphocytes (1). The precise etiology of PBC remains unknown but is related to genetic susceptibility environmental factors (2-4). Although most patients with PBC are asymptomatic and have a normal life expectancy, clinicians sometimes encounter symptomatic PBC cases with severe jaundice or liver failure as a result of the sustained loss of intralobular bile ducts in spite of ursodeoxycholic acid (UDCA) therapy (5,6). Patients with concomitant acute liver injury from autoimmune hepatitis show particularly rapid disease progression (7). The acute exacerbation of PBC from hepatitis virus co-infection is rare in the clinical setting.
The hepatitis E virus (HEV) is a quasi-enveloped, single-stranded RNA virus that causes acute or chronic hepatitis (8,9). With the increase in the number of hepatitis E cases, HEV antibody is now positive in approximately 5% of the general population in Japan (10,11). Among HEV-associated acute hepatitis cases, 0.5-4% of patients progress to fulminant hepatitis (12), leading to high mortality when intensive care and liver transplantation are unavailable. Rare cases of severe acute HEV hepatitis underlying such chronic liver diseases as alcoholic liver disease, nonalcoholic fatty liver disease, chronic viral hepatitis, and PBC have been documented as well (13-15). No autopsy PBC cases displaying acute exacerbation due to superimposed acute HEV infection have been reported to date.
We herein report the autopsy findings of a PBC case in the cirrhotic stage with histological submassive hepatic necrosis caused by acute HEV infection.
Case Report
A 59-year-old woman who had been serologically diagnosed with PBC after the detection of liver dysfunction 26 years earlier was admitted to our hospital for severe jaundice, brown urine, and leg edema. She had suffered from cold-like symptoms and skin jaundice for a month and had received antitussives and antibiotics (levofloxacin 500 mg/day) from her attending physician 2 weeks before admission. She had no symptoms of diarrhea, vomiting, or a history of eating raw meat. She reported no regular ethanol consumption or travel to a foreign country. Although she had been prescribed 600 mg/day UDCA and 400 mg/day bezafibrate for PBC, her medication compliance was extremely poor. She had persistent liver dysfunction [alanine aminotransferase (ALT) at around 100 U/L] and jaundice (total bilirubin at around 3 mg/dL). Eight years before admission, the histological findings of a liver biopsy specimen showed lymphocyte infiltration in the portal area and severe bile duct loss that were consistent with Nakanuma stage 3 (16) and Scheuer stage III (17) classifications (Fig. 1). Three years later, she was clinically diagnosed with cirrhosis-stage PBC. She had also undergone endoscopic gastric varices treatment one year before admission.
Figure 1. Histological findings of a liver biopsy specimen obtained eight years before admission. a, b) Lymphocyte infiltration in the portal area and severe bile duct loss were observed (Hematoxylin and Eosin staining). c) Azan-Mallory staining showed moderate fibrosis in the liver that was consistent with Nakanuma stage 3 and Scheuer stage III classifications.
On an examination at the time of admission, the patient was 165 cm tall, weighed 68 kg, and had a body mass index of 25.0 kg/m2. Her vital signs included Glasgow Coma Scale score E4V5M6, body temperature 37.3 °C, and blood pressure 111/54 mmHg. She exhibited conjunctival and systemic jaundice and front chest vascular spider but no flapping tremor. Laboratory tests on admission revealed elevated serum aspartate aminotransferase (78 U/L), ALT (100 U/L), gamma-glutamyl transpeptidase (105 U/L), alkaline phosphatase (702 U/L), total bilirubin (30.1 mg/dL), and Mac-2-binding protein glycan isomer (M2BPGi) (7.4 C・O・I) but a reduced platelet count (7.2×104/μL), albumin (2.7 g/dL), and prothrombin time activity (67.7%) (Table 1). Testing for hepatitis A virus antibody (immunoglobulin M), hepatitis B virus surface antigen, and anti-hepatitis C virus (HCV) antibody was negative. Serum antibodies to the Epstein-Barr virus and cytomegalovirus both showed a historical infection pattern. Although serum alpha fetoprotein levels were within normal range, levels of protein induced by vitamin K absence or antagonist II were mildly elevated (152 mAU/mL). Among the autoantibodies tested, fluorescent anti-nuclear antibody (× 640) and anti-mitochondrial M2 antibody (168.1 Index) were positive.
Table 1. Laboratory Findings on Admission.
Blood Chemistry / Serology Viral markers
White blood cell count 5,760 /μL Total protein 5.9 g/dL IgM-HAV Ab (-)
Neutrophils 71.2 % Albumin 2.7 g/dL HBs-Ag 0.001 (-) U/mL
Lymphocytes 19.8 % AST 78 U/L HBs-Ab 0.4 (-) mIU/mL
Monocytes 5.7 % ALT 100 U/L HBc-Ab 0.2 (-) C·O·I
Eosinophils 3.0 % Total bilirubin 30.14 mg/dL IgM-HBc Ab (-)
Basophils 0.3 % GGT 105 U/L HCV-Ab 0.1 (-) C·O·I
Red blood cell count 418 ×104/μL ALP 702 U/L IgM-EBV VCA Ab <10 (-) ×
Hemoglobin 13.1 g/dL BUN 12 mg/dL IgG-EBV VCA Ab 40 (+)
Hematocrit 37.4 % Creatinine 0.59 mg/dL EBV EBNA Ab <10 (-) ×
Platelet count 7.2 ×104/μL NH3 29 μg/dL IgM-CMV Ab 0.29 (-) Index
CRP 1.61 mg/dL IgG-CMV Ab 133.6 (+) AU/mL
Coagulation HbA1c 4.2 % IgA-HEV Ab (+)
PT 67.7 % IgM 139 mg/dL
APTT 29.0 sec IgA 292 mg/dL Autoimmune antibodies
Fibrinogen 192.0 mg/dL IgG 1,156 mg/dL FANA 640 ×
D-dimer 2.3 μg/mL M2BPGi 7.4 C·O·I AMA2 168.1 Index
Anti-centromere antibody (-)
Tumor markers LKM-1 (-)
AFP 7.0 ng/mL ASMA (-)
PIVKA II 152 mAU/mL
PT: prothrombin time, APTT: activated partial thromboplastin time, AST: aspartate aminotransferase, ALT: alanine aminotransferase, GGT: gamma-glutamyl transpeptidase, ALP: alkaline phosphatase, BUN: blood urea nitrogen, CRP: C-reactive protein, HbA1c: hemoglobin A1c, M2BPGi: Mac 2-Binding Protein Gylcan Isomer, AFP: alpha fetoprotein, PIVKA II: protein induced by vitamin K absence or antagonist II, FANA: fluorescent anti-nuclear antibody, AMA2: anti-mitochondrial M2 antibody, LKM-1: anti-liver/kidney microsome type 1 antibody, ASMA: anti-smooth muscle antibody, C·O·I: cut off index
Abdominal ultrasonography showed surface irregularity and a coarse parenchyma echotexture of the liver, suggesting cirrhosis (Fig. 2a). Abdominal contrast-enhanced computed tomography portal phase images showed surface undulation of the liver, collateral circulation around the stomach and splenic hilum, and ascites on the surface of the liver and spleen (Fig. 2b). No evidence suggestive of acute hepatitis, such as periportal collar sign, gallbladder atrophy, or wall thickening, was observed, nor were any space-occupying lesions present in the liver.
Figure 2. a) Abdominal ultrasonography showed liver surface irregularity (arrowheads) and a coarse parenchyma echotexture. b) Abdominal contrast-enhanced computed tomography portal phase images revealed surface undulation of the liver, collateral circulation around the stomach and splenic hilum (arrows), and ascites on the surface of the liver and spleen.
Based on the patient’s clinical findings, we suspected that her cirrhotic PBC had deteriorated acutely for some reason. Although she did not meet the criteria for acute liver failure, the presence of severe jaundice and ascites indicated the need for liver transplantation. After being refused for this treatment, we provided supportive care, including bed rest, lactulose administration, and albumin replacement. On day 13 of admission, HEV-IgA antibody was found to be positive in an admission blood sample, suggesting an association between the exacerbation of her PBC and acute HEV infection. However, the patient’s liver atrophy and renal failure were beyond treatment. Her general condition progressively worsened, and she passed away on day 18 of admission. The entire clinical course is summarized in Fig. 3.
Figure 3. Clinical course of the patient. ALT: alanine aminotransferase, PT: prothrombin time, T-Bil: Total bilirubin, Cre: Creatinine, HEV: Hepatitis E virus
A pathological autopsy was performed after obtaining informed consent from her family. Macroscopically, the surface of the liver was atrophied in a nodular manner, indicating complete cirrhosis (Fig. 4a). Microscopic observation of the liver showed severe atrophy with submassive loss and necrosis of hepatocytes from Zone 3 to Zone 2 of the hepatic lobule (Fig. 4b). However, the distribution did not match the centrilobular necrosis typically observed in hepatic ischemia. In some areas, hepatocytes around the central vein were intact (Fig. 4c). In addition, there was no remarkable steatosis inside hepatocytes indicative of hypoxia (Fig. 4c). Based on these findings, hepatic ischemia was not considered as the main cause of submassive loss and necrosis in this case. Although cholestasis was prominent in the lobules, inflammatory cell infiltration related to acute hepatitis was not evident (Fig. 4b, c). Regenerated nodules and highly fibrous septum formation were found in the liver, which were histologically consistent with cirrhosis (Fig. 4d). In the portal area, the infiltration of mononuclear cells and disappearance of bile ducts suggested advanced PBC (Fig. 4e). Extensive bile duct loss was confirmed between the interlobular and septal bile duct levels.
Figure 4. Autopsy findings. a) Macroscopically, the surface of the liver was atrophied in a nodular manner, indicating complete cirrhosis. b) Severe atrophy with submassive loss and necrosis of hepatocytes (red dotted lines) from Zone 3 to Zone 2 of the hepatic lobule were evident (Hematoxylin and Eosin staining). P: portal vein, C: central vein. c) In some areas, hepatocytes around the central vein were relatively intact, with no steatosis inside hepatocytes suggestive of hypoxia. Cholestasis was prominent in the lobules. Inflammatory cell infiltration indicative of acute hepatitis was not detected. d) On Elastica-Goldner staining, regenerated nodules and highly fibrous septum formation were found in the liver, findings that were histologically consistent with cirrhosis. e) In the portal area, infiltration of mononuclear cells and the disappearance of bile ducts were observed, suggesting advanced PBC. P: portal vein
HEV antibodies (IgG, IgM, and IgA) were measured by an enzyme-linked immunosorbent assay using frozen serum samples according to a previously described method (18). The testing results are shown in Table 2 along with the corresponding hepatobiliary enzymes at each time point. HEV RNA was detected by the nested reverse-transcription polymerase chain reaction with primers targeting the open reading frame 2 (ORF2) region of the HEV genome (nucleotide position 5944-6355, excluding primer sequences at both ends: M73218), as described previously (19). HEV RNA, which had been negative at the last visit before admission, had become positive at admission along with increases in all classes of HEV antibodies. HEV RNA became undetectable during the deterioration of her condition, although a high antibody titer persisted. We determined her 412-nucleotide ORF2 sequence and constructed a molecular phylogenetic tree according to a previously described method (20) (Fig. 5). The HEV strain (HE-JA19-0280: DDBJ/EMBL/GenBank accession number LC581383) derived from this case belonged to genotype 3 (subgenotype 3b) and was closest to those of patients recovering from acute hepatitis E in Tokyo and Gunma Prefectures of Japan.
Figure 5. Phylogenetic tree constructed by the neighbor-joining method based on the partial nucleotide sequence (412 nucleotides) of the open reading frame 2 region of hepatitis E virus (HEV) isolates. In addition to the HEV isolate (HE-JA19-0280) obtained in the present study (highlighted with a closed box), 33 representative genotype 3 isolates (subgenotype 3a: n=8, subgenotype 3b: n=22, and subgenotype 3e: n=3), whose entire genomic sequence is known, are included in the tree using the prototype HEV sequences of genotype 1 (M73218), genotype 2 (M74506), and genotype 4 (AJ272108) as outgroups. Three HEV isolates sharing the highest identity of 97.1-97.8% with the HE-JA19-0280 isolate are also included. Each reference sequence is shown with the genotype/subgenotype followed by the accession number, isolate name, and country in which it was isolated. The bootstrap values (>70%) are indicated for nodes as the percentage of data among 1,000 resampling procedures. The scale bar is in units of nuceotide substitutions per site.
Table 2. Transition of Hepatobiliary Enzymes, HEV Antibodies, and HEV RNA.
Day Laboratory data HEV antibodies HEV RNA
AST
(U/L) ALT
(U/L) GGT
(U/L) ALP
(U/L) T-Bil
(mg/dL) IgG (OD450) IgM (OD450) IgA (OD450)
X - 80 137 111 413 940 3.4 0.010 (-) 0.046 (-) 0.020 (-) Negative
X (admission) 78 100 105 702 30.1 1.661 (+) >3.000 (+) 2.374 (+) +: 1.0×101 copies/mL
X+1 69 80 87 588 26.6 1.578 (+) >3.000 (+) 2.346 (+) +: 1.2×101 copies/mL
X+11 43 44 64 568 39.7 1.850 (+) >3.000 (+) 2.002 (+) Negative
X+14 61 66 78 631 46.7 1.970 (+) >3.000 (+) 1.768 (+) Negative
HEV: hepatitis E virus, AST: aspartate aminotransferase, ALT: alanine aminotransferase, GGT: gamma-glutamyl transpeptidase, ALP: alkaline phosphatase, T-Bil: total bilirubin
Discussion
The present autopsy case displayed histological evidence of submassive necrosis in the liver caused by acute HEV infection. The patient was presumed to have been at the liver cirrhosis stage of PBC but suddenly developed severe jaundice due to superimposed HEV infection and succumbed one month later to hepatic failure. The histopathological findings of severe liver atrophy with submassive loss and necrosis of hepatocytes could not be explained by ischemia only, strongly suggesting the involvement of genotype 3b HEV infection in her histopathological findings.
Although PBC patients generally have a normal life expectancy, they sometimes show rapid disease exacerbation due to concomitant autoimmune hepatitis (7,21) or simultaneous HCV infection (22) as a trigger of PBC deterioration. One rare instance of PBC with acute HEV infection has been reported to date (15). To our knowledge, however, an autopsy case of rapid deterioration triggered by HEV infection has not yet been described. As the mechanism underlying PBC exacerbation due to viral hepatitis infection remains unknown, the present case may contribute to the body of knowledge concerning this condition.
HEV is one of the most common causes of acute viral hepatitis (23). In addition to contaminated water, raw meat from pigs, boars, and deer is another common infection source (24-26). Recently, the prevalence of HEV cases without clinical symptoms as well as those of unknown transmission route has been increasing (27). The infection route in the present case could not be identified based on our medical interview. According to previous reports, pregnancy, old age, alcohol intake, and fatty liver are host factors associated with the aggravation of HEV, and co-infection with chronic liver disease is related to the risk of liver failure (13,14). Regarding the HEV genotype, HEV genotype 4 infection is reportedly associated with aggravation (26,28,29). Genotype 3 HEV, as detected in this case, is generally associated with a low tendency of severe clinical manifestations, although a rare case of progressive genotype 3 HEV infection has been reported (28). A mutation of V239A in the helicase region of the genotype 3 HEV genome has been associated with HEV infection aggravation (30). That mutant was absent in this case (data not shown). The patient had no other apparent host or viral factors associated with HEV severity. However, Wang et al. reported that the cirrhosis stage itself carries a potential risk of liver failure due to HEV infection, regardless of etiology; they further described the potentiation of the cirrhotic liver upon HEV infection and more aggressive immune- or inflammatory-mediated activation of cell death in a cirrhotic liver status as possible mechanisms of exacerbation (15). The above results suggested that even if patients have no documented risk factors of HEV aggravation, clinicians should bear in mind that HEV infection at a cirrhotic liver disease stage can become severe.
This patient had been diagnosed with PBC 26 years earlier based on serological criteria. Eight years before admission, she was already at an advanced stage of PBC, with Nakanuma stage 3 and Scheuer stage III classifications according to a liver biopsy. An autopsy specimen of the liver revealed obvious cirrhosis, which was consistent with the natural history of PBC as suggested by elevated serum surrogate markers of M2BPGi (31,32). However, the submassive loss and necrosis of hepatocytes could not solely be explained by the natural PBC history. Inflammatory cell infiltration suggesting acute hepatitis E (33) was not observed, which suggested a post-inflammatory status. Other general clinical features of acute hepatitis, including markedly elevated levels of liver enzymes, were absent as well. Her liver enzymes were only mildly elevated at day X-80, suggesting that asymptomatic hepatitis may have started at that point, followed by further increases in transaminase levels. Thus, one explanation as to why this case showed mild hepatitis was that the hepatitis had occurred after day X-80 and already peaked and ameliorated by the time of admission, such that jaundice represented the major feature. However, no clinical data were available between the patient’s last outpatient visit at day X-80 and her hospitalization. Another hypothesis was that this case had already reached the complete cirrhosis stage, as shown by the pathological findings, which could have induced mild liver enzyme elevations (34).
Patients with hepatitis E sometimes show severe jaundice (35). Although the underlying mechanism is uncertain, HEV has been reported to exhibit not only hepatocytic but also biliary tropism and replicate within bile duct epithelial cells (36,37). The severe jaundice and cholestasis in this case might have been the result of HEV infection complicating the chronic cholestatic liver disease of PBC. The fact that jaundice was more pronounced than elevated liver enzyme levels may support this notion. Although drug-induced liver injury (levofloxacin 500 mg/day) cannot be ruled out, we suspected that HEV infection likely triggered the exacerbation of PBC due to her awareness of jaundice prior to drug administration and the histological considerations described above.
In conclusion, clinicians should consider the possibility of acute HEV infection as a trigger for the acute exacerbation of PBC. In such cases, it may be necessary to treat the patient with the anticipation of severe aggravation.
The authors state that they have no Conflict of Interest (COI).
Acknowledgement
We thank Trevor Ralph for his English editorial assistance. | Not recovered | ReactionOutcome | CC BY-NC-ND | 33518570 | 19,677,427 | 2021-06-15 |
What was the outcome of reaction 'Hepatic failure'? | An Autopsy Case of Primary Biliary Cholangitis with Histological Submassive Hepatic Necrosis Caused by Acute Hepatitis E Virus Infection.
A 59-year-old woman who had been diagnosed with cirrhotic primary biliary cholangitis (PBC) 5 years earlier was admitted for severe jaundice (total bilirubin: 30.1 mg/dL). We suspected that her cirrhotic PBC had deteriorated acutely for some reason. Her general condition deteriorated quickly, and she passed away on day 18 of admission. Hepatitis E virus (HEV)-IgA antibodies were positive, and Genotype 3b HEV involvement was confirmed from a blood sample taken on admission. Histopathological findings revealed cirrhosis and submassive loss and necrosis of hepatocytes. Clinicians should consider the possibility of acute HEV infection as a trigger for acute PBC exacerbation.
Introduction
Primary biliary cholangitis (PBC) is a chronic and slowly progressive cholestatic autoimmune liver disease that is histopathologically characterized by an attack on the small intralobular bile duct by T lymphocytes (1). The precise etiology of PBC remains unknown but is related to genetic susceptibility environmental factors (2-4). Although most patients with PBC are asymptomatic and have a normal life expectancy, clinicians sometimes encounter symptomatic PBC cases with severe jaundice or liver failure as a result of the sustained loss of intralobular bile ducts in spite of ursodeoxycholic acid (UDCA) therapy (5,6). Patients with concomitant acute liver injury from autoimmune hepatitis show particularly rapid disease progression (7). The acute exacerbation of PBC from hepatitis virus co-infection is rare in the clinical setting.
The hepatitis E virus (HEV) is a quasi-enveloped, single-stranded RNA virus that causes acute or chronic hepatitis (8,9). With the increase in the number of hepatitis E cases, HEV antibody is now positive in approximately 5% of the general population in Japan (10,11). Among HEV-associated acute hepatitis cases, 0.5-4% of patients progress to fulminant hepatitis (12), leading to high mortality when intensive care and liver transplantation are unavailable. Rare cases of severe acute HEV hepatitis underlying such chronic liver diseases as alcoholic liver disease, nonalcoholic fatty liver disease, chronic viral hepatitis, and PBC have been documented as well (13-15). No autopsy PBC cases displaying acute exacerbation due to superimposed acute HEV infection have been reported to date.
We herein report the autopsy findings of a PBC case in the cirrhotic stage with histological submassive hepatic necrosis caused by acute HEV infection.
Case Report
A 59-year-old woman who had been serologically diagnosed with PBC after the detection of liver dysfunction 26 years earlier was admitted to our hospital for severe jaundice, brown urine, and leg edema. She had suffered from cold-like symptoms and skin jaundice for a month and had received antitussives and antibiotics (levofloxacin 500 mg/day) from her attending physician 2 weeks before admission. She had no symptoms of diarrhea, vomiting, or a history of eating raw meat. She reported no regular ethanol consumption or travel to a foreign country. Although she had been prescribed 600 mg/day UDCA and 400 mg/day bezafibrate for PBC, her medication compliance was extremely poor. She had persistent liver dysfunction [alanine aminotransferase (ALT) at around 100 U/L] and jaundice (total bilirubin at around 3 mg/dL). Eight years before admission, the histological findings of a liver biopsy specimen showed lymphocyte infiltration in the portal area and severe bile duct loss that were consistent with Nakanuma stage 3 (16) and Scheuer stage III (17) classifications (Fig. 1). Three years later, she was clinically diagnosed with cirrhosis-stage PBC. She had also undergone endoscopic gastric varices treatment one year before admission.
Figure 1. Histological findings of a liver biopsy specimen obtained eight years before admission. a, b) Lymphocyte infiltration in the portal area and severe bile duct loss were observed (Hematoxylin and Eosin staining). c) Azan-Mallory staining showed moderate fibrosis in the liver that was consistent with Nakanuma stage 3 and Scheuer stage III classifications.
On an examination at the time of admission, the patient was 165 cm tall, weighed 68 kg, and had a body mass index of 25.0 kg/m2. Her vital signs included Glasgow Coma Scale score E4V5M6, body temperature 37.3 °C, and blood pressure 111/54 mmHg. She exhibited conjunctival and systemic jaundice and front chest vascular spider but no flapping tremor. Laboratory tests on admission revealed elevated serum aspartate aminotransferase (78 U/L), ALT (100 U/L), gamma-glutamyl transpeptidase (105 U/L), alkaline phosphatase (702 U/L), total bilirubin (30.1 mg/dL), and Mac-2-binding protein glycan isomer (M2BPGi) (7.4 C・O・I) but a reduced platelet count (7.2×104/μL), albumin (2.7 g/dL), and prothrombin time activity (67.7%) (Table 1). Testing for hepatitis A virus antibody (immunoglobulin M), hepatitis B virus surface antigen, and anti-hepatitis C virus (HCV) antibody was negative. Serum antibodies to the Epstein-Barr virus and cytomegalovirus both showed a historical infection pattern. Although serum alpha fetoprotein levels were within normal range, levels of protein induced by vitamin K absence or antagonist II were mildly elevated (152 mAU/mL). Among the autoantibodies tested, fluorescent anti-nuclear antibody (× 640) and anti-mitochondrial M2 antibody (168.1 Index) were positive.
Table 1. Laboratory Findings on Admission.
Blood Chemistry / Serology Viral markers
White blood cell count 5,760 /μL Total protein 5.9 g/dL IgM-HAV Ab (-)
Neutrophils 71.2 % Albumin 2.7 g/dL HBs-Ag 0.001 (-) U/mL
Lymphocytes 19.8 % AST 78 U/L HBs-Ab 0.4 (-) mIU/mL
Monocytes 5.7 % ALT 100 U/L HBc-Ab 0.2 (-) C·O·I
Eosinophils 3.0 % Total bilirubin 30.14 mg/dL IgM-HBc Ab (-)
Basophils 0.3 % GGT 105 U/L HCV-Ab 0.1 (-) C·O·I
Red blood cell count 418 ×104/μL ALP 702 U/L IgM-EBV VCA Ab <10 (-) ×
Hemoglobin 13.1 g/dL BUN 12 mg/dL IgG-EBV VCA Ab 40 (+)
Hematocrit 37.4 % Creatinine 0.59 mg/dL EBV EBNA Ab <10 (-) ×
Platelet count 7.2 ×104/μL NH3 29 μg/dL IgM-CMV Ab 0.29 (-) Index
CRP 1.61 mg/dL IgG-CMV Ab 133.6 (+) AU/mL
Coagulation HbA1c 4.2 % IgA-HEV Ab (+)
PT 67.7 % IgM 139 mg/dL
APTT 29.0 sec IgA 292 mg/dL Autoimmune antibodies
Fibrinogen 192.0 mg/dL IgG 1,156 mg/dL FANA 640 ×
D-dimer 2.3 μg/mL M2BPGi 7.4 C·O·I AMA2 168.1 Index
Anti-centromere antibody (-)
Tumor markers LKM-1 (-)
AFP 7.0 ng/mL ASMA (-)
PIVKA II 152 mAU/mL
PT: prothrombin time, APTT: activated partial thromboplastin time, AST: aspartate aminotransferase, ALT: alanine aminotransferase, GGT: gamma-glutamyl transpeptidase, ALP: alkaline phosphatase, BUN: blood urea nitrogen, CRP: C-reactive protein, HbA1c: hemoglobin A1c, M2BPGi: Mac 2-Binding Protein Gylcan Isomer, AFP: alpha fetoprotein, PIVKA II: protein induced by vitamin K absence or antagonist II, FANA: fluorescent anti-nuclear antibody, AMA2: anti-mitochondrial M2 antibody, LKM-1: anti-liver/kidney microsome type 1 antibody, ASMA: anti-smooth muscle antibody, C·O·I: cut off index
Abdominal ultrasonography showed surface irregularity and a coarse parenchyma echotexture of the liver, suggesting cirrhosis (Fig. 2a). Abdominal contrast-enhanced computed tomography portal phase images showed surface undulation of the liver, collateral circulation around the stomach and splenic hilum, and ascites on the surface of the liver and spleen (Fig. 2b). No evidence suggestive of acute hepatitis, such as periportal collar sign, gallbladder atrophy, or wall thickening, was observed, nor were any space-occupying lesions present in the liver.
Figure 2. a) Abdominal ultrasonography showed liver surface irregularity (arrowheads) and a coarse parenchyma echotexture. b) Abdominal contrast-enhanced computed tomography portal phase images revealed surface undulation of the liver, collateral circulation around the stomach and splenic hilum (arrows), and ascites on the surface of the liver and spleen.
Based on the patient’s clinical findings, we suspected that her cirrhotic PBC had deteriorated acutely for some reason. Although she did not meet the criteria for acute liver failure, the presence of severe jaundice and ascites indicated the need for liver transplantation. After being refused for this treatment, we provided supportive care, including bed rest, lactulose administration, and albumin replacement. On day 13 of admission, HEV-IgA antibody was found to be positive in an admission blood sample, suggesting an association between the exacerbation of her PBC and acute HEV infection. However, the patient’s liver atrophy and renal failure were beyond treatment. Her general condition progressively worsened, and she passed away on day 18 of admission. The entire clinical course is summarized in Fig. 3.
Figure 3. Clinical course of the patient. ALT: alanine aminotransferase, PT: prothrombin time, T-Bil: Total bilirubin, Cre: Creatinine, HEV: Hepatitis E virus
A pathological autopsy was performed after obtaining informed consent from her family. Macroscopically, the surface of the liver was atrophied in a nodular manner, indicating complete cirrhosis (Fig. 4a). Microscopic observation of the liver showed severe atrophy with submassive loss and necrosis of hepatocytes from Zone 3 to Zone 2 of the hepatic lobule (Fig. 4b). However, the distribution did not match the centrilobular necrosis typically observed in hepatic ischemia. In some areas, hepatocytes around the central vein were intact (Fig. 4c). In addition, there was no remarkable steatosis inside hepatocytes indicative of hypoxia (Fig. 4c). Based on these findings, hepatic ischemia was not considered as the main cause of submassive loss and necrosis in this case. Although cholestasis was prominent in the lobules, inflammatory cell infiltration related to acute hepatitis was not evident (Fig. 4b, c). Regenerated nodules and highly fibrous septum formation were found in the liver, which were histologically consistent with cirrhosis (Fig. 4d). In the portal area, the infiltration of mononuclear cells and disappearance of bile ducts suggested advanced PBC (Fig. 4e). Extensive bile duct loss was confirmed between the interlobular and septal bile duct levels.
Figure 4. Autopsy findings. a) Macroscopically, the surface of the liver was atrophied in a nodular manner, indicating complete cirrhosis. b) Severe atrophy with submassive loss and necrosis of hepatocytes (red dotted lines) from Zone 3 to Zone 2 of the hepatic lobule were evident (Hematoxylin and Eosin staining). P: portal vein, C: central vein. c) In some areas, hepatocytes around the central vein were relatively intact, with no steatosis inside hepatocytes suggestive of hypoxia. Cholestasis was prominent in the lobules. Inflammatory cell infiltration indicative of acute hepatitis was not detected. d) On Elastica-Goldner staining, regenerated nodules and highly fibrous septum formation were found in the liver, findings that were histologically consistent with cirrhosis. e) In the portal area, infiltration of mononuclear cells and the disappearance of bile ducts were observed, suggesting advanced PBC. P: portal vein
HEV antibodies (IgG, IgM, and IgA) were measured by an enzyme-linked immunosorbent assay using frozen serum samples according to a previously described method (18). The testing results are shown in Table 2 along with the corresponding hepatobiliary enzymes at each time point. HEV RNA was detected by the nested reverse-transcription polymerase chain reaction with primers targeting the open reading frame 2 (ORF2) region of the HEV genome (nucleotide position 5944-6355, excluding primer sequences at both ends: M73218), as described previously (19). HEV RNA, which had been negative at the last visit before admission, had become positive at admission along with increases in all classes of HEV antibodies. HEV RNA became undetectable during the deterioration of her condition, although a high antibody titer persisted. We determined her 412-nucleotide ORF2 sequence and constructed a molecular phylogenetic tree according to a previously described method (20) (Fig. 5). The HEV strain (HE-JA19-0280: DDBJ/EMBL/GenBank accession number LC581383) derived from this case belonged to genotype 3 (subgenotype 3b) and was closest to those of patients recovering from acute hepatitis E in Tokyo and Gunma Prefectures of Japan.
Figure 5. Phylogenetic tree constructed by the neighbor-joining method based on the partial nucleotide sequence (412 nucleotides) of the open reading frame 2 region of hepatitis E virus (HEV) isolates. In addition to the HEV isolate (HE-JA19-0280) obtained in the present study (highlighted with a closed box), 33 representative genotype 3 isolates (subgenotype 3a: n=8, subgenotype 3b: n=22, and subgenotype 3e: n=3), whose entire genomic sequence is known, are included in the tree using the prototype HEV sequences of genotype 1 (M73218), genotype 2 (M74506), and genotype 4 (AJ272108) as outgroups. Three HEV isolates sharing the highest identity of 97.1-97.8% with the HE-JA19-0280 isolate are also included. Each reference sequence is shown with the genotype/subgenotype followed by the accession number, isolate name, and country in which it was isolated. The bootstrap values (>70%) are indicated for nodes as the percentage of data among 1,000 resampling procedures. The scale bar is in units of nuceotide substitutions per site.
Table 2. Transition of Hepatobiliary Enzymes, HEV Antibodies, and HEV RNA.
Day Laboratory data HEV antibodies HEV RNA
AST
(U/L) ALT
(U/L) GGT
(U/L) ALP
(U/L) T-Bil
(mg/dL) IgG (OD450) IgM (OD450) IgA (OD450)
X - 80 137 111 413 940 3.4 0.010 (-) 0.046 (-) 0.020 (-) Negative
X (admission) 78 100 105 702 30.1 1.661 (+) >3.000 (+) 2.374 (+) +: 1.0×101 copies/mL
X+1 69 80 87 588 26.6 1.578 (+) >3.000 (+) 2.346 (+) +: 1.2×101 copies/mL
X+11 43 44 64 568 39.7 1.850 (+) >3.000 (+) 2.002 (+) Negative
X+14 61 66 78 631 46.7 1.970 (+) >3.000 (+) 1.768 (+) Negative
HEV: hepatitis E virus, AST: aspartate aminotransferase, ALT: alanine aminotransferase, GGT: gamma-glutamyl transpeptidase, ALP: alkaline phosphatase, T-Bil: total bilirubin
Discussion
The present autopsy case displayed histological evidence of submassive necrosis in the liver caused by acute HEV infection. The patient was presumed to have been at the liver cirrhosis stage of PBC but suddenly developed severe jaundice due to superimposed HEV infection and succumbed one month later to hepatic failure. The histopathological findings of severe liver atrophy with submassive loss and necrosis of hepatocytes could not be explained by ischemia only, strongly suggesting the involvement of genotype 3b HEV infection in her histopathological findings.
Although PBC patients generally have a normal life expectancy, they sometimes show rapid disease exacerbation due to concomitant autoimmune hepatitis (7,21) or simultaneous HCV infection (22) as a trigger of PBC deterioration. One rare instance of PBC with acute HEV infection has been reported to date (15). To our knowledge, however, an autopsy case of rapid deterioration triggered by HEV infection has not yet been described. As the mechanism underlying PBC exacerbation due to viral hepatitis infection remains unknown, the present case may contribute to the body of knowledge concerning this condition.
HEV is one of the most common causes of acute viral hepatitis (23). In addition to contaminated water, raw meat from pigs, boars, and deer is another common infection source (24-26). Recently, the prevalence of HEV cases without clinical symptoms as well as those of unknown transmission route has been increasing (27). The infection route in the present case could not be identified based on our medical interview. According to previous reports, pregnancy, old age, alcohol intake, and fatty liver are host factors associated with the aggravation of HEV, and co-infection with chronic liver disease is related to the risk of liver failure (13,14). Regarding the HEV genotype, HEV genotype 4 infection is reportedly associated with aggravation (26,28,29). Genotype 3 HEV, as detected in this case, is generally associated with a low tendency of severe clinical manifestations, although a rare case of progressive genotype 3 HEV infection has been reported (28). A mutation of V239A in the helicase region of the genotype 3 HEV genome has been associated with HEV infection aggravation (30). That mutant was absent in this case (data not shown). The patient had no other apparent host or viral factors associated with HEV severity. However, Wang et al. reported that the cirrhosis stage itself carries a potential risk of liver failure due to HEV infection, regardless of etiology; they further described the potentiation of the cirrhotic liver upon HEV infection and more aggressive immune- or inflammatory-mediated activation of cell death in a cirrhotic liver status as possible mechanisms of exacerbation (15). The above results suggested that even if patients have no documented risk factors of HEV aggravation, clinicians should bear in mind that HEV infection at a cirrhotic liver disease stage can become severe.
This patient had been diagnosed with PBC 26 years earlier based on serological criteria. Eight years before admission, she was already at an advanced stage of PBC, with Nakanuma stage 3 and Scheuer stage III classifications according to a liver biopsy. An autopsy specimen of the liver revealed obvious cirrhosis, which was consistent with the natural history of PBC as suggested by elevated serum surrogate markers of M2BPGi (31,32). However, the submassive loss and necrosis of hepatocytes could not solely be explained by the natural PBC history. Inflammatory cell infiltration suggesting acute hepatitis E (33) was not observed, which suggested a post-inflammatory status. Other general clinical features of acute hepatitis, including markedly elevated levels of liver enzymes, were absent as well. Her liver enzymes were only mildly elevated at day X-80, suggesting that asymptomatic hepatitis may have started at that point, followed by further increases in transaminase levels. Thus, one explanation as to why this case showed mild hepatitis was that the hepatitis had occurred after day X-80 and already peaked and ameliorated by the time of admission, such that jaundice represented the major feature. However, no clinical data were available between the patient’s last outpatient visit at day X-80 and her hospitalization. Another hypothesis was that this case had already reached the complete cirrhosis stage, as shown by the pathological findings, which could have induced mild liver enzyme elevations (34).
Patients with hepatitis E sometimes show severe jaundice (35). Although the underlying mechanism is uncertain, HEV has been reported to exhibit not only hepatocytic but also biliary tropism and replicate within bile duct epithelial cells (36,37). The severe jaundice and cholestasis in this case might have been the result of HEV infection complicating the chronic cholestatic liver disease of PBC. The fact that jaundice was more pronounced than elevated liver enzyme levels may support this notion. Although drug-induced liver injury (levofloxacin 500 mg/day) cannot be ruled out, we suspected that HEV infection likely triggered the exacerbation of PBC due to her awareness of jaundice prior to drug administration and the histological considerations described above.
In conclusion, clinicians should consider the possibility of acute HEV infection as a trigger for the acute exacerbation of PBC. In such cases, it may be necessary to treat the patient with the anticipation of severe aggravation.
The authors state that they have no Conflict of Interest (COI).
Acknowledgement
We thank Trevor Ralph for his English editorial assistance. | Fatal | ReactionOutcome | CC BY-NC-ND | 33518570 | 19,677,427 | 2021-06-15 |
What was the outcome of reaction 'Primary biliary cholangitis'? | An Autopsy Case of Primary Biliary Cholangitis with Histological Submassive Hepatic Necrosis Caused by Acute Hepatitis E Virus Infection.
A 59-year-old woman who had been diagnosed with cirrhotic primary biliary cholangitis (PBC) 5 years earlier was admitted for severe jaundice (total bilirubin: 30.1 mg/dL). We suspected that her cirrhotic PBC had deteriorated acutely for some reason. Her general condition deteriorated quickly, and she passed away on day 18 of admission. Hepatitis E virus (HEV)-IgA antibodies were positive, and Genotype 3b HEV involvement was confirmed from a blood sample taken on admission. Histopathological findings revealed cirrhosis and submassive loss and necrosis of hepatocytes. Clinicians should consider the possibility of acute HEV infection as a trigger for acute PBC exacerbation.
Introduction
Primary biliary cholangitis (PBC) is a chronic and slowly progressive cholestatic autoimmune liver disease that is histopathologically characterized by an attack on the small intralobular bile duct by T lymphocytes (1). The precise etiology of PBC remains unknown but is related to genetic susceptibility environmental factors (2-4). Although most patients with PBC are asymptomatic and have a normal life expectancy, clinicians sometimes encounter symptomatic PBC cases with severe jaundice or liver failure as a result of the sustained loss of intralobular bile ducts in spite of ursodeoxycholic acid (UDCA) therapy (5,6). Patients with concomitant acute liver injury from autoimmune hepatitis show particularly rapid disease progression (7). The acute exacerbation of PBC from hepatitis virus co-infection is rare in the clinical setting.
The hepatitis E virus (HEV) is a quasi-enveloped, single-stranded RNA virus that causes acute or chronic hepatitis (8,9). With the increase in the number of hepatitis E cases, HEV antibody is now positive in approximately 5% of the general population in Japan (10,11). Among HEV-associated acute hepatitis cases, 0.5-4% of patients progress to fulminant hepatitis (12), leading to high mortality when intensive care and liver transplantation are unavailable. Rare cases of severe acute HEV hepatitis underlying such chronic liver diseases as alcoholic liver disease, nonalcoholic fatty liver disease, chronic viral hepatitis, and PBC have been documented as well (13-15). No autopsy PBC cases displaying acute exacerbation due to superimposed acute HEV infection have been reported to date.
We herein report the autopsy findings of a PBC case in the cirrhotic stage with histological submassive hepatic necrosis caused by acute HEV infection.
Case Report
A 59-year-old woman who had been serologically diagnosed with PBC after the detection of liver dysfunction 26 years earlier was admitted to our hospital for severe jaundice, brown urine, and leg edema. She had suffered from cold-like symptoms and skin jaundice for a month and had received antitussives and antibiotics (levofloxacin 500 mg/day) from her attending physician 2 weeks before admission. She had no symptoms of diarrhea, vomiting, or a history of eating raw meat. She reported no regular ethanol consumption or travel to a foreign country. Although she had been prescribed 600 mg/day UDCA and 400 mg/day bezafibrate for PBC, her medication compliance was extremely poor. She had persistent liver dysfunction [alanine aminotransferase (ALT) at around 100 U/L] and jaundice (total bilirubin at around 3 mg/dL). Eight years before admission, the histological findings of a liver biopsy specimen showed lymphocyte infiltration in the portal area and severe bile duct loss that were consistent with Nakanuma stage 3 (16) and Scheuer stage III (17) classifications (Fig. 1). Three years later, she was clinically diagnosed with cirrhosis-stage PBC. She had also undergone endoscopic gastric varices treatment one year before admission.
Figure 1. Histological findings of a liver biopsy specimen obtained eight years before admission. a, b) Lymphocyte infiltration in the portal area and severe bile duct loss were observed (Hematoxylin and Eosin staining). c) Azan-Mallory staining showed moderate fibrosis in the liver that was consistent with Nakanuma stage 3 and Scheuer stage III classifications.
On an examination at the time of admission, the patient was 165 cm tall, weighed 68 kg, and had a body mass index of 25.0 kg/m2. Her vital signs included Glasgow Coma Scale score E4V5M6, body temperature 37.3 °C, and blood pressure 111/54 mmHg. She exhibited conjunctival and systemic jaundice and front chest vascular spider but no flapping tremor. Laboratory tests on admission revealed elevated serum aspartate aminotransferase (78 U/L), ALT (100 U/L), gamma-glutamyl transpeptidase (105 U/L), alkaline phosphatase (702 U/L), total bilirubin (30.1 mg/dL), and Mac-2-binding protein glycan isomer (M2BPGi) (7.4 C・O・I) but a reduced platelet count (7.2×104/μL), albumin (2.7 g/dL), and prothrombin time activity (67.7%) (Table 1). Testing for hepatitis A virus antibody (immunoglobulin M), hepatitis B virus surface antigen, and anti-hepatitis C virus (HCV) antibody was negative. Serum antibodies to the Epstein-Barr virus and cytomegalovirus both showed a historical infection pattern. Although serum alpha fetoprotein levels were within normal range, levels of protein induced by vitamin K absence or antagonist II were mildly elevated (152 mAU/mL). Among the autoantibodies tested, fluorescent anti-nuclear antibody (× 640) and anti-mitochondrial M2 antibody (168.1 Index) were positive.
Table 1. Laboratory Findings on Admission.
Blood Chemistry / Serology Viral markers
White blood cell count 5,760 /μL Total protein 5.9 g/dL IgM-HAV Ab (-)
Neutrophils 71.2 % Albumin 2.7 g/dL HBs-Ag 0.001 (-) U/mL
Lymphocytes 19.8 % AST 78 U/L HBs-Ab 0.4 (-) mIU/mL
Monocytes 5.7 % ALT 100 U/L HBc-Ab 0.2 (-) C·O·I
Eosinophils 3.0 % Total bilirubin 30.14 mg/dL IgM-HBc Ab (-)
Basophils 0.3 % GGT 105 U/L HCV-Ab 0.1 (-) C·O·I
Red blood cell count 418 ×104/μL ALP 702 U/L IgM-EBV VCA Ab <10 (-) ×
Hemoglobin 13.1 g/dL BUN 12 mg/dL IgG-EBV VCA Ab 40 (+)
Hematocrit 37.4 % Creatinine 0.59 mg/dL EBV EBNA Ab <10 (-) ×
Platelet count 7.2 ×104/μL NH3 29 μg/dL IgM-CMV Ab 0.29 (-) Index
CRP 1.61 mg/dL IgG-CMV Ab 133.6 (+) AU/mL
Coagulation HbA1c 4.2 % IgA-HEV Ab (+)
PT 67.7 % IgM 139 mg/dL
APTT 29.0 sec IgA 292 mg/dL Autoimmune antibodies
Fibrinogen 192.0 mg/dL IgG 1,156 mg/dL FANA 640 ×
D-dimer 2.3 μg/mL M2BPGi 7.4 C·O·I AMA2 168.1 Index
Anti-centromere antibody (-)
Tumor markers LKM-1 (-)
AFP 7.0 ng/mL ASMA (-)
PIVKA II 152 mAU/mL
PT: prothrombin time, APTT: activated partial thromboplastin time, AST: aspartate aminotransferase, ALT: alanine aminotransferase, GGT: gamma-glutamyl transpeptidase, ALP: alkaline phosphatase, BUN: blood urea nitrogen, CRP: C-reactive protein, HbA1c: hemoglobin A1c, M2BPGi: Mac 2-Binding Protein Gylcan Isomer, AFP: alpha fetoprotein, PIVKA II: protein induced by vitamin K absence or antagonist II, FANA: fluorescent anti-nuclear antibody, AMA2: anti-mitochondrial M2 antibody, LKM-1: anti-liver/kidney microsome type 1 antibody, ASMA: anti-smooth muscle antibody, C·O·I: cut off index
Abdominal ultrasonography showed surface irregularity and a coarse parenchyma echotexture of the liver, suggesting cirrhosis (Fig. 2a). Abdominal contrast-enhanced computed tomography portal phase images showed surface undulation of the liver, collateral circulation around the stomach and splenic hilum, and ascites on the surface of the liver and spleen (Fig. 2b). No evidence suggestive of acute hepatitis, such as periportal collar sign, gallbladder atrophy, or wall thickening, was observed, nor were any space-occupying lesions present in the liver.
Figure 2. a) Abdominal ultrasonography showed liver surface irregularity (arrowheads) and a coarse parenchyma echotexture. b) Abdominal contrast-enhanced computed tomography portal phase images revealed surface undulation of the liver, collateral circulation around the stomach and splenic hilum (arrows), and ascites on the surface of the liver and spleen.
Based on the patient’s clinical findings, we suspected that her cirrhotic PBC had deteriorated acutely for some reason. Although she did not meet the criteria for acute liver failure, the presence of severe jaundice and ascites indicated the need for liver transplantation. After being refused for this treatment, we provided supportive care, including bed rest, lactulose administration, and albumin replacement. On day 13 of admission, HEV-IgA antibody was found to be positive in an admission blood sample, suggesting an association between the exacerbation of her PBC and acute HEV infection. However, the patient’s liver atrophy and renal failure were beyond treatment. Her general condition progressively worsened, and she passed away on day 18 of admission. The entire clinical course is summarized in Fig. 3.
Figure 3. Clinical course of the patient. ALT: alanine aminotransferase, PT: prothrombin time, T-Bil: Total bilirubin, Cre: Creatinine, HEV: Hepatitis E virus
A pathological autopsy was performed after obtaining informed consent from her family. Macroscopically, the surface of the liver was atrophied in a nodular manner, indicating complete cirrhosis (Fig. 4a). Microscopic observation of the liver showed severe atrophy with submassive loss and necrosis of hepatocytes from Zone 3 to Zone 2 of the hepatic lobule (Fig. 4b). However, the distribution did not match the centrilobular necrosis typically observed in hepatic ischemia. In some areas, hepatocytes around the central vein were intact (Fig. 4c). In addition, there was no remarkable steatosis inside hepatocytes indicative of hypoxia (Fig. 4c). Based on these findings, hepatic ischemia was not considered as the main cause of submassive loss and necrosis in this case. Although cholestasis was prominent in the lobules, inflammatory cell infiltration related to acute hepatitis was not evident (Fig. 4b, c). Regenerated nodules and highly fibrous septum formation were found in the liver, which were histologically consistent with cirrhosis (Fig. 4d). In the portal area, the infiltration of mononuclear cells and disappearance of bile ducts suggested advanced PBC (Fig. 4e). Extensive bile duct loss was confirmed between the interlobular and septal bile duct levels.
Figure 4. Autopsy findings. a) Macroscopically, the surface of the liver was atrophied in a nodular manner, indicating complete cirrhosis. b) Severe atrophy with submassive loss and necrosis of hepatocytes (red dotted lines) from Zone 3 to Zone 2 of the hepatic lobule were evident (Hematoxylin and Eosin staining). P: portal vein, C: central vein. c) In some areas, hepatocytes around the central vein were relatively intact, with no steatosis inside hepatocytes suggestive of hypoxia. Cholestasis was prominent in the lobules. Inflammatory cell infiltration indicative of acute hepatitis was not detected. d) On Elastica-Goldner staining, regenerated nodules and highly fibrous septum formation were found in the liver, findings that were histologically consistent with cirrhosis. e) In the portal area, infiltration of mononuclear cells and the disappearance of bile ducts were observed, suggesting advanced PBC. P: portal vein
HEV antibodies (IgG, IgM, and IgA) were measured by an enzyme-linked immunosorbent assay using frozen serum samples according to a previously described method (18). The testing results are shown in Table 2 along with the corresponding hepatobiliary enzymes at each time point. HEV RNA was detected by the nested reverse-transcription polymerase chain reaction with primers targeting the open reading frame 2 (ORF2) region of the HEV genome (nucleotide position 5944-6355, excluding primer sequences at both ends: M73218), as described previously (19). HEV RNA, which had been negative at the last visit before admission, had become positive at admission along with increases in all classes of HEV antibodies. HEV RNA became undetectable during the deterioration of her condition, although a high antibody titer persisted. We determined her 412-nucleotide ORF2 sequence and constructed a molecular phylogenetic tree according to a previously described method (20) (Fig. 5). The HEV strain (HE-JA19-0280: DDBJ/EMBL/GenBank accession number LC581383) derived from this case belonged to genotype 3 (subgenotype 3b) and was closest to those of patients recovering from acute hepatitis E in Tokyo and Gunma Prefectures of Japan.
Figure 5. Phylogenetic tree constructed by the neighbor-joining method based on the partial nucleotide sequence (412 nucleotides) of the open reading frame 2 region of hepatitis E virus (HEV) isolates. In addition to the HEV isolate (HE-JA19-0280) obtained in the present study (highlighted with a closed box), 33 representative genotype 3 isolates (subgenotype 3a: n=8, subgenotype 3b: n=22, and subgenotype 3e: n=3), whose entire genomic sequence is known, are included in the tree using the prototype HEV sequences of genotype 1 (M73218), genotype 2 (M74506), and genotype 4 (AJ272108) as outgroups. Three HEV isolates sharing the highest identity of 97.1-97.8% with the HE-JA19-0280 isolate are also included. Each reference sequence is shown with the genotype/subgenotype followed by the accession number, isolate name, and country in which it was isolated. The bootstrap values (>70%) are indicated for nodes as the percentage of data among 1,000 resampling procedures. The scale bar is in units of nuceotide substitutions per site.
Table 2. Transition of Hepatobiliary Enzymes, HEV Antibodies, and HEV RNA.
Day Laboratory data HEV antibodies HEV RNA
AST
(U/L) ALT
(U/L) GGT
(U/L) ALP
(U/L) T-Bil
(mg/dL) IgG (OD450) IgM (OD450) IgA (OD450)
X - 80 137 111 413 940 3.4 0.010 (-) 0.046 (-) 0.020 (-) Negative
X (admission) 78 100 105 702 30.1 1.661 (+) >3.000 (+) 2.374 (+) +: 1.0×101 copies/mL
X+1 69 80 87 588 26.6 1.578 (+) >3.000 (+) 2.346 (+) +: 1.2×101 copies/mL
X+11 43 44 64 568 39.7 1.850 (+) >3.000 (+) 2.002 (+) Negative
X+14 61 66 78 631 46.7 1.970 (+) >3.000 (+) 1.768 (+) Negative
HEV: hepatitis E virus, AST: aspartate aminotransferase, ALT: alanine aminotransferase, GGT: gamma-glutamyl transpeptidase, ALP: alkaline phosphatase, T-Bil: total bilirubin
Discussion
The present autopsy case displayed histological evidence of submassive necrosis in the liver caused by acute HEV infection. The patient was presumed to have been at the liver cirrhosis stage of PBC but suddenly developed severe jaundice due to superimposed HEV infection and succumbed one month later to hepatic failure. The histopathological findings of severe liver atrophy with submassive loss and necrosis of hepatocytes could not be explained by ischemia only, strongly suggesting the involvement of genotype 3b HEV infection in her histopathological findings.
Although PBC patients generally have a normal life expectancy, they sometimes show rapid disease exacerbation due to concomitant autoimmune hepatitis (7,21) or simultaneous HCV infection (22) as a trigger of PBC deterioration. One rare instance of PBC with acute HEV infection has been reported to date (15). To our knowledge, however, an autopsy case of rapid deterioration triggered by HEV infection has not yet been described. As the mechanism underlying PBC exacerbation due to viral hepatitis infection remains unknown, the present case may contribute to the body of knowledge concerning this condition.
HEV is one of the most common causes of acute viral hepatitis (23). In addition to contaminated water, raw meat from pigs, boars, and deer is another common infection source (24-26). Recently, the prevalence of HEV cases without clinical symptoms as well as those of unknown transmission route has been increasing (27). The infection route in the present case could not be identified based on our medical interview. According to previous reports, pregnancy, old age, alcohol intake, and fatty liver are host factors associated with the aggravation of HEV, and co-infection with chronic liver disease is related to the risk of liver failure (13,14). Regarding the HEV genotype, HEV genotype 4 infection is reportedly associated with aggravation (26,28,29). Genotype 3 HEV, as detected in this case, is generally associated with a low tendency of severe clinical manifestations, although a rare case of progressive genotype 3 HEV infection has been reported (28). A mutation of V239A in the helicase region of the genotype 3 HEV genome has been associated with HEV infection aggravation (30). That mutant was absent in this case (data not shown). The patient had no other apparent host or viral factors associated with HEV severity. However, Wang et al. reported that the cirrhosis stage itself carries a potential risk of liver failure due to HEV infection, regardless of etiology; they further described the potentiation of the cirrhotic liver upon HEV infection and more aggressive immune- or inflammatory-mediated activation of cell death in a cirrhotic liver status as possible mechanisms of exacerbation (15). The above results suggested that even if patients have no documented risk factors of HEV aggravation, clinicians should bear in mind that HEV infection at a cirrhotic liver disease stage can become severe.
This patient had been diagnosed with PBC 26 years earlier based on serological criteria. Eight years before admission, she was already at an advanced stage of PBC, with Nakanuma stage 3 and Scheuer stage III classifications according to a liver biopsy. An autopsy specimen of the liver revealed obvious cirrhosis, which was consistent with the natural history of PBC as suggested by elevated serum surrogate markers of M2BPGi (31,32). However, the submassive loss and necrosis of hepatocytes could not solely be explained by the natural PBC history. Inflammatory cell infiltration suggesting acute hepatitis E (33) was not observed, which suggested a post-inflammatory status. Other general clinical features of acute hepatitis, including markedly elevated levels of liver enzymes, were absent as well. Her liver enzymes were only mildly elevated at day X-80, suggesting that asymptomatic hepatitis may have started at that point, followed by further increases in transaminase levels. Thus, one explanation as to why this case showed mild hepatitis was that the hepatitis had occurred after day X-80 and already peaked and ameliorated by the time of admission, such that jaundice represented the major feature. However, no clinical data were available between the patient’s last outpatient visit at day X-80 and her hospitalization. Another hypothesis was that this case had already reached the complete cirrhosis stage, as shown by the pathological findings, which could have induced mild liver enzyme elevations (34).
Patients with hepatitis E sometimes show severe jaundice (35). Although the underlying mechanism is uncertain, HEV has been reported to exhibit not only hepatocytic but also biliary tropism and replicate within bile duct epithelial cells (36,37). The severe jaundice and cholestasis in this case might have been the result of HEV infection complicating the chronic cholestatic liver disease of PBC. The fact that jaundice was more pronounced than elevated liver enzyme levels may support this notion. Although drug-induced liver injury (levofloxacin 500 mg/day) cannot be ruled out, we suspected that HEV infection likely triggered the exacerbation of PBC due to her awareness of jaundice prior to drug administration and the histological considerations described above.
In conclusion, clinicians should consider the possibility of acute HEV infection as a trigger for the acute exacerbation of PBC. In such cases, it may be necessary to treat the patient with the anticipation of severe aggravation.
The authors state that they have no Conflict of Interest (COI).
Acknowledgement
We thank Trevor Ralph for his English editorial assistance. | Not recovered | ReactionOutcome | CC BY-NC-ND | 33518570 | 19,677,427 | 2021-06-15 |
What was the outcome of reaction 'Renal failure'? | An Autopsy Case of Primary Biliary Cholangitis with Histological Submassive Hepatic Necrosis Caused by Acute Hepatitis E Virus Infection.
A 59-year-old woman who had been diagnosed with cirrhotic primary biliary cholangitis (PBC) 5 years earlier was admitted for severe jaundice (total bilirubin: 30.1 mg/dL). We suspected that her cirrhotic PBC had deteriorated acutely for some reason. Her general condition deteriorated quickly, and she passed away on day 18 of admission. Hepatitis E virus (HEV)-IgA antibodies were positive, and Genotype 3b HEV involvement was confirmed from a blood sample taken on admission. Histopathological findings revealed cirrhosis and submassive loss and necrosis of hepatocytes. Clinicians should consider the possibility of acute HEV infection as a trigger for acute PBC exacerbation.
Introduction
Primary biliary cholangitis (PBC) is a chronic and slowly progressive cholestatic autoimmune liver disease that is histopathologically characterized by an attack on the small intralobular bile duct by T lymphocytes (1). The precise etiology of PBC remains unknown but is related to genetic susceptibility environmental factors (2-4). Although most patients with PBC are asymptomatic and have a normal life expectancy, clinicians sometimes encounter symptomatic PBC cases with severe jaundice or liver failure as a result of the sustained loss of intralobular bile ducts in spite of ursodeoxycholic acid (UDCA) therapy (5,6). Patients with concomitant acute liver injury from autoimmune hepatitis show particularly rapid disease progression (7). The acute exacerbation of PBC from hepatitis virus co-infection is rare in the clinical setting.
The hepatitis E virus (HEV) is a quasi-enveloped, single-stranded RNA virus that causes acute or chronic hepatitis (8,9). With the increase in the number of hepatitis E cases, HEV antibody is now positive in approximately 5% of the general population in Japan (10,11). Among HEV-associated acute hepatitis cases, 0.5-4% of patients progress to fulminant hepatitis (12), leading to high mortality when intensive care and liver transplantation are unavailable. Rare cases of severe acute HEV hepatitis underlying such chronic liver diseases as alcoholic liver disease, nonalcoholic fatty liver disease, chronic viral hepatitis, and PBC have been documented as well (13-15). No autopsy PBC cases displaying acute exacerbation due to superimposed acute HEV infection have been reported to date.
We herein report the autopsy findings of a PBC case in the cirrhotic stage with histological submassive hepatic necrosis caused by acute HEV infection.
Case Report
A 59-year-old woman who had been serologically diagnosed with PBC after the detection of liver dysfunction 26 years earlier was admitted to our hospital for severe jaundice, brown urine, and leg edema. She had suffered from cold-like symptoms and skin jaundice for a month and had received antitussives and antibiotics (levofloxacin 500 mg/day) from her attending physician 2 weeks before admission. She had no symptoms of diarrhea, vomiting, or a history of eating raw meat. She reported no regular ethanol consumption or travel to a foreign country. Although she had been prescribed 600 mg/day UDCA and 400 mg/day bezafibrate for PBC, her medication compliance was extremely poor. She had persistent liver dysfunction [alanine aminotransferase (ALT) at around 100 U/L] and jaundice (total bilirubin at around 3 mg/dL). Eight years before admission, the histological findings of a liver biopsy specimen showed lymphocyte infiltration in the portal area and severe bile duct loss that were consistent with Nakanuma stage 3 (16) and Scheuer stage III (17) classifications (Fig. 1). Three years later, she was clinically diagnosed with cirrhosis-stage PBC. She had also undergone endoscopic gastric varices treatment one year before admission.
Figure 1. Histological findings of a liver biopsy specimen obtained eight years before admission. a, b) Lymphocyte infiltration in the portal area and severe bile duct loss were observed (Hematoxylin and Eosin staining). c) Azan-Mallory staining showed moderate fibrosis in the liver that was consistent with Nakanuma stage 3 and Scheuer stage III classifications.
On an examination at the time of admission, the patient was 165 cm tall, weighed 68 kg, and had a body mass index of 25.0 kg/m2. Her vital signs included Glasgow Coma Scale score E4V5M6, body temperature 37.3 °C, and blood pressure 111/54 mmHg. She exhibited conjunctival and systemic jaundice and front chest vascular spider but no flapping tremor. Laboratory tests on admission revealed elevated serum aspartate aminotransferase (78 U/L), ALT (100 U/L), gamma-glutamyl transpeptidase (105 U/L), alkaline phosphatase (702 U/L), total bilirubin (30.1 mg/dL), and Mac-2-binding protein glycan isomer (M2BPGi) (7.4 C・O・I) but a reduced platelet count (7.2×104/μL), albumin (2.7 g/dL), and prothrombin time activity (67.7%) (Table 1). Testing for hepatitis A virus antibody (immunoglobulin M), hepatitis B virus surface antigen, and anti-hepatitis C virus (HCV) antibody was negative. Serum antibodies to the Epstein-Barr virus and cytomegalovirus both showed a historical infection pattern. Although serum alpha fetoprotein levels were within normal range, levels of protein induced by vitamin K absence or antagonist II were mildly elevated (152 mAU/mL). Among the autoantibodies tested, fluorescent anti-nuclear antibody (× 640) and anti-mitochondrial M2 antibody (168.1 Index) were positive.
Table 1. Laboratory Findings on Admission.
Blood Chemistry / Serology Viral markers
White blood cell count 5,760 /μL Total protein 5.9 g/dL IgM-HAV Ab (-)
Neutrophils 71.2 % Albumin 2.7 g/dL HBs-Ag 0.001 (-) U/mL
Lymphocytes 19.8 % AST 78 U/L HBs-Ab 0.4 (-) mIU/mL
Monocytes 5.7 % ALT 100 U/L HBc-Ab 0.2 (-) C·O·I
Eosinophils 3.0 % Total bilirubin 30.14 mg/dL IgM-HBc Ab (-)
Basophils 0.3 % GGT 105 U/L HCV-Ab 0.1 (-) C·O·I
Red blood cell count 418 ×104/μL ALP 702 U/L IgM-EBV VCA Ab <10 (-) ×
Hemoglobin 13.1 g/dL BUN 12 mg/dL IgG-EBV VCA Ab 40 (+)
Hematocrit 37.4 % Creatinine 0.59 mg/dL EBV EBNA Ab <10 (-) ×
Platelet count 7.2 ×104/μL NH3 29 μg/dL IgM-CMV Ab 0.29 (-) Index
CRP 1.61 mg/dL IgG-CMV Ab 133.6 (+) AU/mL
Coagulation HbA1c 4.2 % IgA-HEV Ab (+)
PT 67.7 % IgM 139 mg/dL
APTT 29.0 sec IgA 292 mg/dL Autoimmune antibodies
Fibrinogen 192.0 mg/dL IgG 1,156 mg/dL FANA 640 ×
D-dimer 2.3 μg/mL M2BPGi 7.4 C·O·I AMA2 168.1 Index
Anti-centromere antibody (-)
Tumor markers LKM-1 (-)
AFP 7.0 ng/mL ASMA (-)
PIVKA II 152 mAU/mL
PT: prothrombin time, APTT: activated partial thromboplastin time, AST: aspartate aminotransferase, ALT: alanine aminotransferase, GGT: gamma-glutamyl transpeptidase, ALP: alkaline phosphatase, BUN: blood urea nitrogen, CRP: C-reactive protein, HbA1c: hemoglobin A1c, M2BPGi: Mac 2-Binding Protein Gylcan Isomer, AFP: alpha fetoprotein, PIVKA II: protein induced by vitamin K absence or antagonist II, FANA: fluorescent anti-nuclear antibody, AMA2: anti-mitochondrial M2 antibody, LKM-1: anti-liver/kidney microsome type 1 antibody, ASMA: anti-smooth muscle antibody, C·O·I: cut off index
Abdominal ultrasonography showed surface irregularity and a coarse parenchyma echotexture of the liver, suggesting cirrhosis (Fig. 2a). Abdominal contrast-enhanced computed tomography portal phase images showed surface undulation of the liver, collateral circulation around the stomach and splenic hilum, and ascites on the surface of the liver and spleen (Fig. 2b). No evidence suggestive of acute hepatitis, such as periportal collar sign, gallbladder atrophy, or wall thickening, was observed, nor were any space-occupying lesions present in the liver.
Figure 2. a) Abdominal ultrasonography showed liver surface irregularity (arrowheads) and a coarse parenchyma echotexture. b) Abdominal contrast-enhanced computed tomography portal phase images revealed surface undulation of the liver, collateral circulation around the stomach and splenic hilum (arrows), and ascites on the surface of the liver and spleen.
Based on the patient’s clinical findings, we suspected that her cirrhotic PBC had deteriorated acutely for some reason. Although she did not meet the criteria for acute liver failure, the presence of severe jaundice and ascites indicated the need for liver transplantation. After being refused for this treatment, we provided supportive care, including bed rest, lactulose administration, and albumin replacement. On day 13 of admission, HEV-IgA antibody was found to be positive in an admission blood sample, suggesting an association between the exacerbation of her PBC and acute HEV infection. However, the patient’s liver atrophy and renal failure were beyond treatment. Her general condition progressively worsened, and she passed away on day 18 of admission. The entire clinical course is summarized in Fig. 3.
Figure 3. Clinical course of the patient. ALT: alanine aminotransferase, PT: prothrombin time, T-Bil: Total bilirubin, Cre: Creatinine, HEV: Hepatitis E virus
A pathological autopsy was performed after obtaining informed consent from her family. Macroscopically, the surface of the liver was atrophied in a nodular manner, indicating complete cirrhosis (Fig. 4a). Microscopic observation of the liver showed severe atrophy with submassive loss and necrosis of hepatocytes from Zone 3 to Zone 2 of the hepatic lobule (Fig. 4b). However, the distribution did not match the centrilobular necrosis typically observed in hepatic ischemia. In some areas, hepatocytes around the central vein were intact (Fig. 4c). In addition, there was no remarkable steatosis inside hepatocytes indicative of hypoxia (Fig. 4c). Based on these findings, hepatic ischemia was not considered as the main cause of submassive loss and necrosis in this case. Although cholestasis was prominent in the lobules, inflammatory cell infiltration related to acute hepatitis was not evident (Fig. 4b, c). Regenerated nodules and highly fibrous septum formation were found in the liver, which were histologically consistent with cirrhosis (Fig. 4d). In the portal area, the infiltration of mononuclear cells and disappearance of bile ducts suggested advanced PBC (Fig. 4e). Extensive bile duct loss was confirmed between the interlobular and septal bile duct levels.
Figure 4. Autopsy findings. a) Macroscopically, the surface of the liver was atrophied in a nodular manner, indicating complete cirrhosis. b) Severe atrophy with submassive loss and necrosis of hepatocytes (red dotted lines) from Zone 3 to Zone 2 of the hepatic lobule were evident (Hematoxylin and Eosin staining). P: portal vein, C: central vein. c) In some areas, hepatocytes around the central vein were relatively intact, with no steatosis inside hepatocytes suggestive of hypoxia. Cholestasis was prominent in the lobules. Inflammatory cell infiltration indicative of acute hepatitis was not detected. d) On Elastica-Goldner staining, regenerated nodules and highly fibrous septum formation were found in the liver, findings that were histologically consistent with cirrhosis. e) In the portal area, infiltration of mononuclear cells and the disappearance of bile ducts were observed, suggesting advanced PBC. P: portal vein
HEV antibodies (IgG, IgM, and IgA) were measured by an enzyme-linked immunosorbent assay using frozen serum samples according to a previously described method (18). The testing results are shown in Table 2 along with the corresponding hepatobiliary enzymes at each time point. HEV RNA was detected by the nested reverse-transcription polymerase chain reaction with primers targeting the open reading frame 2 (ORF2) region of the HEV genome (nucleotide position 5944-6355, excluding primer sequences at both ends: M73218), as described previously (19). HEV RNA, which had been negative at the last visit before admission, had become positive at admission along with increases in all classes of HEV antibodies. HEV RNA became undetectable during the deterioration of her condition, although a high antibody titer persisted. We determined her 412-nucleotide ORF2 sequence and constructed a molecular phylogenetic tree according to a previously described method (20) (Fig. 5). The HEV strain (HE-JA19-0280: DDBJ/EMBL/GenBank accession number LC581383) derived from this case belonged to genotype 3 (subgenotype 3b) and was closest to those of patients recovering from acute hepatitis E in Tokyo and Gunma Prefectures of Japan.
Figure 5. Phylogenetic tree constructed by the neighbor-joining method based on the partial nucleotide sequence (412 nucleotides) of the open reading frame 2 region of hepatitis E virus (HEV) isolates. In addition to the HEV isolate (HE-JA19-0280) obtained in the present study (highlighted with a closed box), 33 representative genotype 3 isolates (subgenotype 3a: n=8, subgenotype 3b: n=22, and subgenotype 3e: n=3), whose entire genomic sequence is known, are included in the tree using the prototype HEV sequences of genotype 1 (M73218), genotype 2 (M74506), and genotype 4 (AJ272108) as outgroups. Three HEV isolates sharing the highest identity of 97.1-97.8% with the HE-JA19-0280 isolate are also included. Each reference sequence is shown with the genotype/subgenotype followed by the accession number, isolate name, and country in which it was isolated. The bootstrap values (>70%) are indicated for nodes as the percentage of data among 1,000 resampling procedures. The scale bar is in units of nuceotide substitutions per site.
Table 2. Transition of Hepatobiliary Enzymes, HEV Antibodies, and HEV RNA.
Day Laboratory data HEV antibodies HEV RNA
AST
(U/L) ALT
(U/L) GGT
(U/L) ALP
(U/L) T-Bil
(mg/dL) IgG (OD450) IgM (OD450) IgA (OD450)
X - 80 137 111 413 940 3.4 0.010 (-) 0.046 (-) 0.020 (-) Negative
X (admission) 78 100 105 702 30.1 1.661 (+) >3.000 (+) 2.374 (+) +: 1.0×101 copies/mL
X+1 69 80 87 588 26.6 1.578 (+) >3.000 (+) 2.346 (+) +: 1.2×101 copies/mL
X+11 43 44 64 568 39.7 1.850 (+) >3.000 (+) 2.002 (+) Negative
X+14 61 66 78 631 46.7 1.970 (+) >3.000 (+) 1.768 (+) Negative
HEV: hepatitis E virus, AST: aspartate aminotransferase, ALT: alanine aminotransferase, GGT: gamma-glutamyl transpeptidase, ALP: alkaline phosphatase, T-Bil: total bilirubin
Discussion
The present autopsy case displayed histological evidence of submassive necrosis in the liver caused by acute HEV infection. The patient was presumed to have been at the liver cirrhosis stage of PBC but suddenly developed severe jaundice due to superimposed HEV infection and succumbed one month later to hepatic failure. The histopathological findings of severe liver atrophy with submassive loss and necrosis of hepatocytes could not be explained by ischemia only, strongly suggesting the involvement of genotype 3b HEV infection in her histopathological findings.
Although PBC patients generally have a normal life expectancy, they sometimes show rapid disease exacerbation due to concomitant autoimmune hepatitis (7,21) or simultaneous HCV infection (22) as a trigger of PBC deterioration. One rare instance of PBC with acute HEV infection has been reported to date (15). To our knowledge, however, an autopsy case of rapid deterioration triggered by HEV infection has not yet been described. As the mechanism underlying PBC exacerbation due to viral hepatitis infection remains unknown, the present case may contribute to the body of knowledge concerning this condition.
HEV is one of the most common causes of acute viral hepatitis (23). In addition to contaminated water, raw meat from pigs, boars, and deer is another common infection source (24-26). Recently, the prevalence of HEV cases without clinical symptoms as well as those of unknown transmission route has been increasing (27). The infection route in the present case could not be identified based on our medical interview. According to previous reports, pregnancy, old age, alcohol intake, and fatty liver are host factors associated with the aggravation of HEV, and co-infection with chronic liver disease is related to the risk of liver failure (13,14). Regarding the HEV genotype, HEV genotype 4 infection is reportedly associated with aggravation (26,28,29). Genotype 3 HEV, as detected in this case, is generally associated with a low tendency of severe clinical manifestations, although a rare case of progressive genotype 3 HEV infection has been reported (28). A mutation of V239A in the helicase region of the genotype 3 HEV genome has been associated with HEV infection aggravation (30). That mutant was absent in this case (data not shown). The patient had no other apparent host or viral factors associated with HEV severity. However, Wang et al. reported that the cirrhosis stage itself carries a potential risk of liver failure due to HEV infection, regardless of etiology; they further described the potentiation of the cirrhotic liver upon HEV infection and more aggressive immune- or inflammatory-mediated activation of cell death in a cirrhotic liver status as possible mechanisms of exacerbation (15). The above results suggested that even if patients have no documented risk factors of HEV aggravation, clinicians should bear in mind that HEV infection at a cirrhotic liver disease stage can become severe.
This patient had been diagnosed with PBC 26 years earlier based on serological criteria. Eight years before admission, she was already at an advanced stage of PBC, with Nakanuma stage 3 and Scheuer stage III classifications according to a liver biopsy. An autopsy specimen of the liver revealed obvious cirrhosis, which was consistent with the natural history of PBC as suggested by elevated serum surrogate markers of M2BPGi (31,32). However, the submassive loss and necrosis of hepatocytes could not solely be explained by the natural PBC history. Inflammatory cell infiltration suggesting acute hepatitis E (33) was not observed, which suggested a post-inflammatory status. Other general clinical features of acute hepatitis, including markedly elevated levels of liver enzymes, were absent as well. Her liver enzymes were only mildly elevated at day X-80, suggesting that asymptomatic hepatitis may have started at that point, followed by further increases in transaminase levels. Thus, one explanation as to why this case showed mild hepatitis was that the hepatitis had occurred after day X-80 and already peaked and ameliorated by the time of admission, such that jaundice represented the major feature. However, no clinical data were available between the patient’s last outpatient visit at day X-80 and her hospitalization. Another hypothesis was that this case had already reached the complete cirrhosis stage, as shown by the pathological findings, which could have induced mild liver enzyme elevations (34).
Patients with hepatitis E sometimes show severe jaundice (35). Although the underlying mechanism is uncertain, HEV has been reported to exhibit not only hepatocytic but also biliary tropism and replicate within bile duct epithelial cells (36,37). The severe jaundice and cholestasis in this case might have been the result of HEV infection complicating the chronic cholestatic liver disease of PBC. The fact that jaundice was more pronounced than elevated liver enzyme levels may support this notion. Although drug-induced liver injury (levofloxacin 500 mg/day) cannot be ruled out, we suspected that HEV infection likely triggered the exacerbation of PBC due to her awareness of jaundice prior to drug administration and the histological considerations described above.
In conclusion, clinicians should consider the possibility of acute HEV infection as a trigger for the acute exacerbation of PBC. In such cases, it may be necessary to treat the patient with the anticipation of severe aggravation.
The authors state that they have no Conflict of Interest (COI).
Acknowledgement
We thank Trevor Ralph for his English editorial assistance. | Not recovered | ReactionOutcome | CC BY-NC-ND | 33518570 | 19,677,427 | 2021-06-15 |
Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Asthenia'. | Giant Hepatic Cyst: A Possible Cause of Inferior Vena Cava Syndrome.
An 80-year-old man was transferred to our institution with lower limb edema and worsening dyspnea following the administration of diuretic medication. Transthoracic echocardiography and computed tomography revealed a giant hepatic cyst (176×190 mm) compressing his right atrium and inferior vena cava (IVC). Laparoscopic cyst deroofing combined with omental packing and subsequent tube drainage immediately alleviated all his symptoms. The procedure was uneventful, and he was discharged without any complications on postoperative day 9; he had no recurrent symptoms or hepatic cysts at the postoperative 2-month follow-up. Therefore, a giant hepatic cyst can cause IVC syndrome, and laparoscopic deroofing is a beneficial approach for the treatment of accessible cysts.
Introduction
Accurately diagnosing the etiology of clinical symptoms is important; as such, physicians should include every possible etiology as part of a thorough differential diagnosis. Hepatic cyst is a benign disease found in approximately 1-5% of the general population (1). Patients with hepatic cysts infrequently experience complications such as a spontaneous rupture, hemorrhaging, bacterial infection, torsion of a pedunculated cyst, or biliary obstruction (2). We herein describe a rare case of a giant hepatic cyst that compressed the patient's right atrium and inferior vena cava (IVC) thus leading to IVC syndrome. Laparoscopic deroofing was considered as the first-line therapy, which immediately resolved the symptoms.
Case Report
An 80-year-old man presented with lower limb edema, worsening dyspnea, and faintness. His medical history included hypertension and paroxysmal atrial fibrillation. Lower limb edema developed gradually over 4 months. His family doctor diagnosed him with simple idiopathic edema and prescribed 20 mg of furosemide, which induced severe fainting, dyspnea, and feebleness. Thereafter, the patient was transferred to our institution. He was alert with a blood pressure of 131/86 mmHg, a heart rate of 91 bpm, a respiratory rate of 20 bpm, and an oxygen saturation of 98% in room air. His jugular vein and cardiac sounds were normal; however, no respiratory sounds could be auscultated in the right lower lung field, and moderate bilateral pretibial edema was detected (Fig. 1). An electrocardiogram revealed a sinus rhythm with left axis deviation and no significant ST-T change (Fig. 2, left panel). A chest radiograph indicated eventration of the right diaphragm and left deviation of the cardiac silhouette (Fig. 2, right panel). Transthoracic echocardiography revealed that his right atrium and IVC were compressed by an extra-cardiac mass (176×190 mm), while also observing a preserved ejection fraction, an enlarged left atrium, and mild tricuspid regurgitation (Fig. 3). Laboratory evaluations revealed the following values: 1.0 mg/dL of total bilirubin, 48 U/L of aspartate aminotransferase, 50 U/L of alanine aminotransferase, 3.8 g/dL of albumin, 1.11 mg/dL of creatinine, <10 pg/mL of high-sense cardiac troponin I, 39.0 pg/mL of brain natriuretic peptide in the plasma, 1.40 μIU/mL of thyroid stimulating hormone, 2.89 pg/mL of free T3, 1.06 ng/dL of free T4, and no significant albuminuria. Subsequent contrast computed tomography demonstrated a giant hepatic cyst compressing the right atrium and IVC (Fig. 4).
Figure 1. Bilateral pretibial edema at the first visit.
Figure 2. Left panel: an electrocardiogram showing a sinus rhythm with left axis deviation and no significant ST-T change. Right panel: a chest radiograph indicating great eventration of the right diaphragm and left deviation of a cardiac silhouette.
Figure 3. Transthoracic echocardiography (A: 4-chamber view in high-depth. B: 4-chamber view in low-depth) shows the right atrium excluded by the extra-cardiac mass (176×190 mm) with a preserved ejection fraction. The compressed inferior vena cava cannot be detected. HC: hepatic cyst, LA: left atrium, LV: left ventricle, RA: right atrium, RV: right ventricle
Figure 4. Computed tomography shows a giant hepatic cyst compressing the right atrium and IVC. Left panel: plane imaging. Middle panel: arterial phase. Right panel: venous phase. AO: aorta, HC: hepatic cyst, IVC: inferior vena cava, LA: left atrium, LV: left ventricle, PV: pulmonary vein, RA: right atrium, RV: right ventricle, SVC: superior vena cava
Based on these physical and objective findings, we diagnosed the patient with IVC syndrome or secondary Budd-Chiari syndrome along with a congestive liver. The suspected etiology was mechanical compression of the IVC, presenting as lower limb edema and a low pre-load of the left heart due to decreased venous return leading to dyspnea and faintness. As a result, the previously prescribed diuretics were deemed to have exacerbated the patient's dyspnea and fainting spells.
First, the diuretics were discontinued and the surgical team was consulted to plan the removal of the cyst causing mechanical compression. As percutaneous transhepatic cholangio drainage and subsequent minocycline-infusion have some risk of recurrence, laparoscopic deroofing of the giant hepatic cyst was chosen in combination with omental packing and subsequent tube drainage. His congestive liver dysfunction immediately resolved, and the lower limb edema disappeared. The drain tube was removed on postoperative day 7, confirming that the drainage had no bile. The patient was discharged without any complications on postoperative day 9 and he did not experience a recurrence of either any symptoms or hepatic cysts based on computed tomography performed 2 months after his surgery (Fig. 5). We obtained the patient's informed consent to publish this case report.
Figure 5. Computed tomography 2 months after the operation indicates no recurrence of the giant hepatic cyst, thus maintaining the structural integrity and adequate functioning of the right atrium (RA) and inferior vena cava (IVC).
Discussion
This case is instructive and educational, describing an unusual etiology of the IVC syndrome, namely, a giant hepatic cyst compressing the right atrium and IVC. Few reports have been published in this regard (3,4). Our case illustrates two important findings. First, the differential diagnosis of the etiology of patients' clinical symptoms is important for selecting the appropriate treatment. Second, benign hepatic cysts can cause extra-hepatic morbidity.
The symptom of lower limb edema in this case has various etiologies. The relatively most common etiologies are heart failure including right-sided heart failure, hypoalbuminemia, nephrotic syndrome, renal failure, liver cirrhosis, deep venous thrombosis, or lymphedema. As the treatment should be based on its etiology, identifying the specific etiology is key. Right-sided heart failure is actually a representative etiology of lower limb edema, most of which results from left-sided heart failure. In other words, most right-sided heart failure can be treated with medication for left-sided heart failure such as by administering diuretics or vasodilators. However, diuretics without identification of the specific etiologies can also further reduce the systemic venous return and left ventricular pre-load leading to significant symptoms as was seen in our case. This illustrates that the proper identification of the underlying etiology can prevent inappropriate and harmful medications. IVC syndrome causes right-sided heart-failure “like” hemodynamics and mimics right-sided heart failure. Hence, we discontinued diuretics and enforced an appropriate fluid intake, tolerating some lower limb edema. In addition, surgical intervention was the sole intervention required for this patient. After releasing the mechanical compression, he was free from clinical symptoms without any medication.
Though hepatic cysts are benign, our case illustrates they can cause extra-hepatic morbidity. Hepatic cysts are found in approximately 1-5% of the general population (1). Although most hepatic cysts are asymptomatic, a few cases involve complications such as spontaneous rupture, hemorrhaging, bacterial infection, torsion of a pedunculated cyst, or biliary obstruction (2). Compression of the right heart system leading to symptoms such as right-sided heart failure is very rare, but has been reported (3,4). All these morbidities require surgical intervention; this is the sole etiology-orientated treatment in these cases. Several surgical approaches have been suggested for giant hepatic cysts. Simple aspiration could be a symptomatic therapy, but it does not provide any permanent therapeutic benefit in most cases (5). The injection of sclerosants such as minomycin has a low incidence of cyst recurrence or complications (6). Laparoscopic surgery is a less invasive strategy compared to conventional open procedures, and recurrence rates ranging from 0-14.3% and morbidity rates of 0-15% have been reported after laparoscopic deroofing of simple hepatic cysts (7). Laparoscopic deroofing should therefore be considered as a first-line therapy for accessible cysts.
In conclusion, a giant hepatic cyst can cause IVC syndrome. Laparoscopic deroofing is a beneficial choice in cases with accessible cysts.
The authors state that they have no Conflict of Interest (COI). | FUROSEMIDE | DrugsGivenReaction | CC BY-NC-ND | 33518574 | 20,473,573 | 2021-07-01 |
Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Condition aggravated'. | Giant Hepatic Cyst: A Possible Cause of Inferior Vena Cava Syndrome.
An 80-year-old man was transferred to our institution with lower limb edema and worsening dyspnea following the administration of diuretic medication. Transthoracic echocardiography and computed tomography revealed a giant hepatic cyst (176×190 mm) compressing his right atrium and inferior vena cava (IVC). Laparoscopic cyst deroofing combined with omental packing and subsequent tube drainage immediately alleviated all his symptoms. The procedure was uneventful, and he was discharged without any complications on postoperative day 9; he had no recurrent symptoms or hepatic cysts at the postoperative 2-month follow-up. Therefore, a giant hepatic cyst can cause IVC syndrome, and laparoscopic deroofing is a beneficial approach for the treatment of accessible cysts.
Introduction
Accurately diagnosing the etiology of clinical symptoms is important; as such, physicians should include every possible etiology as part of a thorough differential diagnosis. Hepatic cyst is a benign disease found in approximately 1-5% of the general population (1). Patients with hepatic cysts infrequently experience complications such as a spontaneous rupture, hemorrhaging, bacterial infection, torsion of a pedunculated cyst, or biliary obstruction (2). We herein describe a rare case of a giant hepatic cyst that compressed the patient's right atrium and inferior vena cava (IVC) thus leading to IVC syndrome. Laparoscopic deroofing was considered as the first-line therapy, which immediately resolved the symptoms.
Case Report
An 80-year-old man presented with lower limb edema, worsening dyspnea, and faintness. His medical history included hypertension and paroxysmal atrial fibrillation. Lower limb edema developed gradually over 4 months. His family doctor diagnosed him with simple idiopathic edema and prescribed 20 mg of furosemide, which induced severe fainting, dyspnea, and feebleness. Thereafter, the patient was transferred to our institution. He was alert with a blood pressure of 131/86 mmHg, a heart rate of 91 bpm, a respiratory rate of 20 bpm, and an oxygen saturation of 98% in room air. His jugular vein and cardiac sounds were normal; however, no respiratory sounds could be auscultated in the right lower lung field, and moderate bilateral pretibial edema was detected (Fig. 1). An electrocardiogram revealed a sinus rhythm with left axis deviation and no significant ST-T change (Fig. 2, left panel). A chest radiograph indicated eventration of the right diaphragm and left deviation of the cardiac silhouette (Fig. 2, right panel). Transthoracic echocardiography revealed that his right atrium and IVC were compressed by an extra-cardiac mass (176×190 mm), while also observing a preserved ejection fraction, an enlarged left atrium, and mild tricuspid regurgitation (Fig. 3). Laboratory evaluations revealed the following values: 1.0 mg/dL of total bilirubin, 48 U/L of aspartate aminotransferase, 50 U/L of alanine aminotransferase, 3.8 g/dL of albumin, 1.11 mg/dL of creatinine, <10 pg/mL of high-sense cardiac troponin I, 39.0 pg/mL of brain natriuretic peptide in the plasma, 1.40 μIU/mL of thyroid stimulating hormone, 2.89 pg/mL of free T3, 1.06 ng/dL of free T4, and no significant albuminuria. Subsequent contrast computed tomography demonstrated a giant hepatic cyst compressing the right atrium and IVC (Fig. 4).
Figure 1. Bilateral pretibial edema at the first visit.
Figure 2. Left panel: an electrocardiogram showing a sinus rhythm with left axis deviation and no significant ST-T change. Right panel: a chest radiograph indicating great eventration of the right diaphragm and left deviation of a cardiac silhouette.
Figure 3. Transthoracic echocardiography (A: 4-chamber view in high-depth. B: 4-chamber view in low-depth) shows the right atrium excluded by the extra-cardiac mass (176×190 mm) with a preserved ejection fraction. The compressed inferior vena cava cannot be detected. HC: hepatic cyst, LA: left atrium, LV: left ventricle, RA: right atrium, RV: right ventricle
Figure 4. Computed tomography shows a giant hepatic cyst compressing the right atrium and IVC. Left panel: plane imaging. Middle panel: arterial phase. Right panel: venous phase. AO: aorta, HC: hepatic cyst, IVC: inferior vena cava, LA: left atrium, LV: left ventricle, PV: pulmonary vein, RA: right atrium, RV: right ventricle, SVC: superior vena cava
Based on these physical and objective findings, we diagnosed the patient with IVC syndrome or secondary Budd-Chiari syndrome along with a congestive liver. The suspected etiology was mechanical compression of the IVC, presenting as lower limb edema and a low pre-load of the left heart due to decreased venous return leading to dyspnea and faintness. As a result, the previously prescribed diuretics were deemed to have exacerbated the patient's dyspnea and fainting spells.
First, the diuretics were discontinued and the surgical team was consulted to plan the removal of the cyst causing mechanical compression. As percutaneous transhepatic cholangio drainage and subsequent minocycline-infusion have some risk of recurrence, laparoscopic deroofing of the giant hepatic cyst was chosen in combination with omental packing and subsequent tube drainage. His congestive liver dysfunction immediately resolved, and the lower limb edema disappeared. The drain tube was removed on postoperative day 7, confirming that the drainage had no bile. The patient was discharged without any complications on postoperative day 9 and he did not experience a recurrence of either any symptoms or hepatic cysts based on computed tomography performed 2 months after his surgery (Fig. 5). We obtained the patient's informed consent to publish this case report.
Figure 5. Computed tomography 2 months after the operation indicates no recurrence of the giant hepatic cyst, thus maintaining the structural integrity and adequate functioning of the right atrium (RA) and inferior vena cava (IVC).
Discussion
This case is instructive and educational, describing an unusual etiology of the IVC syndrome, namely, a giant hepatic cyst compressing the right atrium and IVC. Few reports have been published in this regard (3,4). Our case illustrates two important findings. First, the differential diagnosis of the etiology of patients' clinical symptoms is important for selecting the appropriate treatment. Second, benign hepatic cysts can cause extra-hepatic morbidity.
The symptom of lower limb edema in this case has various etiologies. The relatively most common etiologies are heart failure including right-sided heart failure, hypoalbuminemia, nephrotic syndrome, renal failure, liver cirrhosis, deep venous thrombosis, or lymphedema. As the treatment should be based on its etiology, identifying the specific etiology is key. Right-sided heart failure is actually a representative etiology of lower limb edema, most of which results from left-sided heart failure. In other words, most right-sided heart failure can be treated with medication for left-sided heart failure such as by administering diuretics or vasodilators. However, diuretics without identification of the specific etiologies can also further reduce the systemic venous return and left ventricular pre-load leading to significant symptoms as was seen in our case. This illustrates that the proper identification of the underlying etiology can prevent inappropriate and harmful medications. IVC syndrome causes right-sided heart-failure “like” hemodynamics and mimics right-sided heart failure. Hence, we discontinued diuretics and enforced an appropriate fluid intake, tolerating some lower limb edema. In addition, surgical intervention was the sole intervention required for this patient. After releasing the mechanical compression, he was free from clinical symptoms without any medication.
Though hepatic cysts are benign, our case illustrates they can cause extra-hepatic morbidity. Hepatic cysts are found in approximately 1-5% of the general population (1). Although most hepatic cysts are asymptomatic, a few cases involve complications such as spontaneous rupture, hemorrhaging, bacterial infection, torsion of a pedunculated cyst, or biliary obstruction (2). Compression of the right heart system leading to symptoms such as right-sided heart failure is very rare, but has been reported (3,4). All these morbidities require surgical intervention; this is the sole etiology-orientated treatment in these cases. Several surgical approaches have been suggested for giant hepatic cysts. Simple aspiration could be a symptomatic therapy, but it does not provide any permanent therapeutic benefit in most cases (5). The injection of sclerosants such as minomycin has a low incidence of cyst recurrence or complications (6). Laparoscopic surgery is a less invasive strategy compared to conventional open procedures, and recurrence rates ranging from 0-14.3% and morbidity rates of 0-15% have been reported after laparoscopic deroofing of simple hepatic cysts (7). Laparoscopic deroofing should therefore be considered as a first-line therapy for accessible cysts.
In conclusion, a giant hepatic cyst can cause IVC syndrome. Laparoscopic deroofing is a beneficial choice in cases with accessible cysts.
The authors state that they have no Conflict of Interest (COI). | FUROSEMIDE | DrugsGivenReaction | CC BY-NC-ND | 33518574 | 20,498,266 | 2021-07-01 |
Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Dyspnoea'. | Giant Hepatic Cyst: A Possible Cause of Inferior Vena Cava Syndrome.
An 80-year-old man was transferred to our institution with lower limb edema and worsening dyspnea following the administration of diuretic medication. Transthoracic echocardiography and computed tomography revealed a giant hepatic cyst (176×190 mm) compressing his right atrium and inferior vena cava (IVC). Laparoscopic cyst deroofing combined with omental packing and subsequent tube drainage immediately alleviated all his symptoms. The procedure was uneventful, and he was discharged without any complications on postoperative day 9; he had no recurrent symptoms or hepatic cysts at the postoperative 2-month follow-up. Therefore, a giant hepatic cyst can cause IVC syndrome, and laparoscopic deroofing is a beneficial approach for the treatment of accessible cysts.
Introduction
Accurately diagnosing the etiology of clinical symptoms is important; as such, physicians should include every possible etiology as part of a thorough differential diagnosis. Hepatic cyst is a benign disease found in approximately 1-5% of the general population (1). Patients with hepatic cysts infrequently experience complications such as a spontaneous rupture, hemorrhaging, bacterial infection, torsion of a pedunculated cyst, or biliary obstruction (2). We herein describe a rare case of a giant hepatic cyst that compressed the patient's right atrium and inferior vena cava (IVC) thus leading to IVC syndrome. Laparoscopic deroofing was considered as the first-line therapy, which immediately resolved the symptoms.
Case Report
An 80-year-old man presented with lower limb edema, worsening dyspnea, and faintness. His medical history included hypertension and paroxysmal atrial fibrillation. Lower limb edema developed gradually over 4 months. His family doctor diagnosed him with simple idiopathic edema and prescribed 20 mg of furosemide, which induced severe fainting, dyspnea, and feebleness. Thereafter, the patient was transferred to our institution. He was alert with a blood pressure of 131/86 mmHg, a heart rate of 91 bpm, a respiratory rate of 20 bpm, and an oxygen saturation of 98% in room air. His jugular vein and cardiac sounds were normal; however, no respiratory sounds could be auscultated in the right lower lung field, and moderate bilateral pretibial edema was detected (Fig. 1). An electrocardiogram revealed a sinus rhythm with left axis deviation and no significant ST-T change (Fig. 2, left panel). A chest radiograph indicated eventration of the right diaphragm and left deviation of the cardiac silhouette (Fig. 2, right panel). Transthoracic echocardiography revealed that his right atrium and IVC were compressed by an extra-cardiac mass (176×190 mm), while also observing a preserved ejection fraction, an enlarged left atrium, and mild tricuspid regurgitation (Fig. 3). Laboratory evaluations revealed the following values: 1.0 mg/dL of total bilirubin, 48 U/L of aspartate aminotransferase, 50 U/L of alanine aminotransferase, 3.8 g/dL of albumin, 1.11 mg/dL of creatinine, <10 pg/mL of high-sense cardiac troponin I, 39.0 pg/mL of brain natriuretic peptide in the plasma, 1.40 μIU/mL of thyroid stimulating hormone, 2.89 pg/mL of free T3, 1.06 ng/dL of free T4, and no significant albuminuria. Subsequent contrast computed tomography demonstrated a giant hepatic cyst compressing the right atrium and IVC (Fig. 4).
Figure 1. Bilateral pretibial edema at the first visit.
Figure 2. Left panel: an electrocardiogram showing a sinus rhythm with left axis deviation and no significant ST-T change. Right panel: a chest radiograph indicating great eventration of the right diaphragm and left deviation of a cardiac silhouette.
Figure 3. Transthoracic echocardiography (A: 4-chamber view in high-depth. B: 4-chamber view in low-depth) shows the right atrium excluded by the extra-cardiac mass (176×190 mm) with a preserved ejection fraction. The compressed inferior vena cava cannot be detected. HC: hepatic cyst, LA: left atrium, LV: left ventricle, RA: right atrium, RV: right ventricle
Figure 4. Computed tomography shows a giant hepatic cyst compressing the right atrium and IVC. Left panel: plane imaging. Middle panel: arterial phase. Right panel: venous phase. AO: aorta, HC: hepatic cyst, IVC: inferior vena cava, LA: left atrium, LV: left ventricle, PV: pulmonary vein, RA: right atrium, RV: right ventricle, SVC: superior vena cava
Based on these physical and objective findings, we diagnosed the patient with IVC syndrome or secondary Budd-Chiari syndrome along with a congestive liver. The suspected etiology was mechanical compression of the IVC, presenting as lower limb edema and a low pre-load of the left heart due to decreased venous return leading to dyspnea and faintness. As a result, the previously prescribed diuretics were deemed to have exacerbated the patient's dyspnea and fainting spells.
First, the diuretics were discontinued and the surgical team was consulted to plan the removal of the cyst causing mechanical compression. As percutaneous transhepatic cholangio drainage and subsequent minocycline-infusion have some risk of recurrence, laparoscopic deroofing of the giant hepatic cyst was chosen in combination with omental packing and subsequent tube drainage. His congestive liver dysfunction immediately resolved, and the lower limb edema disappeared. The drain tube was removed on postoperative day 7, confirming that the drainage had no bile. The patient was discharged without any complications on postoperative day 9 and he did not experience a recurrence of either any symptoms or hepatic cysts based on computed tomography performed 2 months after his surgery (Fig. 5). We obtained the patient's informed consent to publish this case report.
Figure 5. Computed tomography 2 months after the operation indicates no recurrence of the giant hepatic cyst, thus maintaining the structural integrity and adequate functioning of the right atrium (RA) and inferior vena cava (IVC).
Discussion
This case is instructive and educational, describing an unusual etiology of the IVC syndrome, namely, a giant hepatic cyst compressing the right atrium and IVC. Few reports have been published in this regard (3,4). Our case illustrates two important findings. First, the differential diagnosis of the etiology of patients' clinical symptoms is important for selecting the appropriate treatment. Second, benign hepatic cysts can cause extra-hepatic morbidity.
The symptom of lower limb edema in this case has various etiologies. The relatively most common etiologies are heart failure including right-sided heart failure, hypoalbuminemia, nephrotic syndrome, renal failure, liver cirrhosis, deep venous thrombosis, or lymphedema. As the treatment should be based on its etiology, identifying the specific etiology is key. Right-sided heart failure is actually a representative etiology of lower limb edema, most of which results from left-sided heart failure. In other words, most right-sided heart failure can be treated with medication for left-sided heart failure such as by administering diuretics or vasodilators. However, diuretics without identification of the specific etiologies can also further reduce the systemic venous return and left ventricular pre-load leading to significant symptoms as was seen in our case. This illustrates that the proper identification of the underlying etiology can prevent inappropriate and harmful medications. IVC syndrome causes right-sided heart-failure “like” hemodynamics and mimics right-sided heart failure. Hence, we discontinued diuretics and enforced an appropriate fluid intake, tolerating some lower limb edema. In addition, surgical intervention was the sole intervention required for this patient. After releasing the mechanical compression, he was free from clinical symptoms without any medication.
Though hepatic cysts are benign, our case illustrates they can cause extra-hepatic morbidity. Hepatic cysts are found in approximately 1-5% of the general population (1). Although most hepatic cysts are asymptomatic, a few cases involve complications such as spontaneous rupture, hemorrhaging, bacterial infection, torsion of a pedunculated cyst, or biliary obstruction (2). Compression of the right heart system leading to symptoms such as right-sided heart failure is very rare, but has been reported (3,4). All these morbidities require surgical intervention; this is the sole etiology-orientated treatment in these cases. Several surgical approaches have been suggested for giant hepatic cysts. Simple aspiration could be a symptomatic therapy, but it does not provide any permanent therapeutic benefit in most cases (5). The injection of sclerosants such as minomycin has a low incidence of cyst recurrence or complications (6). Laparoscopic surgery is a less invasive strategy compared to conventional open procedures, and recurrence rates ranging from 0-14.3% and morbidity rates of 0-15% have been reported after laparoscopic deroofing of simple hepatic cysts (7). Laparoscopic deroofing should therefore be considered as a first-line therapy for accessible cysts.
In conclusion, a giant hepatic cyst can cause IVC syndrome. Laparoscopic deroofing is a beneficial choice in cases with accessible cysts.
The authors state that they have no Conflict of Interest (COI). | FUROSEMIDE | DrugsGivenReaction | CC BY-NC-ND | 33518574 | 20,473,573 | 2021-07-01 |
Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Syncope'. | Giant Hepatic Cyst: A Possible Cause of Inferior Vena Cava Syndrome.
An 80-year-old man was transferred to our institution with lower limb edema and worsening dyspnea following the administration of diuretic medication. Transthoracic echocardiography and computed tomography revealed a giant hepatic cyst (176×190 mm) compressing his right atrium and inferior vena cava (IVC). Laparoscopic cyst deroofing combined with omental packing and subsequent tube drainage immediately alleviated all his symptoms. The procedure was uneventful, and he was discharged without any complications on postoperative day 9; he had no recurrent symptoms or hepatic cysts at the postoperative 2-month follow-up. Therefore, a giant hepatic cyst can cause IVC syndrome, and laparoscopic deroofing is a beneficial approach for the treatment of accessible cysts.
Introduction
Accurately diagnosing the etiology of clinical symptoms is important; as such, physicians should include every possible etiology as part of a thorough differential diagnosis. Hepatic cyst is a benign disease found in approximately 1-5% of the general population (1). Patients with hepatic cysts infrequently experience complications such as a spontaneous rupture, hemorrhaging, bacterial infection, torsion of a pedunculated cyst, or biliary obstruction (2). We herein describe a rare case of a giant hepatic cyst that compressed the patient's right atrium and inferior vena cava (IVC) thus leading to IVC syndrome. Laparoscopic deroofing was considered as the first-line therapy, which immediately resolved the symptoms.
Case Report
An 80-year-old man presented with lower limb edema, worsening dyspnea, and faintness. His medical history included hypertension and paroxysmal atrial fibrillation. Lower limb edema developed gradually over 4 months. His family doctor diagnosed him with simple idiopathic edema and prescribed 20 mg of furosemide, which induced severe fainting, dyspnea, and feebleness. Thereafter, the patient was transferred to our institution. He was alert with a blood pressure of 131/86 mmHg, a heart rate of 91 bpm, a respiratory rate of 20 bpm, and an oxygen saturation of 98% in room air. His jugular vein and cardiac sounds were normal; however, no respiratory sounds could be auscultated in the right lower lung field, and moderate bilateral pretibial edema was detected (Fig. 1). An electrocardiogram revealed a sinus rhythm with left axis deviation and no significant ST-T change (Fig. 2, left panel). A chest radiograph indicated eventration of the right diaphragm and left deviation of the cardiac silhouette (Fig. 2, right panel). Transthoracic echocardiography revealed that his right atrium and IVC were compressed by an extra-cardiac mass (176×190 mm), while also observing a preserved ejection fraction, an enlarged left atrium, and mild tricuspid regurgitation (Fig. 3). Laboratory evaluations revealed the following values: 1.0 mg/dL of total bilirubin, 48 U/L of aspartate aminotransferase, 50 U/L of alanine aminotransferase, 3.8 g/dL of albumin, 1.11 mg/dL of creatinine, <10 pg/mL of high-sense cardiac troponin I, 39.0 pg/mL of brain natriuretic peptide in the plasma, 1.40 μIU/mL of thyroid stimulating hormone, 2.89 pg/mL of free T3, 1.06 ng/dL of free T4, and no significant albuminuria. Subsequent contrast computed tomography demonstrated a giant hepatic cyst compressing the right atrium and IVC (Fig. 4).
Figure 1. Bilateral pretibial edema at the first visit.
Figure 2. Left panel: an electrocardiogram showing a sinus rhythm with left axis deviation and no significant ST-T change. Right panel: a chest radiograph indicating great eventration of the right diaphragm and left deviation of a cardiac silhouette.
Figure 3. Transthoracic echocardiography (A: 4-chamber view in high-depth. B: 4-chamber view in low-depth) shows the right atrium excluded by the extra-cardiac mass (176×190 mm) with a preserved ejection fraction. The compressed inferior vena cava cannot be detected. HC: hepatic cyst, LA: left atrium, LV: left ventricle, RA: right atrium, RV: right ventricle
Figure 4. Computed tomography shows a giant hepatic cyst compressing the right atrium and IVC. Left panel: plane imaging. Middle panel: arterial phase. Right panel: venous phase. AO: aorta, HC: hepatic cyst, IVC: inferior vena cava, LA: left atrium, LV: left ventricle, PV: pulmonary vein, RA: right atrium, RV: right ventricle, SVC: superior vena cava
Based on these physical and objective findings, we diagnosed the patient with IVC syndrome or secondary Budd-Chiari syndrome along with a congestive liver. The suspected etiology was mechanical compression of the IVC, presenting as lower limb edema and a low pre-load of the left heart due to decreased venous return leading to dyspnea and faintness. As a result, the previously prescribed diuretics were deemed to have exacerbated the patient's dyspnea and fainting spells.
First, the diuretics were discontinued and the surgical team was consulted to plan the removal of the cyst causing mechanical compression. As percutaneous transhepatic cholangio drainage and subsequent minocycline-infusion have some risk of recurrence, laparoscopic deroofing of the giant hepatic cyst was chosen in combination with omental packing and subsequent tube drainage. His congestive liver dysfunction immediately resolved, and the lower limb edema disappeared. The drain tube was removed on postoperative day 7, confirming that the drainage had no bile. The patient was discharged without any complications on postoperative day 9 and he did not experience a recurrence of either any symptoms or hepatic cysts based on computed tomography performed 2 months after his surgery (Fig. 5). We obtained the patient's informed consent to publish this case report.
Figure 5. Computed tomography 2 months after the operation indicates no recurrence of the giant hepatic cyst, thus maintaining the structural integrity and adequate functioning of the right atrium (RA) and inferior vena cava (IVC).
Discussion
This case is instructive and educational, describing an unusual etiology of the IVC syndrome, namely, a giant hepatic cyst compressing the right atrium and IVC. Few reports have been published in this regard (3,4). Our case illustrates two important findings. First, the differential diagnosis of the etiology of patients' clinical symptoms is important for selecting the appropriate treatment. Second, benign hepatic cysts can cause extra-hepatic morbidity.
The symptom of lower limb edema in this case has various etiologies. The relatively most common etiologies are heart failure including right-sided heart failure, hypoalbuminemia, nephrotic syndrome, renal failure, liver cirrhosis, deep venous thrombosis, or lymphedema. As the treatment should be based on its etiology, identifying the specific etiology is key. Right-sided heart failure is actually a representative etiology of lower limb edema, most of which results from left-sided heart failure. In other words, most right-sided heart failure can be treated with medication for left-sided heart failure such as by administering diuretics or vasodilators. However, diuretics without identification of the specific etiologies can also further reduce the systemic venous return and left ventricular pre-load leading to significant symptoms as was seen in our case. This illustrates that the proper identification of the underlying etiology can prevent inappropriate and harmful medications. IVC syndrome causes right-sided heart-failure “like” hemodynamics and mimics right-sided heart failure. Hence, we discontinued diuretics and enforced an appropriate fluid intake, tolerating some lower limb edema. In addition, surgical intervention was the sole intervention required for this patient. After releasing the mechanical compression, he was free from clinical symptoms without any medication.
Though hepatic cysts are benign, our case illustrates they can cause extra-hepatic morbidity. Hepatic cysts are found in approximately 1-5% of the general population (1). Although most hepatic cysts are asymptomatic, a few cases involve complications such as spontaneous rupture, hemorrhaging, bacterial infection, torsion of a pedunculated cyst, or biliary obstruction (2). Compression of the right heart system leading to symptoms such as right-sided heart failure is very rare, but has been reported (3,4). All these morbidities require surgical intervention; this is the sole etiology-orientated treatment in these cases. Several surgical approaches have been suggested for giant hepatic cysts. Simple aspiration could be a symptomatic therapy, but it does not provide any permanent therapeutic benefit in most cases (5). The injection of sclerosants such as minomycin has a low incidence of cyst recurrence or complications (6). Laparoscopic surgery is a less invasive strategy compared to conventional open procedures, and recurrence rates ranging from 0-14.3% and morbidity rates of 0-15% have been reported after laparoscopic deroofing of simple hepatic cysts (7). Laparoscopic deroofing should therefore be considered as a first-line therapy for accessible cysts.
In conclusion, a giant hepatic cyst can cause IVC syndrome. Laparoscopic deroofing is a beneficial choice in cases with accessible cysts.
The authors state that they have no Conflict of Interest (COI). | FUROSEMIDE | DrugsGivenReaction | CC BY-NC-ND | 33518574 | 20,473,573 | 2021-07-01 |
Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Blood magnesium decreased'. | Torsade de Pointes Due to QT Prolongation after Pulmonary Vein Isolation for Persistent Atrial Fibrillation.
We herein report a 60-year-old woman with long-standing persistent atrial fibrillation (AF) who developed QT prolongation and torsade de pointes (TdP) after pulmonary vein isolation (PVI). When electrical cardioversion was performed three months before PVI, prominent QT prolongation was not observed. QT prolongation emerged after PVI and was sustained until AF recurrence on the third day after ablation, and TdP disappeared along with AF recurrence. PVI affects the ganglionated plexi around the atrium, leading to modification of the intrinsic cardiac autonomic system. This case indicates that PVI has the potential risk of inducing lethal ventricular arrhythmias due to QT prolongation.
Introduction
Catheter ablation is a highly effective therapeutic strategy for atrial fibrillation (AF) (1,2). Pulmonary vein isolation (PVI) is a cornerstone of AF ablation. The ablation line of PVI transects the sites where the major atrial ganglionated plexi (GP) exists. GP ablation carries a risk of increasing atrial and ventricular vulnerability to arrhythmias, and GP ablation induced QT prolongation after myocardial infarction in a canine model (3,4,5). QT prolongation and lethal ventricular arrhythmias related to PVI and antiarrhythmic drugs have also been reported (6).
We herein report a patient who developed QT prolongation and torsade de pointes (TdP) after PVI for persistent AF without an antiarrhythmic drug.
Case Report
A 60-year-old woman with long-standing persistent AF was referred to our hospital for catheter ablation. She had no structural heart disease or inherited arrhythmias. Her prescribed medication included bisoprolol fumarate 1.25 mg daily; edoxaban tosilate hydrate 30 mg daily; olmesartan medoxomil 20 mg daily; sodium valproate 200 mg twice daily; and ifenprodil tartrate 20 mg three times a day. Bisoprolol fumarate was discontinued two days before the ablation procedure. We performed electrical cardioversion three months before the ablation procedure, and prominent QT prolongation was not observed early after cardioversion. Intravenous injection of 150 mg thiopental sodium was performed before electrical cardioversion (Fig. 1A).
Figure 1. (A) A 12-lead electrocardiogram acquired soon after electrical cardioversion 3 months before pulmonary vein isolation. The HR was 54 bpm. The raw QT interval was 487 ms, and the Fridericia formula [QTc=QT/ (RR 1/3)]-corrected QTc was 470 ms. (B) A 12-lead electrocardiogram showing atrial fibrillation before catheter ablation. The raw QT was 427 ms, and the Fridericia-corrected QTc was 449 ms. The raw QT was measured using the tangent method as an average of six or more beats.
Recurrence of AF occurred, and a 12-lead electrocardiogram (ECG) showed no QT prolongation before ablation (Fig. 1B). Wide antral ipsilateral PVI using radiofrequency (RF) ablation was performed under the guidance of three-dimensional (3D) ultrasound geometries and 3D merged computed tomography (CT) using the CARTO 3 system (Biosense Webster, Diamond Bar, USA). RF ablation was performed under deep sedation with noninvasive positive pressure ventilation support. Deep sedation was initiated with 6 μg/kg/h dexmedetomidine for 10 min and fentanyl citrate 0.1 mg. Subsequently, it was maintained with 0.6 μg/kg/h dexmedetomidine. The total dexmedetomidine dose was 150 μg. First-pass isolation was achieved in both PVs, and electrical cardioversion was performed to restore sinus rhythm.
We performed right PVI first to avoid the vagal reflex, followed by left PVI (Fig. 2). Intravenous injection of 50 mg thiopental sodium was performed before electrical cardioversion. The bidirectional block was confirmed, and a dissociated potential was observed in both PVs. No complications were observed during the procedure, and the patient returned to the general ward in sinus rhythm. The total procedure time was 104 minutes.
Figure 2. Three-dimensional computed tomography merged voltage map after pulmonary vein isolation. Each tag shows an ablation point.
Seventeen hours after the procedure, TdP suddenly occurred and spontaneously terminated. A 12-lead ECG revealed prominent QT prolongation. Laboratory data showed a slightly low serum magnesium (Mg) level of 1.6 mg/dL. Creatine phosphokinase levels were within the normal limits (85 IU/L). T wave inversions were found in I, aVL, and V2, but there were no obvious local wall motion abnormalities on bedside echocardiography. QT prolongation persisted, and TdP was not suppressed despite normalization of the serum Mg level using intravenous administration of Mg sulfate hydrate (Fig. 3). TdP appeared occasionally but resolved spontaneously and did not progress to ventricular fibrillation. TdP disappeared together with AF recurrence three days after ablation. QT prolongation and negative T waves were also improved (Fig. 4).
Figure 3. QT prolongation was observed two days after pulmonary vein isolation. The HR was 71 bpm. The raw QT was 540 ms, and the Fridericia-corrected QTc was 549 ms. T wave inversions were found in I, aVL, and V2. Torsade de pointes (TdP) occurred despite the normalization of serum Mg levels. TdP disappeared with the recurrence of atrial fibrillation.
Figure 4. A 12-lead electrocardiogram was acquired on the third day after the procedure, showing atrial fibrillation. The raw QT was 362 ms, and the Fridericia-corrected QTc was 440 ms. QT prolongation and negative T waves were improved.
A genetic test using the TruSight Cardio sequencing panel (Illumina, San Diego, USA) detected no known gene mutations related to long QT syndrome. On the sixth day after the procedure, coronary angiography showed no obstruction or stenosis, and left ventriculography reveled no local wall motion abnormalities. She did not take any antiarrhythmic drugs before or after ablation.
Discussion
The QT interval is affected by various factors, including the heart rate, electrolyte disorders, autonomic nervous system, and anesthesia. In this case, the QT interval was prolonged after PVI, and the prolongation was sustained despite the normalization of electrolyte disorders. Exaggerated QT prolongation after cardioversion has been reported (7); however, in the present case, QT prolongation was not observed when electrical cardioversion was performed three months before the ablation. Her prescribed medications did not change after the ablation procedures. These observations suggest the involvement of the PVI procedure in QT prolongation.
The ablation line of PVI for AF transects the sites where the major atrial GP exists; therefore, PVI inadvertently modifies the intrinsic cardiac autonomic nervous system, which is a determinant of the QT interval (8). In animal models, GP ablation is associated with a prolonged QT interval and increased atrial/ventricular vulnerability to arrhythmias (3,4). QT prolongation has also been observed after PVI, especially in the acute phase, in humans (9). Although TdP associated with QT prolongation after PVI with antiarrhythmic drugs has been reported (6), no antiarrhythmic drugs were used in the present case. Approximately 30% of acquired long QT syndrome cases have a known clinical long QT syndrome gene mutation (10), but no relevant genetic background was detected in this case; nevertheless, discontinuation of the beta-blocker two days before the procedure may have been involved in QT prolongation after the ablation procedure.
This case indicates the potential risk of lethal arrhythmia induced by QT prolongation due to PVI, even in patients without a known genetic background of long QT syndrome or antiarrhythmic drug prescription.
The authors state that they have no Conflict of Interest (COI). | BISOPROLOL FUMARATE, DEXMEDETOMIDINE HYDROCHLORIDE, EDOXABAN TOSYLATE, FENTANYL CITRATE, IFENPRODIL TARTRATE, OLMESARTAN MEDOXOMIL, THIOPENTAL SODIUM, VALPROATE SODIUM | DrugsGivenReaction | CC BY-NC-ND | 33518578 | 19,647,376 | 2021-07-01 |
Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Electrocardiogram QT prolonged'. | Torsade de Pointes Due to QT Prolongation after Pulmonary Vein Isolation for Persistent Atrial Fibrillation.
We herein report a 60-year-old woman with long-standing persistent atrial fibrillation (AF) who developed QT prolongation and torsade de pointes (TdP) after pulmonary vein isolation (PVI). When electrical cardioversion was performed three months before PVI, prominent QT prolongation was not observed. QT prolongation emerged after PVI and was sustained until AF recurrence on the third day after ablation, and TdP disappeared along with AF recurrence. PVI affects the ganglionated plexi around the atrium, leading to modification of the intrinsic cardiac autonomic system. This case indicates that PVI has the potential risk of inducing lethal ventricular arrhythmias due to QT prolongation.
Introduction
Catheter ablation is a highly effective therapeutic strategy for atrial fibrillation (AF) (1,2). Pulmonary vein isolation (PVI) is a cornerstone of AF ablation. The ablation line of PVI transects the sites where the major atrial ganglionated plexi (GP) exists. GP ablation carries a risk of increasing atrial and ventricular vulnerability to arrhythmias, and GP ablation induced QT prolongation after myocardial infarction in a canine model (3,4,5). QT prolongation and lethal ventricular arrhythmias related to PVI and antiarrhythmic drugs have also been reported (6).
We herein report a patient who developed QT prolongation and torsade de pointes (TdP) after PVI for persistent AF without an antiarrhythmic drug.
Case Report
A 60-year-old woman with long-standing persistent AF was referred to our hospital for catheter ablation. She had no structural heart disease or inherited arrhythmias. Her prescribed medication included bisoprolol fumarate 1.25 mg daily; edoxaban tosilate hydrate 30 mg daily; olmesartan medoxomil 20 mg daily; sodium valproate 200 mg twice daily; and ifenprodil tartrate 20 mg three times a day. Bisoprolol fumarate was discontinued two days before the ablation procedure. We performed electrical cardioversion three months before the ablation procedure, and prominent QT prolongation was not observed early after cardioversion. Intravenous injection of 150 mg thiopental sodium was performed before electrical cardioversion (Fig. 1A).
Figure 1. (A) A 12-lead electrocardiogram acquired soon after electrical cardioversion 3 months before pulmonary vein isolation. The HR was 54 bpm. The raw QT interval was 487 ms, and the Fridericia formula [QTc=QT/ (RR 1/3)]-corrected QTc was 470 ms. (B) A 12-lead electrocardiogram showing atrial fibrillation before catheter ablation. The raw QT was 427 ms, and the Fridericia-corrected QTc was 449 ms. The raw QT was measured using the tangent method as an average of six or more beats.
Recurrence of AF occurred, and a 12-lead electrocardiogram (ECG) showed no QT prolongation before ablation (Fig. 1B). Wide antral ipsilateral PVI using radiofrequency (RF) ablation was performed under the guidance of three-dimensional (3D) ultrasound geometries and 3D merged computed tomography (CT) using the CARTO 3 system (Biosense Webster, Diamond Bar, USA). RF ablation was performed under deep sedation with noninvasive positive pressure ventilation support. Deep sedation was initiated with 6 μg/kg/h dexmedetomidine for 10 min and fentanyl citrate 0.1 mg. Subsequently, it was maintained with 0.6 μg/kg/h dexmedetomidine. The total dexmedetomidine dose was 150 μg. First-pass isolation was achieved in both PVs, and electrical cardioversion was performed to restore sinus rhythm.
We performed right PVI first to avoid the vagal reflex, followed by left PVI (Fig. 2). Intravenous injection of 50 mg thiopental sodium was performed before electrical cardioversion. The bidirectional block was confirmed, and a dissociated potential was observed in both PVs. No complications were observed during the procedure, and the patient returned to the general ward in sinus rhythm. The total procedure time was 104 minutes.
Figure 2. Three-dimensional computed tomography merged voltage map after pulmonary vein isolation. Each tag shows an ablation point.
Seventeen hours after the procedure, TdP suddenly occurred and spontaneously terminated. A 12-lead ECG revealed prominent QT prolongation. Laboratory data showed a slightly low serum magnesium (Mg) level of 1.6 mg/dL. Creatine phosphokinase levels were within the normal limits (85 IU/L). T wave inversions were found in I, aVL, and V2, but there were no obvious local wall motion abnormalities on bedside echocardiography. QT prolongation persisted, and TdP was not suppressed despite normalization of the serum Mg level using intravenous administration of Mg sulfate hydrate (Fig. 3). TdP appeared occasionally but resolved spontaneously and did not progress to ventricular fibrillation. TdP disappeared together with AF recurrence three days after ablation. QT prolongation and negative T waves were also improved (Fig. 4).
Figure 3. QT prolongation was observed two days after pulmonary vein isolation. The HR was 71 bpm. The raw QT was 540 ms, and the Fridericia-corrected QTc was 549 ms. T wave inversions were found in I, aVL, and V2. Torsade de pointes (TdP) occurred despite the normalization of serum Mg levels. TdP disappeared with the recurrence of atrial fibrillation.
Figure 4. A 12-lead electrocardiogram was acquired on the third day after the procedure, showing atrial fibrillation. The raw QT was 362 ms, and the Fridericia-corrected QTc was 440 ms. QT prolongation and negative T waves were improved.
A genetic test using the TruSight Cardio sequencing panel (Illumina, San Diego, USA) detected no known gene mutations related to long QT syndrome. On the sixth day after the procedure, coronary angiography showed no obstruction or stenosis, and left ventriculography reveled no local wall motion abnormalities. She did not take any antiarrhythmic drugs before or after ablation.
Discussion
The QT interval is affected by various factors, including the heart rate, electrolyte disorders, autonomic nervous system, and anesthesia. In this case, the QT interval was prolonged after PVI, and the prolongation was sustained despite the normalization of electrolyte disorders. Exaggerated QT prolongation after cardioversion has been reported (7); however, in the present case, QT prolongation was not observed when electrical cardioversion was performed three months before the ablation. Her prescribed medications did not change after the ablation procedures. These observations suggest the involvement of the PVI procedure in QT prolongation.
The ablation line of PVI for AF transects the sites where the major atrial GP exists; therefore, PVI inadvertently modifies the intrinsic cardiac autonomic nervous system, which is a determinant of the QT interval (8). In animal models, GP ablation is associated with a prolonged QT interval and increased atrial/ventricular vulnerability to arrhythmias (3,4). QT prolongation has also been observed after PVI, especially in the acute phase, in humans (9). Although TdP associated with QT prolongation after PVI with antiarrhythmic drugs has been reported (6), no antiarrhythmic drugs were used in the present case. Approximately 30% of acquired long QT syndrome cases have a known clinical long QT syndrome gene mutation (10), but no relevant genetic background was detected in this case; nevertheless, discontinuation of the beta-blocker two days before the procedure may have been involved in QT prolongation after the ablation procedure.
This case indicates the potential risk of lethal arrhythmia induced by QT prolongation due to PVI, even in patients without a known genetic background of long QT syndrome or antiarrhythmic drug prescription.
The authors state that they have no Conflict of Interest (COI). | BISOPROLOL FUMARATE, DEXMEDETOMIDINE HYDROCHLORIDE, EDOXABAN TOSYLATE, FENTANYL CITRATE, IFENPRODIL TARTRATE, OLMESARTAN MEDOXOMIL, THIOPENTAL SODIUM, VALPROATE SODIUM | DrugsGivenReaction | CC BY-NC-ND | 33518578 | 19,647,376 | 2021-07-01 |
Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Torsade de pointes'. | Torsade de Pointes Due to QT Prolongation after Pulmonary Vein Isolation for Persistent Atrial Fibrillation.
We herein report a 60-year-old woman with long-standing persistent atrial fibrillation (AF) who developed QT prolongation and torsade de pointes (TdP) after pulmonary vein isolation (PVI). When electrical cardioversion was performed three months before PVI, prominent QT prolongation was not observed. QT prolongation emerged after PVI and was sustained until AF recurrence on the third day after ablation, and TdP disappeared along with AF recurrence. PVI affects the ganglionated plexi around the atrium, leading to modification of the intrinsic cardiac autonomic system. This case indicates that PVI has the potential risk of inducing lethal ventricular arrhythmias due to QT prolongation.
Introduction
Catheter ablation is a highly effective therapeutic strategy for atrial fibrillation (AF) (1,2). Pulmonary vein isolation (PVI) is a cornerstone of AF ablation. The ablation line of PVI transects the sites where the major atrial ganglionated plexi (GP) exists. GP ablation carries a risk of increasing atrial and ventricular vulnerability to arrhythmias, and GP ablation induced QT prolongation after myocardial infarction in a canine model (3,4,5). QT prolongation and lethal ventricular arrhythmias related to PVI and antiarrhythmic drugs have also been reported (6).
We herein report a patient who developed QT prolongation and torsade de pointes (TdP) after PVI for persistent AF without an antiarrhythmic drug.
Case Report
A 60-year-old woman with long-standing persistent AF was referred to our hospital for catheter ablation. She had no structural heart disease or inherited arrhythmias. Her prescribed medication included bisoprolol fumarate 1.25 mg daily; edoxaban tosilate hydrate 30 mg daily; olmesartan medoxomil 20 mg daily; sodium valproate 200 mg twice daily; and ifenprodil tartrate 20 mg three times a day. Bisoprolol fumarate was discontinued two days before the ablation procedure. We performed electrical cardioversion three months before the ablation procedure, and prominent QT prolongation was not observed early after cardioversion. Intravenous injection of 150 mg thiopental sodium was performed before electrical cardioversion (Fig. 1A).
Figure 1. (A) A 12-lead electrocardiogram acquired soon after electrical cardioversion 3 months before pulmonary vein isolation. The HR was 54 bpm. The raw QT interval was 487 ms, and the Fridericia formula [QTc=QT/ (RR 1/3)]-corrected QTc was 470 ms. (B) A 12-lead electrocardiogram showing atrial fibrillation before catheter ablation. The raw QT was 427 ms, and the Fridericia-corrected QTc was 449 ms. The raw QT was measured using the tangent method as an average of six or more beats.
Recurrence of AF occurred, and a 12-lead electrocardiogram (ECG) showed no QT prolongation before ablation (Fig. 1B). Wide antral ipsilateral PVI using radiofrequency (RF) ablation was performed under the guidance of three-dimensional (3D) ultrasound geometries and 3D merged computed tomography (CT) using the CARTO 3 system (Biosense Webster, Diamond Bar, USA). RF ablation was performed under deep sedation with noninvasive positive pressure ventilation support. Deep sedation was initiated with 6 μg/kg/h dexmedetomidine for 10 min and fentanyl citrate 0.1 mg. Subsequently, it was maintained with 0.6 μg/kg/h dexmedetomidine. The total dexmedetomidine dose was 150 μg. First-pass isolation was achieved in both PVs, and electrical cardioversion was performed to restore sinus rhythm.
We performed right PVI first to avoid the vagal reflex, followed by left PVI (Fig. 2). Intravenous injection of 50 mg thiopental sodium was performed before electrical cardioversion. The bidirectional block was confirmed, and a dissociated potential was observed in both PVs. No complications were observed during the procedure, and the patient returned to the general ward in sinus rhythm. The total procedure time was 104 minutes.
Figure 2. Three-dimensional computed tomography merged voltage map after pulmonary vein isolation. Each tag shows an ablation point.
Seventeen hours after the procedure, TdP suddenly occurred and spontaneously terminated. A 12-lead ECG revealed prominent QT prolongation. Laboratory data showed a slightly low serum magnesium (Mg) level of 1.6 mg/dL. Creatine phosphokinase levels were within the normal limits (85 IU/L). T wave inversions were found in I, aVL, and V2, but there were no obvious local wall motion abnormalities on bedside echocardiography. QT prolongation persisted, and TdP was not suppressed despite normalization of the serum Mg level using intravenous administration of Mg sulfate hydrate (Fig. 3). TdP appeared occasionally but resolved spontaneously and did not progress to ventricular fibrillation. TdP disappeared together with AF recurrence three days after ablation. QT prolongation and negative T waves were also improved (Fig. 4).
Figure 3. QT prolongation was observed two days after pulmonary vein isolation. The HR was 71 bpm. The raw QT was 540 ms, and the Fridericia-corrected QTc was 549 ms. T wave inversions were found in I, aVL, and V2. Torsade de pointes (TdP) occurred despite the normalization of serum Mg levels. TdP disappeared with the recurrence of atrial fibrillation.
Figure 4. A 12-lead electrocardiogram was acquired on the third day after the procedure, showing atrial fibrillation. The raw QT was 362 ms, and the Fridericia-corrected QTc was 440 ms. QT prolongation and negative T waves were improved.
A genetic test using the TruSight Cardio sequencing panel (Illumina, San Diego, USA) detected no known gene mutations related to long QT syndrome. On the sixth day after the procedure, coronary angiography showed no obstruction or stenosis, and left ventriculography reveled no local wall motion abnormalities. She did not take any antiarrhythmic drugs before or after ablation.
Discussion
The QT interval is affected by various factors, including the heart rate, electrolyte disorders, autonomic nervous system, and anesthesia. In this case, the QT interval was prolonged after PVI, and the prolongation was sustained despite the normalization of electrolyte disorders. Exaggerated QT prolongation after cardioversion has been reported (7); however, in the present case, QT prolongation was not observed when electrical cardioversion was performed three months before the ablation. Her prescribed medications did not change after the ablation procedures. These observations suggest the involvement of the PVI procedure in QT prolongation.
The ablation line of PVI for AF transects the sites where the major atrial GP exists; therefore, PVI inadvertently modifies the intrinsic cardiac autonomic nervous system, which is a determinant of the QT interval (8). In animal models, GP ablation is associated with a prolonged QT interval and increased atrial/ventricular vulnerability to arrhythmias (3,4). QT prolongation has also been observed after PVI, especially in the acute phase, in humans (9). Although TdP associated with QT prolongation after PVI with antiarrhythmic drugs has been reported (6), no antiarrhythmic drugs were used in the present case. Approximately 30% of acquired long QT syndrome cases have a known clinical long QT syndrome gene mutation (10), but no relevant genetic background was detected in this case; nevertheless, discontinuation of the beta-blocker two days before the procedure may have been involved in QT prolongation after the ablation procedure.
This case indicates the potential risk of lethal arrhythmia induced by QT prolongation due to PVI, even in patients without a known genetic background of long QT syndrome or antiarrhythmic drug prescription.
The authors state that they have no Conflict of Interest (COI). | BISOPROLOL FUMARATE, DEXMEDETOMIDINE HYDROCHLORIDE, EDOXABAN TOSYLATE, FENTANYL CITRATE, IFENPRODIL TARTRATE, OLMESARTAN MEDOXOMIL, THIOPENTAL SODIUM, VALPROATE SODIUM | DrugsGivenReaction | CC BY-NC-ND | 33518578 | 19,647,376 | 2021-07-01 |
What was the administration route of drug 'THIOPENTAL SODIUM'? | Torsade de Pointes Due to QT Prolongation after Pulmonary Vein Isolation for Persistent Atrial Fibrillation.
We herein report a 60-year-old woman with long-standing persistent atrial fibrillation (AF) who developed QT prolongation and torsade de pointes (TdP) after pulmonary vein isolation (PVI). When electrical cardioversion was performed three months before PVI, prominent QT prolongation was not observed. QT prolongation emerged after PVI and was sustained until AF recurrence on the third day after ablation, and TdP disappeared along with AF recurrence. PVI affects the ganglionated plexi around the atrium, leading to modification of the intrinsic cardiac autonomic system. This case indicates that PVI has the potential risk of inducing lethal ventricular arrhythmias due to QT prolongation.
Introduction
Catheter ablation is a highly effective therapeutic strategy for atrial fibrillation (AF) (1,2). Pulmonary vein isolation (PVI) is a cornerstone of AF ablation. The ablation line of PVI transects the sites where the major atrial ganglionated plexi (GP) exists. GP ablation carries a risk of increasing atrial and ventricular vulnerability to arrhythmias, and GP ablation induced QT prolongation after myocardial infarction in a canine model (3,4,5). QT prolongation and lethal ventricular arrhythmias related to PVI and antiarrhythmic drugs have also been reported (6).
We herein report a patient who developed QT prolongation and torsade de pointes (TdP) after PVI for persistent AF without an antiarrhythmic drug.
Case Report
A 60-year-old woman with long-standing persistent AF was referred to our hospital for catheter ablation. She had no structural heart disease or inherited arrhythmias. Her prescribed medication included bisoprolol fumarate 1.25 mg daily; edoxaban tosilate hydrate 30 mg daily; olmesartan medoxomil 20 mg daily; sodium valproate 200 mg twice daily; and ifenprodil tartrate 20 mg three times a day. Bisoprolol fumarate was discontinued two days before the ablation procedure. We performed electrical cardioversion three months before the ablation procedure, and prominent QT prolongation was not observed early after cardioversion. Intravenous injection of 150 mg thiopental sodium was performed before electrical cardioversion (Fig. 1A).
Figure 1. (A) A 12-lead electrocardiogram acquired soon after electrical cardioversion 3 months before pulmonary vein isolation. The HR was 54 bpm. The raw QT interval was 487 ms, and the Fridericia formula [QTc=QT/ (RR 1/3)]-corrected QTc was 470 ms. (B) A 12-lead electrocardiogram showing atrial fibrillation before catheter ablation. The raw QT was 427 ms, and the Fridericia-corrected QTc was 449 ms. The raw QT was measured using the tangent method as an average of six or more beats.
Recurrence of AF occurred, and a 12-lead electrocardiogram (ECG) showed no QT prolongation before ablation (Fig. 1B). Wide antral ipsilateral PVI using radiofrequency (RF) ablation was performed under the guidance of three-dimensional (3D) ultrasound geometries and 3D merged computed tomography (CT) using the CARTO 3 system (Biosense Webster, Diamond Bar, USA). RF ablation was performed under deep sedation with noninvasive positive pressure ventilation support. Deep sedation was initiated with 6 μg/kg/h dexmedetomidine for 10 min and fentanyl citrate 0.1 mg. Subsequently, it was maintained with 0.6 μg/kg/h dexmedetomidine. The total dexmedetomidine dose was 150 μg. First-pass isolation was achieved in both PVs, and electrical cardioversion was performed to restore sinus rhythm.
We performed right PVI first to avoid the vagal reflex, followed by left PVI (Fig. 2). Intravenous injection of 50 mg thiopental sodium was performed before electrical cardioversion. The bidirectional block was confirmed, and a dissociated potential was observed in both PVs. No complications were observed during the procedure, and the patient returned to the general ward in sinus rhythm. The total procedure time was 104 minutes.
Figure 2. Three-dimensional computed tomography merged voltage map after pulmonary vein isolation. Each tag shows an ablation point.
Seventeen hours after the procedure, TdP suddenly occurred and spontaneously terminated. A 12-lead ECG revealed prominent QT prolongation. Laboratory data showed a slightly low serum magnesium (Mg) level of 1.6 mg/dL. Creatine phosphokinase levels were within the normal limits (85 IU/L). T wave inversions were found in I, aVL, and V2, but there were no obvious local wall motion abnormalities on bedside echocardiography. QT prolongation persisted, and TdP was not suppressed despite normalization of the serum Mg level using intravenous administration of Mg sulfate hydrate (Fig. 3). TdP appeared occasionally but resolved spontaneously and did not progress to ventricular fibrillation. TdP disappeared together with AF recurrence three days after ablation. QT prolongation and negative T waves were also improved (Fig. 4).
Figure 3. QT prolongation was observed two days after pulmonary vein isolation. The HR was 71 bpm. The raw QT was 540 ms, and the Fridericia-corrected QTc was 549 ms. T wave inversions were found in I, aVL, and V2. Torsade de pointes (TdP) occurred despite the normalization of serum Mg levels. TdP disappeared with the recurrence of atrial fibrillation.
Figure 4. A 12-lead electrocardiogram was acquired on the third day after the procedure, showing atrial fibrillation. The raw QT was 362 ms, and the Fridericia-corrected QTc was 440 ms. QT prolongation and negative T waves were improved.
A genetic test using the TruSight Cardio sequencing panel (Illumina, San Diego, USA) detected no known gene mutations related to long QT syndrome. On the sixth day after the procedure, coronary angiography showed no obstruction or stenosis, and left ventriculography reveled no local wall motion abnormalities. She did not take any antiarrhythmic drugs before or after ablation.
Discussion
The QT interval is affected by various factors, including the heart rate, electrolyte disorders, autonomic nervous system, and anesthesia. In this case, the QT interval was prolonged after PVI, and the prolongation was sustained despite the normalization of electrolyte disorders. Exaggerated QT prolongation after cardioversion has been reported (7); however, in the present case, QT prolongation was not observed when electrical cardioversion was performed three months before the ablation. Her prescribed medications did not change after the ablation procedures. These observations suggest the involvement of the PVI procedure in QT prolongation.
The ablation line of PVI for AF transects the sites where the major atrial GP exists; therefore, PVI inadvertently modifies the intrinsic cardiac autonomic nervous system, which is a determinant of the QT interval (8). In animal models, GP ablation is associated with a prolonged QT interval and increased atrial/ventricular vulnerability to arrhythmias (3,4). QT prolongation has also been observed after PVI, especially in the acute phase, in humans (9). Although TdP associated with QT prolongation after PVI with antiarrhythmic drugs has been reported (6), no antiarrhythmic drugs were used in the present case. Approximately 30% of acquired long QT syndrome cases have a known clinical long QT syndrome gene mutation (10), but no relevant genetic background was detected in this case; nevertheless, discontinuation of the beta-blocker two days before the procedure may have been involved in QT prolongation after the ablation procedure.
This case indicates the potential risk of lethal arrhythmia induced by QT prolongation due to PVI, even in patients without a known genetic background of long QT syndrome or antiarrhythmic drug prescription.
The authors state that they have no Conflict of Interest (COI). | Intravenous (not otherwise specified) | DrugAdministrationRoute | CC BY-NC-ND | 33518578 | 19,647,376 | 2021-07-01 |
What was the dosage of drug 'BISOPROLOL FUMARATE'? | Torsade de Pointes Due to QT Prolongation after Pulmonary Vein Isolation for Persistent Atrial Fibrillation.
We herein report a 60-year-old woman with long-standing persistent atrial fibrillation (AF) who developed QT prolongation and torsade de pointes (TdP) after pulmonary vein isolation (PVI). When electrical cardioversion was performed three months before PVI, prominent QT prolongation was not observed. QT prolongation emerged after PVI and was sustained until AF recurrence on the third day after ablation, and TdP disappeared along with AF recurrence. PVI affects the ganglionated plexi around the atrium, leading to modification of the intrinsic cardiac autonomic system. This case indicates that PVI has the potential risk of inducing lethal ventricular arrhythmias due to QT prolongation.
Introduction
Catheter ablation is a highly effective therapeutic strategy for atrial fibrillation (AF) (1,2). Pulmonary vein isolation (PVI) is a cornerstone of AF ablation. The ablation line of PVI transects the sites where the major atrial ganglionated plexi (GP) exists. GP ablation carries a risk of increasing atrial and ventricular vulnerability to arrhythmias, and GP ablation induced QT prolongation after myocardial infarction in a canine model (3,4,5). QT prolongation and lethal ventricular arrhythmias related to PVI and antiarrhythmic drugs have also been reported (6).
We herein report a patient who developed QT prolongation and torsade de pointes (TdP) after PVI for persistent AF without an antiarrhythmic drug.
Case Report
A 60-year-old woman with long-standing persistent AF was referred to our hospital for catheter ablation. She had no structural heart disease or inherited arrhythmias. Her prescribed medication included bisoprolol fumarate 1.25 mg daily; edoxaban tosilate hydrate 30 mg daily; olmesartan medoxomil 20 mg daily; sodium valproate 200 mg twice daily; and ifenprodil tartrate 20 mg three times a day. Bisoprolol fumarate was discontinued two days before the ablation procedure. We performed electrical cardioversion three months before the ablation procedure, and prominent QT prolongation was not observed early after cardioversion. Intravenous injection of 150 mg thiopental sodium was performed before electrical cardioversion (Fig. 1A).
Figure 1. (A) A 12-lead electrocardiogram acquired soon after electrical cardioversion 3 months before pulmonary vein isolation. The HR was 54 bpm. The raw QT interval was 487 ms, and the Fridericia formula [QTc=QT/ (RR 1/3)]-corrected QTc was 470 ms. (B) A 12-lead electrocardiogram showing atrial fibrillation before catheter ablation. The raw QT was 427 ms, and the Fridericia-corrected QTc was 449 ms. The raw QT was measured using the tangent method as an average of six or more beats.
Recurrence of AF occurred, and a 12-lead electrocardiogram (ECG) showed no QT prolongation before ablation (Fig. 1B). Wide antral ipsilateral PVI using radiofrequency (RF) ablation was performed under the guidance of three-dimensional (3D) ultrasound geometries and 3D merged computed tomography (CT) using the CARTO 3 system (Biosense Webster, Diamond Bar, USA). RF ablation was performed under deep sedation with noninvasive positive pressure ventilation support. Deep sedation was initiated with 6 μg/kg/h dexmedetomidine for 10 min and fentanyl citrate 0.1 mg. Subsequently, it was maintained with 0.6 μg/kg/h dexmedetomidine. The total dexmedetomidine dose was 150 μg. First-pass isolation was achieved in both PVs, and electrical cardioversion was performed to restore sinus rhythm.
We performed right PVI first to avoid the vagal reflex, followed by left PVI (Fig. 2). Intravenous injection of 50 mg thiopental sodium was performed before electrical cardioversion. The bidirectional block was confirmed, and a dissociated potential was observed in both PVs. No complications were observed during the procedure, and the patient returned to the general ward in sinus rhythm. The total procedure time was 104 minutes.
Figure 2. Three-dimensional computed tomography merged voltage map after pulmonary vein isolation. Each tag shows an ablation point.
Seventeen hours after the procedure, TdP suddenly occurred and spontaneously terminated. A 12-lead ECG revealed prominent QT prolongation. Laboratory data showed a slightly low serum magnesium (Mg) level of 1.6 mg/dL. Creatine phosphokinase levels were within the normal limits (85 IU/L). T wave inversions were found in I, aVL, and V2, but there were no obvious local wall motion abnormalities on bedside echocardiography. QT prolongation persisted, and TdP was not suppressed despite normalization of the serum Mg level using intravenous administration of Mg sulfate hydrate (Fig. 3). TdP appeared occasionally but resolved spontaneously and did not progress to ventricular fibrillation. TdP disappeared together with AF recurrence three days after ablation. QT prolongation and negative T waves were also improved (Fig. 4).
Figure 3. QT prolongation was observed two days after pulmonary vein isolation. The HR was 71 bpm. The raw QT was 540 ms, and the Fridericia-corrected QTc was 549 ms. T wave inversions were found in I, aVL, and V2. Torsade de pointes (TdP) occurred despite the normalization of serum Mg levels. TdP disappeared with the recurrence of atrial fibrillation.
Figure 4. A 12-lead electrocardiogram was acquired on the third day after the procedure, showing atrial fibrillation. The raw QT was 362 ms, and the Fridericia-corrected QTc was 440 ms. QT prolongation and negative T waves were improved.
A genetic test using the TruSight Cardio sequencing panel (Illumina, San Diego, USA) detected no known gene mutations related to long QT syndrome. On the sixth day after the procedure, coronary angiography showed no obstruction or stenosis, and left ventriculography reveled no local wall motion abnormalities. She did not take any antiarrhythmic drugs before or after ablation.
Discussion
The QT interval is affected by various factors, including the heart rate, electrolyte disorders, autonomic nervous system, and anesthesia. In this case, the QT interval was prolonged after PVI, and the prolongation was sustained despite the normalization of electrolyte disorders. Exaggerated QT prolongation after cardioversion has been reported (7); however, in the present case, QT prolongation was not observed when electrical cardioversion was performed three months before the ablation. Her prescribed medications did not change after the ablation procedures. These observations suggest the involvement of the PVI procedure in QT prolongation.
The ablation line of PVI for AF transects the sites where the major atrial GP exists; therefore, PVI inadvertently modifies the intrinsic cardiac autonomic nervous system, which is a determinant of the QT interval (8). In animal models, GP ablation is associated with a prolonged QT interval and increased atrial/ventricular vulnerability to arrhythmias (3,4). QT prolongation has also been observed after PVI, especially in the acute phase, in humans (9). Although TdP associated with QT prolongation after PVI with antiarrhythmic drugs has been reported (6), no antiarrhythmic drugs were used in the present case. Approximately 30% of acquired long QT syndrome cases have a known clinical long QT syndrome gene mutation (10), but no relevant genetic background was detected in this case; nevertheless, discontinuation of the beta-blocker two days before the procedure may have been involved in QT prolongation after the ablation procedure.
This case indicates the potential risk of lethal arrhythmia induced by QT prolongation due to PVI, even in patients without a known genetic background of long QT syndrome or antiarrhythmic drug prescription.
The authors state that they have no Conflict of Interest (COI). | 1.25MG/DAY | DrugDosageText | CC BY-NC-ND | 33518578 | 19,647,376 | 2021-07-01 |
What was the dosage of drug 'DEXMEDETOMIDINE HYDROCHLORIDE'? | Torsade de Pointes Due to QT Prolongation after Pulmonary Vein Isolation for Persistent Atrial Fibrillation.
We herein report a 60-year-old woman with long-standing persistent atrial fibrillation (AF) who developed QT prolongation and torsade de pointes (TdP) after pulmonary vein isolation (PVI). When electrical cardioversion was performed three months before PVI, prominent QT prolongation was not observed. QT prolongation emerged after PVI and was sustained until AF recurrence on the third day after ablation, and TdP disappeared along with AF recurrence. PVI affects the ganglionated plexi around the atrium, leading to modification of the intrinsic cardiac autonomic system. This case indicates that PVI has the potential risk of inducing lethal ventricular arrhythmias due to QT prolongation.
Introduction
Catheter ablation is a highly effective therapeutic strategy for atrial fibrillation (AF) (1,2). Pulmonary vein isolation (PVI) is a cornerstone of AF ablation. The ablation line of PVI transects the sites where the major atrial ganglionated plexi (GP) exists. GP ablation carries a risk of increasing atrial and ventricular vulnerability to arrhythmias, and GP ablation induced QT prolongation after myocardial infarction in a canine model (3,4,5). QT prolongation and lethal ventricular arrhythmias related to PVI and antiarrhythmic drugs have also been reported (6).
We herein report a patient who developed QT prolongation and torsade de pointes (TdP) after PVI for persistent AF without an antiarrhythmic drug.
Case Report
A 60-year-old woman with long-standing persistent AF was referred to our hospital for catheter ablation. She had no structural heart disease or inherited arrhythmias. Her prescribed medication included bisoprolol fumarate 1.25 mg daily; edoxaban tosilate hydrate 30 mg daily; olmesartan medoxomil 20 mg daily; sodium valproate 200 mg twice daily; and ifenprodil tartrate 20 mg three times a day. Bisoprolol fumarate was discontinued two days before the ablation procedure. We performed electrical cardioversion three months before the ablation procedure, and prominent QT prolongation was not observed early after cardioversion. Intravenous injection of 150 mg thiopental sodium was performed before electrical cardioversion (Fig. 1A).
Figure 1. (A) A 12-lead electrocardiogram acquired soon after electrical cardioversion 3 months before pulmonary vein isolation. The HR was 54 bpm. The raw QT interval was 487 ms, and the Fridericia formula [QTc=QT/ (RR 1/3)]-corrected QTc was 470 ms. (B) A 12-lead electrocardiogram showing atrial fibrillation before catheter ablation. The raw QT was 427 ms, and the Fridericia-corrected QTc was 449 ms. The raw QT was measured using the tangent method as an average of six or more beats.
Recurrence of AF occurred, and a 12-lead electrocardiogram (ECG) showed no QT prolongation before ablation (Fig. 1B). Wide antral ipsilateral PVI using radiofrequency (RF) ablation was performed under the guidance of three-dimensional (3D) ultrasound geometries and 3D merged computed tomography (CT) using the CARTO 3 system (Biosense Webster, Diamond Bar, USA). RF ablation was performed under deep sedation with noninvasive positive pressure ventilation support. Deep sedation was initiated with 6 μg/kg/h dexmedetomidine for 10 min and fentanyl citrate 0.1 mg. Subsequently, it was maintained with 0.6 μg/kg/h dexmedetomidine. The total dexmedetomidine dose was 150 μg. First-pass isolation was achieved in both PVs, and electrical cardioversion was performed to restore sinus rhythm.
We performed right PVI first to avoid the vagal reflex, followed by left PVI (Fig. 2). Intravenous injection of 50 mg thiopental sodium was performed before electrical cardioversion. The bidirectional block was confirmed, and a dissociated potential was observed in both PVs. No complications were observed during the procedure, and the patient returned to the general ward in sinus rhythm. The total procedure time was 104 minutes.
Figure 2. Three-dimensional computed tomography merged voltage map after pulmonary vein isolation. Each tag shows an ablation point.
Seventeen hours after the procedure, TdP suddenly occurred and spontaneously terminated. A 12-lead ECG revealed prominent QT prolongation. Laboratory data showed a slightly low serum magnesium (Mg) level of 1.6 mg/dL. Creatine phosphokinase levels were within the normal limits (85 IU/L). T wave inversions were found in I, aVL, and V2, but there were no obvious local wall motion abnormalities on bedside echocardiography. QT prolongation persisted, and TdP was not suppressed despite normalization of the serum Mg level using intravenous administration of Mg sulfate hydrate (Fig. 3). TdP appeared occasionally but resolved spontaneously and did not progress to ventricular fibrillation. TdP disappeared together with AF recurrence three days after ablation. QT prolongation and negative T waves were also improved (Fig. 4).
Figure 3. QT prolongation was observed two days after pulmonary vein isolation. The HR was 71 bpm. The raw QT was 540 ms, and the Fridericia-corrected QTc was 549 ms. T wave inversions were found in I, aVL, and V2. Torsade de pointes (TdP) occurred despite the normalization of serum Mg levels. TdP disappeared with the recurrence of atrial fibrillation.
Figure 4. A 12-lead electrocardiogram was acquired on the third day after the procedure, showing atrial fibrillation. The raw QT was 362 ms, and the Fridericia-corrected QTc was 440 ms. QT prolongation and negative T waves were improved.
A genetic test using the TruSight Cardio sequencing panel (Illumina, San Diego, USA) detected no known gene mutations related to long QT syndrome. On the sixth day after the procedure, coronary angiography showed no obstruction or stenosis, and left ventriculography reveled no local wall motion abnormalities. She did not take any antiarrhythmic drugs before or after ablation.
Discussion
The QT interval is affected by various factors, including the heart rate, electrolyte disorders, autonomic nervous system, and anesthesia. In this case, the QT interval was prolonged after PVI, and the prolongation was sustained despite the normalization of electrolyte disorders. Exaggerated QT prolongation after cardioversion has been reported (7); however, in the present case, QT prolongation was not observed when electrical cardioversion was performed three months before the ablation. Her prescribed medications did not change after the ablation procedures. These observations suggest the involvement of the PVI procedure in QT prolongation.
The ablation line of PVI for AF transects the sites where the major atrial GP exists; therefore, PVI inadvertently modifies the intrinsic cardiac autonomic nervous system, which is a determinant of the QT interval (8). In animal models, GP ablation is associated with a prolonged QT interval and increased atrial/ventricular vulnerability to arrhythmias (3,4). QT prolongation has also been observed after PVI, especially in the acute phase, in humans (9). Although TdP associated with QT prolongation after PVI with antiarrhythmic drugs has been reported (6), no antiarrhythmic drugs were used in the present case. Approximately 30% of acquired long QT syndrome cases have a known clinical long QT syndrome gene mutation (10), but no relevant genetic background was detected in this case; nevertheless, discontinuation of the beta-blocker two days before the procedure may have been involved in QT prolongation after the ablation procedure.
This case indicates the potential risk of lethal arrhythmia induced by QT prolongation due to PVI, even in patients without a known genetic background of long QT syndrome or antiarrhythmic drug prescription.
The authors state that they have no Conflict of Interest (COI). | 150UG/DAY | DrugDosageText | CC BY-NC-ND | 33518578 | 19,647,376 | 2021-07-01 |
What was the dosage of drug 'EDOXABAN TOSYLATE'? | Torsade de Pointes Due to QT Prolongation after Pulmonary Vein Isolation for Persistent Atrial Fibrillation.
We herein report a 60-year-old woman with long-standing persistent atrial fibrillation (AF) who developed QT prolongation and torsade de pointes (TdP) after pulmonary vein isolation (PVI). When electrical cardioversion was performed three months before PVI, prominent QT prolongation was not observed. QT prolongation emerged after PVI and was sustained until AF recurrence on the third day after ablation, and TdP disappeared along with AF recurrence. PVI affects the ganglionated plexi around the atrium, leading to modification of the intrinsic cardiac autonomic system. This case indicates that PVI has the potential risk of inducing lethal ventricular arrhythmias due to QT prolongation.
Introduction
Catheter ablation is a highly effective therapeutic strategy for atrial fibrillation (AF) (1,2). Pulmonary vein isolation (PVI) is a cornerstone of AF ablation. The ablation line of PVI transects the sites where the major atrial ganglionated plexi (GP) exists. GP ablation carries a risk of increasing atrial and ventricular vulnerability to arrhythmias, and GP ablation induced QT prolongation after myocardial infarction in a canine model (3,4,5). QT prolongation and lethal ventricular arrhythmias related to PVI and antiarrhythmic drugs have also been reported (6).
We herein report a patient who developed QT prolongation and torsade de pointes (TdP) after PVI for persistent AF without an antiarrhythmic drug.
Case Report
A 60-year-old woman with long-standing persistent AF was referred to our hospital for catheter ablation. She had no structural heart disease or inherited arrhythmias. Her prescribed medication included bisoprolol fumarate 1.25 mg daily; edoxaban tosilate hydrate 30 mg daily; olmesartan medoxomil 20 mg daily; sodium valproate 200 mg twice daily; and ifenprodil tartrate 20 mg three times a day. Bisoprolol fumarate was discontinued two days before the ablation procedure. We performed electrical cardioversion three months before the ablation procedure, and prominent QT prolongation was not observed early after cardioversion. Intravenous injection of 150 mg thiopental sodium was performed before electrical cardioversion (Fig. 1A).
Figure 1. (A) A 12-lead electrocardiogram acquired soon after electrical cardioversion 3 months before pulmonary vein isolation. The HR was 54 bpm. The raw QT interval was 487 ms, and the Fridericia formula [QTc=QT/ (RR 1/3)]-corrected QTc was 470 ms. (B) A 12-lead electrocardiogram showing atrial fibrillation before catheter ablation. The raw QT was 427 ms, and the Fridericia-corrected QTc was 449 ms. The raw QT was measured using the tangent method as an average of six or more beats.
Recurrence of AF occurred, and a 12-lead electrocardiogram (ECG) showed no QT prolongation before ablation (Fig. 1B). Wide antral ipsilateral PVI using radiofrequency (RF) ablation was performed under the guidance of three-dimensional (3D) ultrasound geometries and 3D merged computed tomography (CT) using the CARTO 3 system (Biosense Webster, Diamond Bar, USA). RF ablation was performed under deep sedation with noninvasive positive pressure ventilation support. Deep sedation was initiated with 6 μg/kg/h dexmedetomidine for 10 min and fentanyl citrate 0.1 mg. Subsequently, it was maintained with 0.6 μg/kg/h dexmedetomidine. The total dexmedetomidine dose was 150 μg. First-pass isolation was achieved in both PVs, and electrical cardioversion was performed to restore sinus rhythm.
We performed right PVI first to avoid the vagal reflex, followed by left PVI (Fig. 2). Intravenous injection of 50 mg thiopental sodium was performed before electrical cardioversion. The bidirectional block was confirmed, and a dissociated potential was observed in both PVs. No complications were observed during the procedure, and the patient returned to the general ward in sinus rhythm. The total procedure time was 104 minutes.
Figure 2. Three-dimensional computed tomography merged voltage map after pulmonary vein isolation. Each tag shows an ablation point.
Seventeen hours after the procedure, TdP suddenly occurred and spontaneously terminated. A 12-lead ECG revealed prominent QT prolongation. Laboratory data showed a slightly low serum magnesium (Mg) level of 1.6 mg/dL. Creatine phosphokinase levels were within the normal limits (85 IU/L). T wave inversions were found in I, aVL, and V2, but there were no obvious local wall motion abnormalities on bedside echocardiography. QT prolongation persisted, and TdP was not suppressed despite normalization of the serum Mg level using intravenous administration of Mg sulfate hydrate (Fig. 3). TdP appeared occasionally but resolved spontaneously and did not progress to ventricular fibrillation. TdP disappeared together with AF recurrence three days after ablation. QT prolongation and negative T waves were also improved (Fig. 4).
Figure 3. QT prolongation was observed two days after pulmonary vein isolation. The HR was 71 bpm. The raw QT was 540 ms, and the Fridericia-corrected QTc was 549 ms. T wave inversions were found in I, aVL, and V2. Torsade de pointes (TdP) occurred despite the normalization of serum Mg levels. TdP disappeared with the recurrence of atrial fibrillation.
Figure 4. A 12-lead electrocardiogram was acquired on the third day after the procedure, showing atrial fibrillation. The raw QT was 362 ms, and the Fridericia-corrected QTc was 440 ms. QT prolongation and negative T waves were improved.
A genetic test using the TruSight Cardio sequencing panel (Illumina, San Diego, USA) detected no known gene mutations related to long QT syndrome. On the sixth day after the procedure, coronary angiography showed no obstruction or stenosis, and left ventriculography reveled no local wall motion abnormalities. She did not take any antiarrhythmic drugs before or after ablation.
Discussion
The QT interval is affected by various factors, including the heart rate, electrolyte disorders, autonomic nervous system, and anesthesia. In this case, the QT interval was prolonged after PVI, and the prolongation was sustained despite the normalization of electrolyte disorders. Exaggerated QT prolongation after cardioversion has been reported (7); however, in the present case, QT prolongation was not observed when electrical cardioversion was performed three months before the ablation. Her prescribed medications did not change after the ablation procedures. These observations suggest the involvement of the PVI procedure in QT prolongation.
The ablation line of PVI for AF transects the sites where the major atrial GP exists; therefore, PVI inadvertently modifies the intrinsic cardiac autonomic nervous system, which is a determinant of the QT interval (8). In animal models, GP ablation is associated with a prolonged QT interval and increased atrial/ventricular vulnerability to arrhythmias (3,4). QT prolongation has also been observed after PVI, especially in the acute phase, in humans (9). Although TdP associated with QT prolongation after PVI with antiarrhythmic drugs has been reported (6), no antiarrhythmic drugs were used in the present case. Approximately 30% of acquired long QT syndrome cases have a known clinical long QT syndrome gene mutation (10), but no relevant genetic background was detected in this case; nevertheless, discontinuation of the beta-blocker two days before the procedure may have been involved in QT prolongation after the ablation procedure.
This case indicates the potential risk of lethal arrhythmia induced by QT prolongation due to PVI, even in patients without a known genetic background of long QT syndrome or antiarrhythmic drug prescription.
The authors state that they have no Conflict of Interest (COI). | 30MG/DAY | DrugDosageText | CC BY-NC-ND | 33518578 | 19,647,376 | 2021-07-01 |
What was the dosage of drug 'FENTANYL CITRATE'? | Torsade de Pointes Due to QT Prolongation after Pulmonary Vein Isolation for Persistent Atrial Fibrillation.
We herein report a 60-year-old woman with long-standing persistent atrial fibrillation (AF) who developed QT prolongation and torsade de pointes (TdP) after pulmonary vein isolation (PVI). When electrical cardioversion was performed three months before PVI, prominent QT prolongation was not observed. QT prolongation emerged after PVI and was sustained until AF recurrence on the third day after ablation, and TdP disappeared along with AF recurrence. PVI affects the ganglionated plexi around the atrium, leading to modification of the intrinsic cardiac autonomic system. This case indicates that PVI has the potential risk of inducing lethal ventricular arrhythmias due to QT prolongation.
Introduction
Catheter ablation is a highly effective therapeutic strategy for atrial fibrillation (AF) (1,2). Pulmonary vein isolation (PVI) is a cornerstone of AF ablation. The ablation line of PVI transects the sites where the major atrial ganglionated plexi (GP) exists. GP ablation carries a risk of increasing atrial and ventricular vulnerability to arrhythmias, and GP ablation induced QT prolongation after myocardial infarction in a canine model (3,4,5). QT prolongation and lethal ventricular arrhythmias related to PVI and antiarrhythmic drugs have also been reported (6).
We herein report a patient who developed QT prolongation and torsade de pointes (TdP) after PVI for persistent AF without an antiarrhythmic drug.
Case Report
A 60-year-old woman with long-standing persistent AF was referred to our hospital for catheter ablation. She had no structural heart disease or inherited arrhythmias. Her prescribed medication included bisoprolol fumarate 1.25 mg daily; edoxaban tosilate hydrate 30 mg daily; olmesartan medoxomil 20 mg daily; sodium valproate 200 mg twice daily; and ifenprodil tartrate 20 mg three times a day. Bisoprolol fumarate was discontinued two days before the ablation procedure. We performed electrical cardioversion three months before the ablation procedure, and prominent QT prolongation was not observed early after cardioversion. Intravenous injection of 150 mg thiopental sodium was performed before electrical cardioversion (Fig. 1A).
Figure 1. (A) A 12-lead electrocardiogram acquired soon after electrical cardioversion 3 months before pulmonary vein isolation. The HR was 54 bpm. The raw QT interval was 487 ms, and the Fridericia formula [QTc=QT/ (RR 1/3)]-corrected QTc was 470 ms. (B) A 12-lead electrocardiogram showing atrial fibrillation before catheter ablation. The raw QT was 427 ms, and the Fridericia-corrected QTc was 449 ms. The raw QT was measured using the tangent method as an average of six or more beats.
Recurrence of AF occurred, and a 12-lead electrocardiogram (ECG) showed no QT prolongation before ablation (Fig. 1B). Wide antral ipsilateral PVI using radiofrequency (RF) ablation was performed under the guidance of three-dimensional (3D) ultrasound geometries and 3D merged computed tomography (CT) using the CARTO 3 system (Biosense Webster, Diamond Bar, USA). RF ablation was performed under deep sedation with noninvasive positive pressure ventilation support. Deep sedation was initiated with 6 μg/kg/h dexmedetomidine for 10 min and fentanyl citrate 0.1 mg. Subsequently, it was maintained with 0.6 μg/kg/h dexmedetomidine. The total dexmedetomidine dose was 150 μg. First-pass isolation was achieved in both PVs, and electrical cardioversion was performed to restore sinus rhythm.
We performed right PVI first to avoid the vagal reflex, followed by left PVI (Fig. 2). Intravenous injection of 50 mg thiopental sodium was performed before electrical cardioversion. The bidirectional block was confirmed, and a dissociated potential was observed in both PVs. No complications were observed during the procedure, and the patient returned to the general ward in sinus rhythm. The total procedure time was 104 minutes.
Figure 2. Three-dimensional computed tomography merged voltage map after pulmonary vein isolation. Each tag shows an ablation point.
Seventeen hours after the procedure, TdP suddenly occurred and spontaneously terminated. A 12-lead ECG revealed prominent QT prolongation. Laboratory data showed a slightly low serum magnesium (Mg) level of 1.6 mg/dL. Creatine phosphokinase levels were within the normal limits (85 IU/L). T wave inversions were found in I, aVL, and V2, but there were no obvious local wall motion abnormalities on bedside echocardiography. QT prolongation persisted, and TdP was not suppressed despite normalization of the serum Mg level using intravenous administration of Mg sulfate hydrate (Fig. 3). TdP appeared occasionally but resolved spontaneously and did not progress to ventricular fibrillation. TdP disappeared together with AF recurrence three days after ablation. QT prolongation and negative T waves were also improved (Fig. 4).
Figure 3. QT prolongation was observed two days after pulmonary vein isolation. The HR was 71 bpm. The raw QT was 540 ms, and the Fridericia-corrected QTc was 549 ms. T wave inversions were found in I, aVL, and V2. Torsade de pointes (TdP) occurred despite the normalization of serum Mg levels. TdP disappeared with the recurrence of atrial fibrillation.
Figure 4. A 12-lead electrocardiogram was acquired on the third day after the procedure, showing atrial fibrillation. The raw QT was 362 ms, and the Fridericia-corrected QTc was 440 ms. QT prolongation and negative T waves were improved.
A genetic test using the TruSight Cardio sequencing panel (Illumina, San Diego, USA) detected no known gene mutations related to long QT syndrome. On the sixth day after the procedure, coronary angiography showed no obstruction or stenosis, and left ventriculography reveled no local wall motion abnormalities. She did not take any antiarrhythmic drugs before or after ablation.
Discussion
The QT interval is affected by various factors, including the heart rate, electrolyte disorders, autonomic nervous system, and anesthesia. In this case, the QT interval was prolonged after PVI, and the prolongation was sustained despite the normalization of electrolyte disorders. Exaggerated QT prolongation after cardioversion has been reported (7); however, in the present case, QT prolongation was not observed when electrical cardioversion was performed three months before the ablation. Her prescribed medications did not change after the ablation procedures. These observations suggest the involvement of the PVI procedure in QT prolongation.
The ablation line of PVI for AF transects the sites where the major atrial GP exists; therefore, PVI inadvertently modifies the intrinsic cardiac autonomic nervous system, which is a determinant of the QT interval (8). In animal models, GP ablation is associated with a prolonged QT interval and increased atrial/ventricular vulnerability to arrhythmias (3,4). QT prolongation has also been observed after PVI, especially in the acute phase, in humans (9). Although TdP associated with QT prolongation after PVI with antiarrhythmic drugs has been reported (6), no antiarrhythmic drugs were used in the present case. Approximately 30% of acquired long QT syndrome cases have a known clinical long QT syndrome gene mutation (10), but no relevant genetic background was detected in this case; nevertheless, discontinuation of the beta-blocker two days before the procedure may have been involved in QT prolongation after the ablation procedure.
This case indicates the potential risk of lethal arrhythmia induced by QT prolongation due to PVI, even in patients without a known genetic background of long QT syndrome or antiarrhythmic drug prescription.
The authors state that they have no Conflict of Interest (COI). | 0.1MG/DAY | DrugDosageText | CC BY-NC-ND | 33518578 | 19,647,376 | 2021-07-01 |
What was the dosage of drug 'OLMESARTAN MEDOXOMIL'? | Torsade de Pointes Due to QT Prolongation after Pulmonary Vein Isolation for Persistent Atrial Fibrillation.
We herein report a 60-year-old woman with long-standing persistent atrial fibrillation (AF) who developed QT prolongation and torsade de pointes (TdP) after pulmonary vein isolation (PVI). When electrical cardioversion was performed three months before PVI, prominent QT prolongation was not observed. QT prolongation emerged after PVI and was sustained until AF recurrence on the third day after ablation, and TdP disappeared along with AF recurrence. PVI affects the ganglionated plexi around the atrium, leading to modification of the intrinsic cardiac autonomic system. This case indicates that PVI has the potential risk of inducing lethal ventricular arrhythmias due to QT prolongation.
Introduction
Catheter ablation is a highly effective therapeutic strategy for atrial fibrillation (AF) (1,2). Pulmonary vein isolation (PVI) is a cornerstone of AF ablation. The ablation line of PVI transects the sites where the major atrial ganglionated plexi (GP) exists. GP ablation carries a risk of increasing atrial and ventricular vulnerability to arrhythmias, and GP ablation induced QT prolongation after myocardial infarction in a canine model (3,4,5). QT prolongation and lethal ventricular arrhythmias related to PVI and antiarrhythmic drugs have also been reported (6).
We herein report a patient who developed QT prolongation and torsade de pointes (TdP) after PVI for persistent AF without an antiarrhythmic drug.
Case Report
A 60-year-old woman with long-standing persistent AF was referred to our hospital for catheter ablation. She had no structural heart disease or inherited arrhythmias. Her prescribed medication included bisoprolol fumarate 1.25 mg daily; edoxaban tosilate hydrate 30 mg daily; olmesartan medoxomil 20 mg daily; sodium valproate 200 mg twice daily; and ifenprodil tartrate 20 mg three times a day. Bisoprolol fumarate was discontinued two days before the ablation procedure. We performed electrical cardioversion three months before the ablation procedure, and prominent QT prolongation was not observed early after cardioversion. Intravenous injection of 150 mg thiopental sodium was performed before electrical cardioversion (Fig. 1A).
Figure 1. (A) A 12-lead electrocardiogram acquired soon after electrical cardioversion 3 months before pulmonary vein isolation. The HR was 54 bpm. The raw QT interval was 487 ms, and the Fridericia formula [QTc=QT/ (RR 1/3)]-corrected QTc was 470 ms. (B) A 12-lead electrocardiogram showing atrial fibrillation before catheter ablation. The raw QT was 427 ms, and the Fridericia-corrected QTc was 449 ms. The raw QT was measured using the tangent method as an average of six or more beats.
Recurrence of AF occurred, and a 12-lead electrocardiogram (ECG) showed no QT prolongation before ablation (Fig. 1B). Wide antral ipsilateral PVI using radiofrequency (RF) ablation was performed under the guidance of three-dimensional (3D) ultrasound geometries and 3D merged computed tomography (CT) using the CARTO 3 system (Biosense Webster, Diamond Bar, USA). RF ablation was performed under deep sedation with noninvasive positive pressure ventilation support. Deep sedation was initiated with 6 μg/kg/h dexmedetomidine for 10 min and fentanyl citrate 0.1 mg. Subsequently, it was maintained with 0.6 μg/kg/h dexmedetomidine. The total dexmedetomidine dose was 150 μg. First-pass isolation was achieved in both PVs, and electrical cardioversion was performed to restore sinus rhythm.
We performed right PVI first to avoid the vagal reflex, followed by left PVI (Fig. 2). Intravenous injection of 50 mg thiopental sodium was performed before electrical cardioversion. The bidirectional block was confirmed, and a dissociated potential was observed in both PVs. No complications were observed during the procedure, and the patient returned to the general ward in sinus rhythm. The total procedure time was 104 minutes.
Figure 2. Three-dimensional computed tomography merged voltage map after pulmonary vein isolation. Each tag shows an ablation point.
Seventeen hours after the procedure, TdP suddenly occurred and spontaneously terminated. A 12-lead ECG revealed prominent QT prolongation. Laboratory data showed a slightly low serum magnesium (Mg) level of 1.6 mg/dL. Creatine phosphokinase levels were within the normal limits (85 IU/L). T wave inversions were found in I, aVL, and V2, but there were no obvious local wall motion abnormalities on bedside echocardiography. QT prolongation persisted, and TdP was not suppressed despite normalization of the serum Mg level using intravenous administration of Mg sulfate hydrate (Fig. 3). TdP appeared occasionally but resolved spontaneously and did not progress to ventricular fibrillation. TdP disappeared together with AF recurrence three days after ablation. QT prolongation and negative T waves were also improved (Fig. 4).
Figure 3. QT prolongation was observed two days after pulmonary vein isolation. The HR was 71 bpm. The raw QT was 540 ms, and the Fridericia-corrected QTc was 549 ms. T wave inversions were found in I, aVL, and V2. Torsade de pointes (TdP) occurred despite the normalization of serum Mg levels. TdP disappeared with the recurrence of atrial fibrillation.
Figure 4. A 12-lead electrocardiogram was acquired on the third day after the procedure, showing atrial fibrillation. The raw QT was 362 ms, and the Fridericia-corrected QTc was 440 ms. QT prolongation and negative T waves were improved.
A genetic test using the TruSight Cardio sequencing panel (Illumina, San Diego, USA) detected no known gene mutations related to long QT syndrome. On the sixth day after the procedure, coronary angiography showed no obstruction or stenosis, and left ventriculography reveled no local wall motion abnormalities. She did not take any antiarrhythmic drugs before or after ablation.
Discussion
The QT interval is affected by various factors, including the heart rate, electrolyte disorders, autonomic nervous system, and anesthesia. In this case, the QT interval was prolonged after PVI, and the prolongation was sustained despite the normalization of electrolyte disorders. Exaggerated QT prolongation after cardioversion has been reported (7); however, in the present case, QT prolongation was not observed when electrical cardioversion was performed three months before the ablation. Her prescribed medications did not change after the ablation procedures. These observations suggest the involvement of the PVI procedure in QT prolongation.
The ablation line of PVI for AF transects the sites where the major atrial GP exists; therefore, PVI inadvertently modifies the intrinsic cardiac autonomic nervous system, which is a determinant of the QT interval (8). In animal models, GP ablation is associated with a prolonged QT interval and increased atrial/ventricular vulnerability to arrhythmias (3,4). QT prolongation has also been observed after PVI, especially in the acute phase, in humans (9). Although TdP associated with QT prolongation after PVI with antiarrhythmic drugs has been reported (6), no antiarrhythmic drugs were used in the present case. Approximately 30% of acquired long QT syndrome cases have a known clinical long QT syndrome gene mutation (10), but no relevant genetic background was detected in this case; nevertheless, discontinuation of the beta-blocker two days before the procedure may have been involved in QT prolongation after the ablation procedure.
This case indicates the potential risk of lethal arrhythmia induced by QT prolongation due to PVI, even in patients without a known genetic background of long QT syndrome or antiarrhythmic drug prescription.
The authors state that they have no Conflict of Interest (COI). | 20MG/DAY | DrugDosageText | CC BY-NC-ND | 33518578 | 19,647,376 | 2021-07-01 |
What was the outcome of reaction 'Blood magnesium decreased'? | Torsade de Pointes Due to QT Prolongation after Pulmonary Vein Isolation for Persistent Atrial Fibrillation.
We herein report a 60-year-old woman with long-standing persistent atrial fibrillation (AF) who developed QT prolongation and torsade de pointes (TdP) after pulmonary vein isolation (PVI). When electrical cardioversion was performed three months before PVI, prominent QT prolongation was not observed. QT prolongation emerged after PVI and was sustained until AF recurrence on the third day after ablation, and TdP disappeared along with AF recurrence. PVI affects the ganglionated plexi around the atrium, leading to modification of the intrinsic cardiac autonomic system. This case indicates that PVI has the potential risk of inducing lethal ventricular arrhythmias due to QT prolongation.
Introduction
Catheter ablation is a highly effective therapeutic strategy for atrial fibrillation (AF) (1,2). Pulmonary vein isolation (PVI) is a cornerstone of AF ablation. The ablation line of PVI transects the sites where the major atrial ganglionated plexi (GP) exists. GP ablation carries a risk of increasing atrial and ventricular vulnerability to arrhythmias, and GP ablation induced QT prolongation after myocardial infarction in a canine model (3,4,5). QT prolongation and lethal ventricular arrhythmias related to PVI and antiarrhythmic drugs have also been reported (6).
We herein report a patient who developed QT prolongation and torsade de pointes (TdP) after PVI for persistent AF without an antiarrhythmic drug.
Case Report
A 60-year-old woman with long-standing persistent AF was referred to our hospital for catheter ablation. She had no structural heart disease or inherited arrhythmias. Her prescribed medication included bisoprolol fumarate 1.25 mg daily; edoxaban tosilate hydrate 30 mg daily; olmesartan medoxomil 20 mg daily; sodium valproate 200 mg twice daily; and ifenprodil tartrate 20 mg three times a day. Bisoprolol fumarate was discontinued two days before the ablation procedure. We performed electrical cardioversion three months before the ablation procedure, and prominent QT prolongation was not observed early after cardioversion. Intravenous injection of 150 mg thiopental sodium was performed before electrical cardioversion (Fig. 1A).
Figure 1. (A) A 12-lead electrocardiogram acquired soon after electrical cardioversion 3 months before pulmonary vein isolation. The HR was 54 bpm. The raw QT interval was 487 ms, and the Fridericia formula [QTc=QT/ (RR 1/3)]-corrected QTc was 470 ms. (B) A 12-lead electrocardiogram showing atrial fibrillation before catheter ablation. The raw QT was 427 ms, and the Fridericia-corrected QTc was 449 ms. The raw QT was measured using the tangent method as an average of six or more beats.
Recurrence of AF occurred, and a 12-lead electrocardiogram (ECG) showed no QT prolongation before ablation (Fig. 1B). Wide antral ipsilateral PVI using radiofrequency (RF) ablation was performed under the guidance of three-dimensional (3D) ultrasound geometries and 3D merged computed tomography (CT) using the CARTO 3 system (Biosense Webster, Diamond Bar, USA). RF ablation was performed under deep sedation with noninvasive positive pressure ventilation support. Deep sedation was initiated with 6 μg/kg/h dexmedetomidine for 10 min and fentanyl citrate 0.1 mg. Subsequently, it was maintained with 0.6 μg/kg/h dexmedetomidine. The total dexmedetomidine dose was 150 μg. First-pass isolation was achieved in both PVs, and electrical cardioversion was performed to restore sinus rhythm.
We performed right PVI first to avoid the vagal reflex, followed by left PVI (Fig. 2). Intravenous injection of 50 mg thiopental sodium was performed before electrical cardioversion. The bidirectional block was confirmed, and a dissociated potential was observed in both PVs. No complications were observed during the procedure, and the patient returned to the general ward in sinus rhythm. The total procedure time was 104 minutes.
Figure 2. Three-dimensional computed tomography merged voltage map after pulmonary vein isolation. Each tag shows an ablation point.
Seventeen hours after the procedure, TdP suddenly occurred and spontaneously terminated. A 12-lead ECG revealed prominent QT prolongation. Laboratory data showed a slightly low serum magnesium (Mg) level of 1.6 mg/dL. Creatine phosphokinase levels were within the normal limits (85 IU/L). T wave inversions were found in I, aVL, and V2, but there were no obvious local wall motion abnormalities on bedside echocardiography. QT prolongation persisted, and TdP was not suppressed despite normalization of the serum Mg level using intravenous administration of Mg sulfate hydrate (Fig. 3). TdP appeared occasionally but resolved spontaneously and did not progress to ventricular fibrillation. TdP disappeared together with AF recurrence three days after ablation. QT prolongation and negative T waves were also improved (Fig. 4).
Figure 3. QT prolongation was observed two days after pulmonary vein isolation. The HR was 71 bpm. The raw QT was 540 ms, and the Fridericia-corrected QTc was 549 ms. T wave inversions were found in I, aVL, and V2. Torsade de pointes (TdP) occurred despite the normalization of serum Mg levels. TdP disappeared with the recurrence of atrial fibrillation.
Figure 4. A 12-lead electrocardiogram was acquired on the third day after the procedure, showing atrial fibrillation. The raw QT was 362 ms, and the Fridericia-corrected QTc was 440 ms. QT prolongation and negative T waves were improved.
A genetic test using the TruSight Cardio sequencing panel (Illumina, San Diego, USA) detected no known gene mutations related to long QT syndrome. On the sixth day after the procedure, coronary angiography showed no obstruction or stenosis, and left ventriculography reveled no local wall motion abnormalities. She did not take any antiarrhythmic drugs before or after ablation.
Discussion
The QT interval is affected by various factors, including the heart rate, electrolyte disorders, autonomic nervous system, and anesthesia. In this case, the QT interval was prolonged after PVI, and the prolongation was sustained despite the normalization of electrolyte disorders. Exaggerated QT prolongation after cardioversion has been reported (7); however, in the present case, QT prolongation was not observed when electrical cardioversion was performed three months before the ablation. Her prescribed medications did not change after the ablation procedures. These observations suggest the involvement of the PVI procedure in QT prolongation.
The ablation line of PVI for AF transects the sites where the major atrial GP exists; therefore, PVI inadvertently modifies the intrinsic cardiac autonomic nervous system, which is a determinant of the QT interval (8). In animal models, GP ablation is associated with a prolonged QT interval and increased atrial/ventricular vulnerability to arrhythmias (3,4). QT prolongation has also been observed after PVI, especially in the acute phase, in humans (9). Although TdP associated with QT prolongation after PVI with antiarrhythmic drugs has been reported (6), no antiarrhythmic drugs were used in the present case. Approximately 30% of acquired long QT syndrome cases have a known clinical long QT syndrome gene mutation (10), but no relevant genetic background was detected in this case; nevertheless, discontinuation of the beta-blocker two days before the procedure may have been involved in QT prolongation after the ablation procedure.
This case indicates the potential risk of lethal arrhythmia induced by QT prolongation due to PVI, even in patients without a known genetic background of long QT syndrome or antiarrhythmic drug prescription.
The authors state that they have no Conflict of Interest (COI). | Recovered | ReactionOutcome | CC BY-NC-ND | 33518578 | 19,647,376 | 2021-07-01 |
What was the outcome of reaction 'Electrocardiogram QT prolonged'? | Torsade de Pointes Due to QT Prolongation after Pulmonary Vein Isolation for Persistent Atrial Fibrillation.
We herein report a 60-year-old woman with long-standing persistent atrial fibrillation (AF) who developed QT prolongation and torsade de pointes (TdP) after pulmonary vein isolation (PVI). When electrical cardioversion was performed three months before PVI, prominent QT prolongation was not observed. QT prolongation emerged after PVI and was sustained until AF recurrence on the third day after ablation, and TdP disappeared along with AF recurrence. PVI affects the ganglionated plexi around the atrium, leading to modification of the intrinsic cardiac autonomic system. This case indicates that PVI has the potential risk of inducing lethal ventricular arrhythmias due to QT prolongation.
Introduction
Catheter ablation is a highly effective therapeutic strategy for atrial fibrillation (AF) (1,2). Pulmonary vein isolation (PVI) is a cornerstone of AF ablation. The ablation line of PVI transects the sites where the major atrial ganglionated plexi (GP) exists. GP ablation carries a risk of increasing atrial and ventricular vulnerability to arrhythmias, and GP ablation induced QT prolongation after myocardial infarction in a canine model (3,4,5). QT prolongation and lethal ventricular arrhythmias related to PVI and antiarrhythmic drugs have also been reported (6).
We herein report a patient who developed QT prolongation and torsade de pointes (TdP) after PVI for persistent AF without an antiarrhythmic drug.
Case Report
A 60-year-old woman with long-standing persistent AF was referred to our hospital for catheter ablation. She had no structural heart disease or inherited arrhythmias. Her prescribed medication included bisoprolol fumarate 1.25 mg daily; edoxaban tosilate hydrate 30 mg daily; olmesartan medoxomil 20 mg daily; sodium valproate 200 mg twice daily; and ifenprodil tartrate 20 mg three times a day. Bisoprolol fumarate was discontinued two days before the ablation procedure. We performed electrical cardioversion three months before the ablation procedure, and prominent QT prolongation was not observed early after cardioversion. Intravenous injection of 150 mg thiopental sodium was performed before electrical cardioversion (Fig. 1A).
Figure 1. (A) A 12-lead electrocardiogram acquired soon after electrical cardioversion 3 months before pulmonary vein isolation. The HR was 54 bpm. The raw QT interval was 487 ms, and the Fridericia formula [QTc=QT/ (RR 1/3)]-corrected QTc was 470 ms. (B) A 12-lead electrocardiogram showing atrial fibrillation before catheter ablation. The raw QT was 427 ms, and the Fridericia-corrected QTc was 449 ms. The raw QT was measured using the tangent method as an average of six or more beats.
Recurrence of AF occurred, and a 12-lead electrocardiogram (ECG) showed no QT prolongation before ablation (Fig. 1B). Wide antral ipsilateral PVI using radiofrequency (RF) ablation was performed under the guidance of three-dimensional (3D) ultrasound geometries and 3D merged computed tomography (CT) using the CARTO 3 system (Biosense Webster, Diamond Bar, USA). RF ablation was performed under deep sedation with noninvasive positive pressure ventilation support. Deep sedation was initiated with 6 μg/kg/h dexmedetomidine for 10 min and fentanyl citrate 0.1 mg. Subsequently, it was maintained with 0.6 μg/kg/h dexmedetomidine. The total dexmedetomidine dose was 150 μg. First-pass isolation was achieved in both PVs, and electrical cardioversion was performed to restore sinus rhythm.
We performed right PVI first to avoid the vagal reflex, followed by left PVI (Fig. 2). Intravenous injection of 50 mg thiopental sodium was performed before electrical cardioversion. The bidirectional block was confirmed, and a dissociated potential was observed in both PVs. No complications were observed during the procedure, and the patient returned to the general ward in sinus rhythm. The total procedure time was 104 minutes.
Figure 2. Three-dimensional computed tomography merged voltage map after pulmonary vein isolation. Each tag shows an ablation point.
Seventeen hours after the procedure, TdP suddenly occurred and spontaneously terminated. A 12-lead ECG revealed prominent QT prolongation. Laboratory data showed a slightly low serum magnesium (Mg) level of 1.6 mg/dL. Creatine phosphokinase levels were within the normal limits (85 IU/L). T wave inversions were found in I, aVL, and V2, but there were no obvious local wall motion abnormalities on bedside echocardiography. QT prolongation persisted, and TdP was not suppressed despite normalization of the serum Mg level using intravenous administration of Mg sulfate hydrate (Fig. 3). TdP appeared occasionally but resolved spontaneously and did not progress to ventricular fibrillation. TdP disappeared together with AF recurrence three days after ablation. QT prolongation and negative T waves were also improved (Fig. 4).
Figure 3. QT prolongation was observed two days after pulmonary vein isolation. The HR was 71 bpm. The raw QT was 540 ms, and the Fridericia-corrected QTc was 549 ms. T wave inversions were found in I, aVL, and V2. Torsade de pointes (TdP) occurred despite the normalization of serum Mg levels. TdP disappeared with the recurrence of atrial fibrillation.
Figure 4. A 12-lead electrocardiogram was acquired on the third day after the procedure, showing atrial fibrillation. The raw QT was 362 ms, and the Fridericia-corrected QTc was 440 ms. QT prolongation and negative T waves were improved.
A genetic test using the TruSight Cardio sequencing panel (Illumina, San Diego, USA) detected no known gene mutations related to long QT syndrome. On the sixth day after the procedure, coronary angiography showed no obstruction or stenosis, and left ventriculography reveled no local wall motion abnormalities. She did not take any antiarrhythmic drugs before or after ablation.
Discussion
The QT interval is affected by various factors, including the heart rate, electrolyte disorders, autonomic nervous system, and anesthesia. In this case, the QT interval was prolonged after PVI, and the prolongation was sustained despite the normalization of electrolyte disorders. Exaggerated QT prolongation after cardioversion has been reported (7); however, in the present case, QT prolongation was not observed when electrical cardioversion was performed three months before the ablation. Her prescribed medications did not change after the ablation procedures. These observations suggest the involvement of the PVI procedure in QT prolongation.
The ablation line of PVI for AF transects the sites where the major atrial GP exists; therefore, PVI inadvertently modifies the intrinsic cardiac autonomic nervous system, which is a determinant of the QT interval (8). In animal models, GP ablation is associated with a prolonged QT interval and increased atrial/ventricular vulnerability to arrhythmias (3,4). QT prolongation has also been observed after PVI, especially in the acute phase, in humans (9). Although TdP associated with QT prolongation after PVI with antiarrhythmic drugs has been reported (6), no antiarrhythmic drugs were used in the present case. Approximately 30% of acquired long QT syndrome cases have a known clinical long QT syndrome gene mutation (10), but no relevant genetic background was detected in this case; nevertheless, discontinuation of the beta-blocker two days before the procedure may have been involved in QT prolongation after the ablation procedure.
This case indicates the potential risk of lethal arrhythmia induced by QT prolongation due to PVI, even in patients without a known genetic background of long QT syndrome or antiarrhythmic drug prescription.
The authors state that they have no Conflict of Interest (COI). | Recovering | ReactionOutcome | CC BY-NC-ND | 33518578 | 19,647,376 | 2021-07-01 |
What was the outcome of reaction 'Torsade de pointes'? | Torsade de Pointes Due to QT Prolongation after Pulmonary Vein Isolation for Persistent Atrial Fibrillation.
We herein report a 60-year-old woman with long-standing persistent atrial fibrillation (AF) who developed QT prolongation and torsade de pointes (TdP) after pulmonary vein isolation (PVI). When electrical cardioversion was performed three months before PVI, prominent QT prolongation was not observed. QT prolongation emerged after PVI and was sustained until AF recurrence on the third day after ablation, and TdP disappeared along with AF recurrence. PVI affects the ganglionated plexi around the atrium, leading to modification of the intrinsic cardiac autonomic system. This case indicates that PVI has the potential risk of inducing lethal ventricular arrhythmias due to QT prolongation.
Introduction
Catheter ablation is a highly effective therapeutic strategy for atrial fibrillation (AF) (1,2). Pulmonary vein isolation (PVI) is a cornerstone of AF ablation. The ablation line of PVI transects the sites where the major atrial ganglionated plexi (GP) exists. GP ablation carries a risk of increasing atrial and ventricular vulnerability to arrhythmias, and GP ablation induced QT prolongation after myocardial infarction in a canine model (3,4,5). QT prolongation and lethal ventricular arrhythmias related to PVI and antiarrhythmic drugs have also been reported (6).
We herein report a patient who developed QT prolongation and torsade de pointes (TdP) after PVI for persistent AF without an antiarrhythmic drug.
Case Report
A 60-year-old woman with long-standing persistent AF was referred to our hospital for catheter ablation. She had no structural heart disease or inherited arrhythmias. Her prescribed medication included bisoprolol fumarate 1.25 mg daily; edoxaban tosilate hydrate 30 mg daily; olmesartan medoxomil 20 mg daily; sodium valproate 200 mg twice daily; and ifenprodil tartrate 20 mg three times a day. Bisoprolol fumarate was discontinued two days before the ablation procedure. We performed electrical cardioversion three months before the ablation procedure, and prominent QT prolongation was not observed early after cardioversion. Intravenous injection of 150 mg thiopental sodium was performed before electrical cardioversion (Fig. 1A).
Figure 1. (A) A 12-lead electrocardiogram acquired soon after electrical cardioversion 3 months before pulmonary vein isolation. The HR was 54 bpm. The raw QT interval was 487 ms, and the Fridericia formula [QTc=QT/ (RR 1/3)]-corrected QTc was 470 ms. (B) A 12-lead electrocardiogram showing atrial fibrillation before catheter ablation. The raw QT was 427 ms, and the Fridericia-corrected QTc was 449 ms. The raw QT was measured using the tangent method as an average of six or more beats.
Recurrence of AF occurred, and a 12-lead electrocardiogram (ECG) showed no QT prolongation before ablation (Fig. 1B). Wide antral ipsilateral PVI using radiofrequency (RF) ablation was performed under the guidance of three-dimensional (3D) ultrasound geometries and 3D merged computed tomography (CT) using the CARTO 3 system (Biosense Webster, Diamond Bar, USA). RF ablation was performed under deep sedation with noninvasive positive pressure ventilation support. Deep sedation was initiated with 6 μg/kg/h dexmedetomidine for 10 min and fentanyl citrate 0.1 mg. Subsequently, it was maintained with 0.6 μg/kg/h dexmedetomidine. The total dexmedetomidine dose was 150 μg. First-pass isolation was achieved in both PVs, and electrical cardioversion was performed to restore sinus rhythm.
We performed right PVI first to avoid the vagal reflex, followed by left PVI (Fig. 2). Intravenous injection of 50 mg thiopental sodium was performed before electrical cardioversion. The bidirectional block was confirmed, and a dissociated potential was observed in both PVs. No complications were observed during the procedure, and the patient returned to the general ward in sinus rhythm. The total procedure time was 104 minutes.
Figure 2. Three-dimensional computed tomography merged voltage map after pulmonary vein isolation. Each tag shows an ablation point.
Seventeen hours after the procedure, TdP suddenly occurred and spontaneously terminated. A 12-lead ECG revealed prominent QT prolongation. Laboratory data showed a slightly low serum magnesium (Mg) level of 1.6 mg/dL. Creatine phosphokinase levels were within the normal limits (85 IU/L). T wave inversions were found in I, aVL, and V2, but there were no obvious local wall motion abnormalities on bedside echocardiography. QT prolongation persisted, and TdP was not suppressed despite normalization of the serum Mg level using intravenous administration of Mg sulfate hydrate (Fig. 3). TdP appeared occasionally but resolved spontaneously and did not progress to ventricular fibrillation. TdP disappeared together with AF recurrence three days after ablation. QT prolongation and negative T waves were also improved (Fig. 4).
Figure 3. QT prolongation was observed two days after pulmonary vein isolation. The HR was 71 bpm. The raw QT was 540 ms, and the Fridericia-corrected QTc was 549 ms. T wave inversions were found in I, aVL, and V2. Torsade de pointes (TdP) occurred despite the normalization of serum Mg levels. TdP disappeared with the recurrence of atrial fibrillation.
Figure 4. A 12-lead electrocardiogram was acquired on the third day after the procedure, showing atrial fibrillation. The raw QT was 362 ms, and the Fridericia-corrected QTc was 440 ms. QT prolongation and negative T waves were improved.
A genetic test using the TruSight Cardio sequencing panel (Illumina, San Diego, USA) detected no known gene mutations related to long QT syndrome. On the sixth day after the procedure, coronary angiography showed no obstruction or stenosis, and left ventriculography reveled no local wall motion abnormalities. She did not take any antiarrhythmic drugs before or after ablation.
Discussion
The QT interval is affected by various factors, including the heart rate, electrolyte disorders, autonomic nervous system, and anesthesia. In this case, the QT interval was prolonged after PVI, and the prolongation was sustained despite the normalization of electrolyte disorders. Exaggerated QT prolongation after cardioversion has been reported (7); however, in the present case, QT prolongation was not observed when electrical cardioversion was performed three months before the ablation. Her prescribed medications did not change after the ablation procedures. These observations suggest the involvement of the PVI procedure in QT prolongation.
The ablation line of PVI for AF transects the sites where the major atrial GP exists; therefore, PVI inadvertently modifies the intrinsic cardiac autonomic nervous system, which is a determinant of the QT interval (8). In animal models, GP ablation is associated with a prolonged QT interval and increased atrial/ventricular vulnerability to arrhythmias (3,4). QT prolongation has also been observed after PVI, especially in the acute phase, in humans (9). Although TdP associated with QT prolongation after PVI with antiarrhythmic drugs has been reported (6), no antiarrhythmic drugs were used in the present case. Approximately 30% of acquired long QT syndrome cases have a known clinical long QT syndrome gene mutation (10), but no relevant genetic background was detected in this case; nevertheless, discontinuation of the beta-blocker two days before the procedure may have been involved in QT prolongation after the ablation procedure.
This case indicates the potential risk of lethal arrhythmia induced by QT prolongation due to PVI, even in patients without a known genetic background of long QT syndrome or antiarrhythmic drug prescription.
The authors state that they have no Conflict of Interest (COI). | Recovered | ReactionOutcome | CC BY-NC-ND | 33518578 | 19,647,376 | 2021-07-01 |
Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Malignant neoplasm progression'. | Cardiac Metastasis Caused Fatal Ventricular Arrhythmia in a Patient with a Rectal Neuroendocrine Tumor.
A 60-year-old man had received octreotide for a metastatic neuroendocrine tumor (NET) in the rectum. Computed tomography and ultrasonography revealed a cardiac tumor, diffuse thickness of the ventricular wall and pericardial effusion, which was diagnosed as cardiac metastasis. The metastatic lesions continued to grow despite the alteration of chemotherapy, and the patient complained of repeated syncope and was admitted to our hospital at 11 months after the diagnosis of cardiac metastasis. An electrocardiogram during syncope showed sustained ventricular tachycardia, which was considered to be caused by the cardiac metastasis. We herein report a case of NET with cardiac metastasis which caused lethal arrhythmia along with a review of the pertinent literature.
Introduction
Neuroendocrine tumors (NETs) are relatively rare, but their incidence is reportedly 3.51 and 6.98 per 100,000 persons-year in nationwide cohorts of Japan and the United States, respectively, with 2- to 3-fold increases noted in the last several decades (1,2). NETs originate mainly in the gastrointestinal tract, pancreas and pulmonary tract. Metastases of NET generally occur in the liver, lung and bone, with other sites suggested to be rare (3). However, despite their rare frequency, metastases to sites such as the heart and brain still occur and can cause serious complications in patients with metastatic NET. While quite a few cases of cardiac metastases in NET with fatal arrhythmia have been reported (4,5), the clinical course and optimal therapeutic strategy remain unclear.
We herein report a rare case of cardiac metastases in a rectal NET patient with fatal arrhythmia.
Case Report
A 60-year-old man who complained of bloody stool was diagnosed to have a rectal NET (WHO classification grade 2) with multiple metastases to the lymph node, liver and bone three years previously (Fig. 1). He had no relevant medical or familial history. In addition, he had no typical symptoms of carcinoid syndrome, hyperparathyroidism, hyperthyroidism or hyperepinephrinemia. The laboratory data at the time of the initial diagnosis are shown in Table 1. The electrolyte and hormone values were within the normal ranges. The serum carcinoembryonic antigen (CEA) level had increased at the time of the initial diagnosis; however, this abnormality was not considered to be due to the tumor because the change was not proportional to the degree of tumor progression, and there were no other tumorous lesions on CT or endoscopic examinations. The patient's smoking history was thought to have caused the high level of CEA. Furthermore, computed tomography showed no abnormal findings of the endocrine organs, which excluded functional NET and multiple endocrine neoplasia. The endoscopic, histologic and immunohistochemical findings at the initial diagnosis are shown in Fig. 2. He had been treated with octreotide for 17 months after the first diagnosis; however, the liver metastases increased, and lung metastases were newly detected with computed tomography (CT). Therefore, chemotherapy was changed to everolimus.
Figure 1. CT findings at the initial diagnosis of NET. Computed tomography at the initial diagnosis showed swelling of multiple lymph nodes (A: arrowheads) without the detection of the primary lesion and liver metastasis (B: arrowhead), consolidation of the vertebra and iliac bone (C), and findings of a tumor and an abnormal enhancement in the left ventricle and septum (D).
Table 1. Laboratory Data at the Initial Diagnosis.
Measured value Normal range Measured value Normal range
WBC 6,070 /µL 3,500-8,500 FT3 2.44 pg/mL 2.30-4.00
Hb 12.3 g/dL 13.5-17.0 FT4 1.28 ng/dL 0.90-1.70
Plt 20.2 104/µL 15.0-35.0 TSH 2.12 µIU/mL 0.50-5.00
Alb 3.8 g/dL 3.9-4.9 i-PTH 60.9 pg/mL 15.0-65.0
Na 141 mmol/L 135-150 IRI <0.20 µU/mL 0.0-18.7
K 4.3 mmol/L 3.5-5.0 Glucagon 81 pg/mL 70-174
Cl 103 mmol/L 96-110 Gastrin 95 pg/mL ≤ 200
Ca 9.0 mg/dL 8.7-11.0 CEA 17.4 ng/mL ≤ 5.0
CRP 0.37 mg/dL ≤ 0.30 NSE 14.9 ng/mL ≤ 16.3
WBC: white blood cell count, Hb: hemoglobin, Plt: Platelet, Alb: serum albumin, Na: sodium, K: potassium, Cl: chlorine, Ca: calcium, CRP: C-reactive protein, FT3: free T3, FT4: free T4, TSH: thyroid stimulating hormone, i-PTH: intact parathyroid hormone, IRI: immunoreactive insulin, CEA: carcinoembryonic antigen, NSE: neuron-specific enolase
Figure 2. Endoscopic, histological and immunohistochemical findings at the initial diagnosis of the rectal tumor. Colonoscopy revealed a yellowish submucosal tumor measuring 25 mm in diameter, accompanied by dilated vessels at the surface and depression in the central part (A). Histological findings of the biopsied specimen (Hematoxylin and Eosin staining; B ×100) showed a rope-shaped or ribbon-like arrangement of cells with elliptic nuclei and eosinophilic cytoplasm, and the immunohistochemical findings were positive for CD56 (C ×100) and synaptophysin (D ×100), with about 10% of cells positively reactive for MIB-1 (E ×100), consistent with NET grade 2 according to the WHO classification 2010.
He complained of dyspnea and general fatigue six months after starting chemotherapy with everolimus. CT showed bilateral pleural effusion, pericardial effusion, wall thickening in the ventricular septum and areas of poor enhancement in the left ventricle (Fig. 3A, B) in addition to the progression of liver and lung metastases and the appearance of new metastases in the right kidney. Transthoracic echocardiography (TTE) revealed pericardial effusion, a tumor measuring 15 mm in diameter in the ventricular septum (Fig. 3C) and heterogenous thickening of the left ventricular wall (Fig. 3D) at 24 months after the initial diagnosis. In addition, TTE revealed no right-sided valvular disease (tricuspid and pulmonary arterial valve), which excluded carcinoid heart syndrome. The pericardial effusion fluid obtained by a puncture was bloody, but negative for neuroendocrine cells. While the tumor in the heart was not biopsied, both the tumor and the irregular thickening of the ventricular wall were diagnosed as cardiac metastases derived from the rectal NET based on the progression of metastases in other organs. The bilateral pleural effusion was thought to represent leakage due to a low serum albumin level rather than pleural metastasis or diastolic dysfunction because of the rapid improvement after the intake of a diuretic drug and albumin supplementation. However, although a cytological examination was negative for pleural metastasis, the coexistence of pleural metastasis could not be ruled out.
Figure 3. CT and TTE findings in the heart at the time of the detection of cardiac metastases. Contrast-enhanced CT revealed a tumor with a poor enhancement in the ventricular septum (A; arrowhead) and heterogenous wall thickening of the left ventricle (B; arrowheads) along with pericardial effusion (A, B). TTE showed that the mass originated from the ventricular septum and protruded into the right ventricle lumen on a parasternal long-axis tomogram (C; arrowhead), and diffuse wall thickening of the left and right ventricle was noted on an apical 4-chamber tomogram (D; arrowheads).
The cardiac metastases continued to grow regardless of the chemotherapy being changed to streptozocin and lanreotide. He complained of repeated syncope and was admitted to our hospital at 34 months after the initial diagnosis (which was 11 months after the diagnosis of cardiac metastases). An electrocardiogram during syncope showed ventricular tachycardia (VT) (Fig. 4). In addition, the patient's pulse was not detected on palpation while VT was detected on the monitor and electrocardiogram. VT successfully recovered by defibrillation; however, CT and TTE showed progression of the ventricular tumor and wall thickening, which by now had invaded almost the entire ventricular wall (Fig. 5). Thereafter, pulseless VT occurred repeatedly and the patient died on the following day. An autopsy was not performed based on his family's request. Sustained pulseless VT was considered to be the final cause of death.
Figure 4. Electrocardiogram recorded at syncope. An electrocardiogram recorded at syncope showed ventricular tachycardia.
Figure 5. CT and TTE findings in the heart when complicated with ventricular arrhythmia. The progression of the tumor and wall thickening with the poor enhancement in the ventricular septum and wall are observed on CT (A; arrowheads), and the progression of the protruding mass in the ventricular septum (B; arrowhead) and exacerbation of diffuse thickening of the ventricular wall were detected with TTE (B; arrows).
Discussion
We herein report a rare case of cardiac metastases in a patient with rectal NET causing fatal ventricular arrhythmia. The incidence of metastatic cardiac tumor in patients with malignant tumor has been reported to range from 2.3% to 18.3%, the main primary sites of which consisted of malignant melanoma and mediastinal tumor (6). According to the European Neuroendocrine Tumor Society (ENETS) Consensus Guidelines for the Management of Brain, Cardiac and Ovarian Metastases from Neuroendocrine Tumors (3), cardiac metastases are extremely rare, with only 36 previously reported cases. Most cases with cardiac metastases in NETs have been reported to be derived from the mid-gut, such as ileo-cecal NETs, while in our case, the primary tumor existed in the hindgut rectum.
Only two NET patients with cardiac metastases causing arrhythmia have been previously reported (Table 2) (4,5). In these three cases, including our own, the primary sites consisted of the bronchus, ileo-cecum and rectum, and two cases (excluding one with no description) had previously and/or synchronously multiple distant metastases in addition to those in the heart. Cardiac metastases were detected in the ventricular wall and/or septum in the heart in all cases. The lesions were diagnosed with US and CT, and one case was diagnosed with somatostatin scintigraphy plus US and CT. Chemotherapy was performed in two cases, while a solitary cardiac metastasis was surgically removed in one case who exhibited a long-term survival after resection.
Table 2. Summary of the Reported Cases of Cardiac Metastasis Causing Fatal Arrhythmia in Patients with NETs.
No. Age (years) gender Location PE Diagnostic procedure Primary site Tumor grade Carcinoid syndrome Distant metastasis Types of a rrhythmia Treatment Prognosis after the diagnosis (or treatment) of cardiac metastases Reference
1 78 F LVwall RV wall Septum + TTE CT MRI Bronchus - - ND VA Somatostatin Dead 1 year after diagnosis 4
2 54 M RV wall - TTE CT Scintigraphy Ileo-ecum - + Per LN VA Resection, Sandostatin therapy after resection Survive at least 2 years after the resection 5
3 60 M LV wall RV wall Septum + TTE CT Rectum G2 - Liver Lung Bone VT Everolimus Store ptozocin lanreotide Dead at 11 months after the diagnosis Present case
LV: left ventricle, RV: right ventricle, PE: pericardial effusion, TTE: transthoracic echocardiography, CT: computed tomography, MRI: magnetic resonance imaging, ND: not described, Per: peritoneum, LN: lymph node, VA: ventricular arrhythmia, VT: ventricular tachycardia
While detecting cardiac metastases measuring less than 10 mm in a diameter has been difficult using CT and/or TTE, somatostatin receptor-positron emission CT has demonstrated a high efficacy for detecting small cardiac metastases in NET patients (7-9). Following the development of this CT procedure, the incidence of cardiac metastases has increased from 0.7% to 4.3%. Because cardiac metastases might cause severe complications, such as heart failure, lethal arrhythmia and cardiac tamponade, surveillance of cardiac metastases in NET patients using somatostatin receptor-positron emission CT is recommended.
Recently, multidisciplinary therapeutic approaches, including chemotherapy, such as somatostatin analogue, molecular-targeted drugs and cytotoxic agents, have been rapidly developed for the treatment of patients with metastatic NETs (10), thus contributing to a prolonged survival of such patients (11). However, in our case, somatostatin analogues, molecular-targeted drugs and cytotoxic agents were not sufficiently effective as the cardiac metastasis had already markedly progressed by the time that it was detected. The establishment of appropriate therapeutic strategies for cardiac metastases as well as an aggressive screening program for small cardiac metastasis using somatostatin receptor-positron emission CT are expected to improve the outcomes of NET patients.
NETs have been reported to cause carcinoid heart disease in more than 50% of the patients with carcinoid syndrome, which is present in about 20% of patients with NETs at the time of diagnosis (12,13). Carcinoid heart disease was suggested to induce atrial fibrillation and ventricular tachycardia due to right-sided heart failure, valvular disease and serotonin-associated diseases (14,15). According to previous reports, the incidence of cardiac metastases in NETs was suggested to be rarer than that of carcinoid heart disease (16). However, given the differences in the treatment plan, we need to accurately distinguish cardiac metastases from carcinoid-associated heart diseases when NET patients have chest symptoms, cardiac effusion, arrhythmia and heart failure. In our case, normal hormone levels and the absence of any concomitant symptoms indicated a non-functional NET without carcinoid syndrome. TTE revealed signs of right-sided heart failure which was suggested to have resulted from bloody pericardial effusion, while TTE revealed no right-sided valvular disease or dysfunction associated with carcinoid heart syndrome. On the other hand, a tumor and heterogenous wall thickening were detected in the right and left ventricular walls and septa. Furthermore, the patient had no history of heart disease and other factors which were possible to cause ventricular arrhythmia such as abnormal electrolyte. These findings strongly suggested that the patient's ventricular tachycardia had been caused by cardiac metastases from the rectal NET.
In conclusion, we encountered a rare case of cardiac metastases in a patient with a rectal NET causing fatal ventricular arrhythmia. Because of the risk of severe complications, such as fatal arrhythmia and pericardial effusion, appropriate screening and optimal therapeutic approaches for NET patients with cardiac metastases need to be established based on studies in a large number of such patients.
Author's disclosure of potential Conflicts of Interest (COI).
Mikihiro Fujiya: Honoraria, Teijin Pharma and Nobelpharma; Research funding, Nobelpharma. | OCTREOTIDE ACETATE | DrugsGivenReaction | CC BY-NC-ND | 33518610 | 19,999,754 | 2021 |
Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Blood lactate dehydrogenase increased'. | Drug-induced Hypersensitivity Syndrome by EGFR-TKI in a Patient with Lung Cancer.
An 83-years-old woman diagnosed with advanced Epidermal growth factor receptor (EGFR)-mutant lung adenocarcinoma was administered afatinib as a first-line treatment. On Day 17, the patient presented with grade 3 diarrhea and a blood test analysis showed an increased inflammatory response. Afatinib treatment was discontinued on the same day. On Day 26, the patient displayed blepharedema and multiple irregular erythema covering her entire body. Drug-induced hypersensitivity syndrome (DIHS) was suspected, and the systemic administration of 30 mg/day prednisolone was administered. The symptoms subsided thereafter. A blood test analysis 3 weeks after onset revealed a reactivation of Human herpesvirus 6 (HHV-6) and a diagnosis of DIHS due to afatinib therapy was confirmed.
Introduction
Drug-induced hypersensitivity syndrome (DIHS) is a severe drug allergy characterized by fever and a delayed severe rash that can result in multiple organ dysfunction. One main characteristic is the reactivation of human herpesvirus 6 (HHV-6) 10 to 30 days after onset, and in many cases, fever and hepatic impairment are observed with the viral reactivation (1). The drugs known to cause DIHS include; anticonvulsants carbamazepine, phenytoin, phenobarbital, and zonisamide, while occasional cases of antibacterial minocycline have been reported (2). We herein report a case of DIHS in a patient treated with epidermal growth factor receptor-tyrosine kinase inhibitor (EGFR-TKI) afatinib for EGFR-mutant pulmonary adenocarcinoma. This is a first DIHS case report caused by afatinib.
Case Report
An 83-year-old woman with a performance status 1, and a history of hypertension and hyperlipidemia had previously been treated with nifedipine and pitavastatin calcium. The patient had no smoking history or any known allergies. She was referred to our institution for consultation after presenting with a cough. Lung cancer in the lower left lung field was suspected from routine chest radiography. Computed tomography (CT)-guided biopsy, positron emission tomography (PET)-CT, and magnetic resonance imaging (MRI) were performed, revealing adenocarcinoma with multiple metastases at both lungs and for the liver and brain. She was diagnosed with primary pulmonary adenocarcinoma Stage IVB, harbouring an EGFR mutation (exon 19 deletion).
First-line treatment with 40 mg/day afatinib was initiated. On Day 17, the patient had grade 3 diarrhea and a grade 2 fever. Blood test findings showed no elevation of white blood cells (WBC) or eosinophils. However, grade 1 elevation of liver enzymes/lactate dehydrogenase (LDH), and high C-reactive protein (CRP) was seen [WBC 4,600/μL (Seg/Neutro 52%, Lympho 13.5%, Mono 5.5%, Eosino 6.5%, Atypical-lympho 0.5%), Aspartate aminotransferase (AST) 53 IU/L, Alanine aminotransferase (ALT) 45 IU/L, Alkaline phosphatase (ALP) 364 IU/L, LDH 259 IU/L, γ-glutamy transferase 49 IU/L, CRP 6.62 ng/mL]. A physical examination did not suggest infection, and influenza antigen was negative. Afatinib treatment was discontinued due to treatment-emergent adverse events. The oral administration of loperamide for diarrhea was initiated and the fever was followed-up. On Day 19, the WBC count remained stable, but the eosinophil counts had risen 10%. From Day 23, the results were higher, with grade 2 elevation of biliary enzymes, elevated eosinophils, and the emergence of atypical lymphocytes [WBC 10,400/μL (Seg/Neutro 47%, Lympho 20.0%, Mono 9.5%, Eosino 14.5%, Atypical-lympho 6.5%), AST 74 IU/L, ALT 60 IU/L, ALP 1,005 IU/L]. On Day 26, the patient displayed blepharedema and an exacerbation of multiple irregular erythema covering her entire body (Fig. 1). Due to this severe drug rash, DIHS due to afatinib was suspected. Since the rash worsened with the use of topical steroids, treatment with 30 mg/day prednisolone (PSL) (0.5 mg/kg) was initiated on Day 26 without performing a skin biopsy. After starting PSL, her erythema appeared to subside, and improvements in both liver function and fever were observed. Subsequently, the PSL dosage was gradually reduced. On Day 41, we tested for HHV-DNA, and the patient was discharged on Day 44. We strongly suspected DIHS since the patient experienced rapidly spreading erythema, a delay of at least 2 weeks after withdrawal of the causative drug, a fever of at least 38°C, abnormal liver function, an increase in atypical lymphocytes and eosinophil, and enlarged lymph nodes. HHV-DNA was found to be 250 times the reference level, and HHV-IgG measured at the same time was 640 times the reference. Moreover, paired sera measured approximately 3 weeks later was 640 times the reference. These points made it possible to make a definitive diagnosis of DIHS (Table) (3). The clinical course is shown in Fig. 2.
Figure 1. Blepharedema and erythema.
Table. Japanese Consensus Group Diagnostic Criteria for Drug-induced Hypersensitivity Syndrome (DIHS).
Main findings
1.Maculopapular rash develops 2~3 weeks after start of therapy with a limited number of drugs
2.Prolonged clinical symptoms 2 weeks after discontinuation of the suspected drug
3.Fever (>38°C)
4.Liver abnormalities or other organ involvement
5.Leukocyte abnormalities (at least one of the following)
a. Leukocytosis (>11,000/mm3)
b. Atypical lymphocytosis (>5%)
c. Eosinophilia (>1,500/mm3)
6. Lymphadenopathy
7. HHV-6 reactivation
Seven criteria needed for diagnosis of DIHS or the first five criteria required for diagnosis of atypical DIHS.
Figure 2. Clinical course.
Discussion
Outside Japan, DIHS is referred to as drug rash with eosinophilia and systemic symptoms (DRESS) (4). In 1998, Suzuki et al. and Tohyama et al. reported that anti-HHV-6 IgG levels become high 3 to 4 weeks after onset (5,6). The drugs causing DIHS trigger a marked decline in IgG, B cells, and natural killer (NK) cells, and the resulting immunosuppression has been reported to lead to HHV-6 reactivation of the organs in the early stages, followed by the reactivation of HHV-6 in the blood (2). However, the clinical pathology of DIHS is not yet fully understood. DIHS caused by Nivolumab and similar drugs, and the involvement of regulatory T-cells have also been reported (4,7). Furthermore, it has been reported that HHV-7, Epstein-Barr virus (EBV), and cytomegalovirus (CMV) reactivation can also cause DIHS (8). One report indicated between 40% and 70% of cases exhibit all four characteristics of DIHS, namely lymph node enlargement, atypical lymphocytes, eosinophilia, and viral reactivation, and that DIHS cannot be ruled out regardless of elevated HHV-6 IgG (9). In this present case, a definitive diagnosis was made since all the diagnostic criteria for DIHS were satisfied (3). Treatment requires systemic steroid administration to suppress hypersensitivity syndrome accompanying HHV-6 reactivation. The use of immunosuppressants like cyclosporine or gamma globulin preparations can also be considered (10). In this case, DIHS treatment was started with PSL 0.5 mg/kg/day, after which an improvement was observed. Subsequently, the steroid dose was gradually decreased. Unlike general drug rashes, a drug-induced lymphocyte stimulation test (DLST) results at 1 month after DIHS onset have been reported. However, we could not perform DLST because the rash had deteriorated after the PSL dose was reduced to 5 mg. CMV and EBV reactivation had been considered after blood test in this case. On day27, CMV-IgG was elevated to 37.7, however there was no increase seen for CMV-IgM. EBV nuclear antigen and EBV capsid antigen increased to 2.7 and 5.9, respectively. No increase was reported for EBV capsid antigen. On day 49, there was an increase of CMV-IgG to 34.8, but no increased IgM. We considered two reasons why afatinib caused DIHS. First is the time between administration of the drug causing DIHS and onset is thought to be around 2 to 8 weeks, which is clearly longer than the 5 to 14 days seen with other drug rashes. In this case, the rash appeared on Day 26 after afatinib administration. The timing of DIHS onset matches the clinical course for afatinib. In DIHS, fever and eruption do not always occur at the same time. Fever preceded erythema in this case. Second, typical eruptions caused by afatinib are different to erythema in this case. Common skin disorders caused by afatinib are acne (89%), perionychia (61%), dry skin (29%), and latching (18%) (11). On the other hand, blepharedema and erythema are uncommon. The blepharedema and erythema seen in this case are typical but severe drug eruptions. The frequency of skin rashes and flare-ups have been reported during DIHS treatment and occurred twice during the clinical course in our case. Therefore, we believe that this may be the DIHS case caused by afatinib. Anticonvulsants are well-known to cause DIHS. There have also been reports of DIHS caused by the multi-kinase inhibitor sorafenib and the BRAF inhibitor vemurafenib (12,13). As DIHS can be triggered by drugs used in the field of oncology, doctors should therefore include DIHS in the differential diagnosis and and select appropriate treatments when serious drug rashes occur.
The authors state that they have no Conflict of Interest (COI). | AFATINIB, NIFEDIPINE, PITAVASTATIN CALCIUM | DrugsGivenReaction | CC BY-NC-ND | 33518612 | 18,875,893 | 2021 |
Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'C-reactive protein increased'. | Drug-induced Hypersensitivity Syndrome by EGFR-TKI in a Patient with Lung Cancer.
An 83-years-old woman diagnosed with advanced Epidermal growth factor receptor (EGFR)-mutant lung adenocarcinoma was administered afatinib as a first-line treatment. On Day 17, the patient presented with grade 3 diarrhea and a blood test analysis showed an increased inflammatory response. Afatinib treatment was discontinued on the same day. On Day 26, the patient displayed blepharedema and multiple irregular erythema covering her entire body. Drug-induced hypersensitivity syndrome (DIHS) was suspected, and the systemic administration of 30 mg/day prednisolone was administered. The symptoms subsided thereafter. A blood test analysis 3 weeks after onset revealed a reactivation of Human herpesvirus 6 (HHV-6) and a diagnosis of DIHS due to afatinib therapy was confirmed.
Introduction
Drug-induced hypersensitivity syndrome (DIHS) is a severe drug allergy characterized by fever and a delayed severe rash that can result in multiple organ dysfunction. One main characteristic is the reactivation of human herpesvirus 6 (HHV-6) 10 to 30 days after onset, and in many cases, fever and hepatic impairment are observed with the viral reactivation (1). The drugs known to cause DIHS include; anticonvulsants carbamazepine, phenytoin, phenobarbital, and zonisamide, while occasional cases of antibacterial minocycline have been reported (2). We herein report a case of DIHS in a patient treated with epidermal growth factor receptor-tyrosine kinase inhibitor (EGFR-TKI) afatinib for EGFR-mutant pulmonary adenocarcinoma. This is a first DIHS case report caused by afatinib.
Case Report
An 83-year-old woman with a performance status 1, and a history of hypertension and hyperlipidemia had previously been treated with nifedipine and pitavastatin calcium. The patient had no smoking history or any known allergies. She was referred to our institution for consultation after presenting with a cough. Lung cancer in the lower left lung field was suspected from routine chest radiography. Computed tomography (CT)-guided biopsy, positron emission tomography (PET)-CT, and magnetic resonance imaging (MRI) were performed, revealing adenocarcinoma with multiple metastases at both lungs and for the liver and brain. She was diagnosed with primary pulmonary adenocarcinoma Stage IVB, harbouring an EGFR mutation (exon 19 deletion).
First-line treatment with 40 mg/day afatinib was initiated. On Day 17, the patient had grade 3 diarrhea and a grade 2 fever. Blood test findings showed no elevation of white blood cells (WBC) or eosinophils. However, grade 1 elevation of liver enzymes/lactate dehydrogenase (LDH), and high C-reactive protein (CRP) was seen [WBC 4,600/μL (Seg/Neutro 52%, Lympho 13.5%, Mono 5.5%, Eosino 6.5%, Atypical-lympho 0.5%), Aspartate aminotransferase (AST) 53 IU/L, Alanine aminotransferase (ALT) 45 IU/L, Alkaline phosphatase (ALP) 364 IU/L, LDH 259 IU/L, γ-glutamy transferase 49 IU/L, CRP 6.62 ng/mL]. A physical examination did not suggest infection, and influenza antigen was negative. Afatinib treatment was discontinued due to treatment-emergent adverse events. The oral administration of loperamide for diarrhea was initiated and the fever was followed-up. On Day 19, the WBC count remained stable, but the eosinophil counts had risen 10%. From Day 23, the results were higher, with grade 2 elevation of biliary enzymes, elevated eosinophils, and the emergence of atypical lymphocytes [WBC 10,400/μL (Seg/Neutro 47%, Lympho 20.0%, Mono 9.5%, Eosino 14.5%, Atypical-lympho 6.5%), AST 74 IU/L, ALT 60 IU/L, ALP 1,005 IU/L]. On Day 26, the patient displayed blepharedema and an exacerbation of multiple irregular erythema covering her entire body (Fig. 1). Due to this severe drug rash, DIHS due to afatinib was suspected. Since the rash worsened with the use of topical steroids, treatment with 30 mg/day prednisolone (PSL) (0.5 mg/kg) was initiated on Day 26 without performing a skin biopsy. After starting PSL, her erythema appeared to subside, and improvements in both liver function and fever were observed. Subsequently, the PSL dosage was gradually reduced. On Day 41, we tested for HHV-DNA, and the patient was discharged on Day 44. We strongly suspected DIHS since the patient experienced rapidly spreading erythema, a delay of at least 2 weeks after withdrawal of the causative drug, a fever of at least 38°C, abnormal liver function, an increase in atypical lymphocytes and eosinophil, and enlarged lymph nodes. HHV-DNA was found to be 250 times the reference level, and HHV-IgG measured at the same time was 640 times the reference. Moreover, paired sera measured approximately 3 weeks later was 640 times the reference. These points made it possible to make a definitive diagnosis of DIHS (Table) (3). The clinical course is shown in Fig. 2.
Figure 1. Blepharedema and erythema.
Table. Japanese Consensus Group Diagnostic Criteria for Drug-induced Hypersensitivity Syndrome (DIHS).
Main findings
1.Maculopapular rash develops 2~3 weeks after start of therapy with a limited number of drugs
2.Prolonged clinical symptoms 2 weeks after discontinuation of the suspected drug
3.Fever (>38°C)
4.Liver abnormalities or other organ involvement
5.Leukocyte abnormalities (at least one of the following)
a. Leukocytosis (>11,000/mm3)
b. Atypical lymphocytosis (>5%)
c. Eosinophilia (>1,500/mm3)
6. Lymphadenopathy
7. HHV-6 reactivation
Seven criteria needed for diagnosis of DIHS or the first five criteria required for diagnosis of atypical DIHS.
Figure 2. Clinical course.
Discussion
Outside Japan, DIHS is referred to as drug rash with eosinophilia and systemic symptoms (DRESS) (4). In 1998, Suzuki et al. and Tohyama et al. reported that anti-HHV-6 IgG levels become high 3 to 4 weeks after onset (5,6). The drugs causing DIHS trigger a marked decline in IgG, B cells, and natural killer (NK) cells, and the resulting immunosuppression has been reported to lead to HHV-6 reactivation of the organs in the early stages, followed by the reactivation of HHV-6 in the blood (2). However, the clinical pathology of DIHS is not yet fully understood. DIHS caused by Nivolumab and similar drugs, and the involvement of regulatory T-cells have also been reported (4,7). Furthermore, it has been reported that HHV-7, Epstein-Barr virus (EBV), and cytomegalovirus (CMV) reactivation can also cause DIHS (8). One report indicated between 40% and 70% of cases exhibit all four characteristics of DIHS, namely lymph node enlargement, atypical lymphocytes, eosinophilia, and viral reactivation, and that DIHS cannot be ruled out regardless of elevated HHV-6 IgG (9). In this present case, a definitive diagnosis was made since all the diagnostic criteria for DIHS were satisfied (3). Treatment requires systemic steroid administration to suppress hypersensitivity syndrome accompanying HHV-6 reactivation. The use of immunosuppressants like cyclosporine or gamma globulin preparations can also be considered (10). In this case, DIHS treatment was started with PSL 0.5 mg/kg/day, after which an improvement was observed. Subsequently, the steroid dose was gradually decreased. Unlike general drug rashes, a drug-induced lymphocyte stimulation test (DLST) results at 1 month after DIHS onset have been reported. However, we could not perform DLST because the rash had deteriorated after the PSL dose was reduced to 5 mg. CMV and EBV reactivation had been considered after blood test in this case. On day27, CMV-IgG was elevated to 37.7, however there was no increase seen for CMV-IgM. EBV nuclear antigen and EBV capsid antigen increased to 2.7 and 5.9, respectively. No increase was reported for EBV capsid antigen. On day 49, there was an increase of CMV-IgG to 34.8, but no increased IgM. We considered two reasons why afatinib caused DIHS. First is the time between administration of the drug causing DIHS and onset is thought to be around 2 to 8 weeks, which is clearly longer than the 5 to 14 days seen with other drug rashes. In this case, the rash appeared on Day 26 after afatinib administration. The timing of DIHS onset matches the clinical course for afatinib. In DIHS, fever and eruption do not always occur at the same time. Fever preceded erythema in this case. Second, typical eruptions caused by afatinib are different to erythema in this case. Common skin disorders caused by afatinib are acne (89%), perionychia (61%), dry skin (29%), and latching (18%) (11). On the other hand, blepharedema and erythema are uncommon. The blepharedema and erythema seen in this case are typical but severe drug eruptions. The frequency of skin rashes and flare-ups have been reported during DIHS treatment and occurred twice during the clinical course in our case. Therefore, we believe that this may be the DIHS case caused by afatinib. Anticonvulsants are well-known to cause DIHS. There have also been reports of DIHS caused by the multi-kinase inhibitor sorafenib and the BRAF inhibitor vemurafenib (12,13). As DIHS can be triggered by drugs used in the field of oncology, doctors should therefore include DIHS in the differential diagnosis and and select appropriate treatments when serious drug rashes occur.
The authors state that they have no Conflict of Interest (COI). | AFATINIB, NIFEDIPINE, PITAVASTATIN CALCIUM | DrugsGivenReaction | CC BY-NC-ND | 33518612 | 18,875,893 | 2021 |
Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Diarrhoea'. | Drug-induced Hypersensitivity Syndrome by EGFR-TKI in a Patient with Lung Cancer.
An 83-years-old woman diagnosed with advanced Epidermal growth factor receptor (EGFR)-mutant lung adenocarcinoma was administered afatinib as a first-line treatment. On Day 17, the patient presented with grade 3 diarrhea and a blood test analysis showed an increased inflammatory response. Afatinib treatment was discontinued on the same day. On Day 26, the patient displayed blepharedema and multiple irregular erythema covering her entire body. Drug-induced hypersensitivity syndrome (DIHS) was suspected, and the systemic administration of 30 mg/day prednisolone was administered. The symptoms subsided thereafter. A blood test analysis 3 weeks after onset revealed a reactivation of Human herpesvirus 6 (HHV-6) and a diagnosis of DIHS due to afatinib therapy was confirmed.
Introduction
Drug-induced hypersensitivity syndrome (DIHS) is a severe drug allergy characterized by fever and a delayed severe rash that can result in multiple organ dysfunction. One main characteristic is the reactivation of human herpesvirus 6 (HHV-6) 10 to 30 days after onset, and in many cases, fever and hepatic impairment are observed with the viral reactivation (1). The drugs known to cause DIHS include; anticonvulsants carbamazepine, phenytoin, phenobarbital, and zonisamide, while occasional cases of antibacterial minocycline have been reported (2). We herein report a case of DIHS in a patient treated with epidermal growth factor receptor-tyrosine kinase inhibitor (EGFR-TKI) afatinib for EGFR-mutant pulmonary adenocarcinoma. This is a first DIHS case report caused by afatinib.
Case Report
An 83-year-old woman with a performance status 1, and a history of hypertension and hyperlipidemia had previously been treated with nifedipine and pitavastatin calcium. The patient had no smoking history or any known allergies. She was referred to our institution for consultation after presenting with a cough. Lung cancer in the lower left lung field was suspected from routine chest radiography. Computed tomography (CT)-guided biopsy, positron emission tomography (PET)-CT, and magnetic resonance imaging (MRI) were performed, revealing adenocarcinoma with multiple metastases at both lungs and for the liver and brain. She was diagnosed with primary pulmonary adenocarcinoma Stage IVB, harbouring an EGFR mutation (exon 19 deletion).
First-line treatment with 40 mg/day afatinib was initiated. On Day 17, the patient had grade 3 diarrhea and a grade 2 fever. Blood test findings showed no elevation of white blood cells (WBC) or eosinophils. However, grade 1 elevation of liver enzymes/lactate dehydrogenase (LDH), and high C-reactive protein (CRP) was seen [WBC 4,600/μL (Seg/Neutro 52%, Lympho 13.5%, Mono 5.5%, Eosino 6.5%, Atypical-lympho 0.5%), Aspartate aminotransferase (AST) 53 IU/L, Alanine aminotransferase (ALT) 45 IU/L, Alkaline phosphatase (ALP) 364 IU/L, LDH 259 IU/L, γ-glutamy transferase 49 IU/L, CRP 6.62 ng/mL]. A physical examination did not suggest infection, and influenza antigen was negative. Afatinib treatment was discontinued due to treatment-emergent adverse events. The oral administration of loperamide for diarrhea was initiated and the fever was followed-up. On Day 19, the WBC count remained stable, but the eosinophil counts had risen 10%. From Day 23, the results were higher, with grade 2 elevation of biliary enzymes, elevated eosinophils, and the emergence of atypical lymphocytes [WBC 10,400/μL (Seg/Neutro 47%, Lympho 20.0%, Mono 9.5%, Eosino 14.5%, Atypical-lympho 6.5%), AST 74 IU/L, ALT 60 IU/L, ALP 1,005 IU/L]. On Day 26, the patient displayed blepharedema and an exacerbation of multiple irregular erythema covering her entire body (Fig. 1). Due to this severe drug rash, DIHS due to afatinib was suspected. Since the rash worsened with the use of topical steroids, treatment with 30 mg/day prednisolone (PSL) (0.5 mg/kg) was initiated on Day 26 without performing a skin biopsy. After starting PSL, her erythema appeared to subside, and improvements in both liver function and fever were observed. Subsequently, the PSL dosage was gradually reduced. On Day 41, we tested for HHV-DNA, and the patient was discharged on Day 44. We strongly suspected DIHS since the patient experienced rapidly spreading erythema, a delay of at least 2 weeks after withdrawal of the causative drug, a fever of at least 38°C, abnormal liver function, an increase in atypical lymphocytes and eosinophil, and enlarged lymph nodes. HHV-DNA was found to be 250 times the reference level, and HHV-IgG measured at the same time was 640 times the reference. Moreover, paired sera measured approximately 3 weeks later was 640 times the reference. These points made it possible to make a definitive diagnosis of DIHS (Table) (3). The clinical course is shown in Fig. 2.
Figure 1. Blepharedema and erythema.
Table. Japanese Consensus Group Diagnostic Criteria for Drug-induced Hypersensitivity Syndrome (DIHS).
Main findings
1.Maculopapular rash develops 2~3 weeks after start of therapy with a limited number of drugs
2.Prolonged clinical symptoms 2 weeks after discontinuation of the suspected drug
3.Fever (>38°C)
4.Liver abnormalities or other organ involvement
5.Leukocyte abnormalities (at least one of the following)
a. Leukocytosis (>11,000/mm3)
b. Atypical lymphocytosis (>5%)
c. Eosinophilia (>1,500/mm3)
6. Lymphadenopathy
7. HHV-6 reactivation
Seven criteria needed for diagnosis of DIHS or the first five criteria required for diagnosis of atypical DIHS.
Figure 2. Clinical course.
Discussion
Outside Japan, DIHS is referred to as drug rash with eosinophilia and systemic symptoms (DRESS) (4). In 1998, Suzuki et al. and Tohyama et al. reported that anti-HHV-6 IgG levels become high 3 to 4 weeks after onset (5,6). The drugs causing DIHS trigger a marked decline in IgG, B cells, and natural killer (NK) cells, and the resulting immunosuppression has been reported to lead to HHV-6 reactivation of the organs in the early stages, followed by the reactivation of HHV-6 in the blood (2). However, the clinical pathology of DIHS is not yet fully understood. DIHS caused by Nivolumab and similar drugs, and the involvement of regulatory T-cells have also been reported (4,7). Furthermore, it has been reported that HHV-7, Epstein-Barr virus (EBV), and cytomegalovirus (CMV) reactivation can also cause DIHS (8). One report indicated between 40% and 70% of cases exhibit all four characteristics of DIHS, namely lymph node enlargement, atypical lymphocytes, eosinophilia, and viral reactivation, and that DIHS cannot be ruled out regardless of elevated HHV-6 IgG (9). In this present case, a definitive diagnosis was made since all the diagnostic criteria for DIHS were satisfied (3). Treatment requires systemic steroid administration to suppress hypersensitivity syndrome accompanying HHV-6 reactivation. The use of immunosuppressants like cyclosporine or gamma globulin preparations can also be considered (10). In this case, DIHS treatment was started with PSL 0.5 mg/kg/day, after which an improvement was observed. Subsequently, the steroid dose was gradually decreased. Unlike general drug rashes, a drug-induced lymphocyte stimulation test (DLST) results at 1 month after DIHS onset have been reported. However, we could not perform DLST because the rash had deteriorated after the PSL dose was reduced to 5 mg. CMV and EBV reactivation had been considered after blood test in this case. On day27, CMV-IgG was elevated to 37.7, however there was no increase seen for CMV-IgM. EBV nuclear antigen and EBV capsid antigen increased to 2.7 and 5.9, respectively. No increase was reported for EBV capsid antigen. On day 49, there was an increase of CMV-IgG to 34.8, but no increased IgM. We considered two reasons why afatinib caused DIHS. First is the time between administration of the drug causing DIHS and onset is thought to be around 2 to 8 weeks, which is clearly longer than the 5 to 14 days seen with other drug rashes. In this case, the rash appeared on Day 26 after afatinib administration. The timing of DIHS onset matches the clinical course for afatinib. In DIHS, fever and eruption do not always occur at the same time. Fever preceded erythema in this case. Second, typical eruptions caused by afatinib are different to erythema in this case. Common skin disorders caused by afatinib are acne (89%), perionychia (61%), dry skin (29%), and latching (18%) (11). On the other hand, blepharedema and erythema are uncommon. The blepharedema and erythema seen in this case are typical but severe drug eruptions. The frequency of skin rashes and flare-ups have been reported during DIHS treatment and occurred twice during the clinical course in our case. Therefore, we believe that this may be the DIHS case caused by afatinib. Anticonvulsants are well-known to cause DIHS. There have also been reports of DIHS caused by the multi-kinase inhibitor sorafenib and the BRAF inhibitor vemurafenib (12,13). As DIHS can be triggered by drugs used in the field of oncology, doctors should therefore include DIHS in the differential diagnosis and and select appropriate treatments when serious drug rashes occur.
The authors state that they have no Conflict of Interest (COI). | AFATINIB, NIFEDIPINE, PITAVASTATIN CALCIUM | DrugsGivenReaction | CC BY-NC-ND | 33518612 | 18,875,893 | 2021 |
Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Drug reaction with eosinophilia and systemic symptoms'. | Drug-induced Hypersensitivity Syndrome by EGFR-TKI in a Patient with Lung Cancer.
An 83-years-old woman diagnosed with advanced Epidermal growth factor receptor (EGFR)-mutant lung adenocarcinoma was administered afatinib as a first-line treatment. On Day 17, the patient presented with grade 3 diarrhea and a blood test analysis showed an increased inflammatory response. Afatinib treatment was discontinued on the same day. On Day 26, the patient displayed blepharedema and multiple irregular erythema covering her entire body. Drug-induced hypersensitivity syndrome (DIHS) was suspected, and the systemic administration of 30 mg/day prednisolone was administered. The symptoms subsided thereafter. A blood test analysis 3 weeks after onset revealed a reactivation of Human herpesvirus 6 (HHV-6) and a diagnosis of DIHS due to afatinib therapy was confirmed.
Introduction
Drug-induced hypersensitivity syndrome (DIHS) is a severe drug allergy characterized by fever and a delayed severe rash that can result in multiple organ dysfunction. One main characteristic is the reactivation of human herpesvirus 6 (HHV-6) 10 to 30 days after onset, and in many cases, fever and hepatic impairment are observed with the viral reactivation (1). The drugs known to cause DIHS include; anticonvulsants carbamazepine, phenytoin, phenobarbital, and zonisamide, while occasional cases of antibacterial minocycline have been reported (2). We herein report a case of DIHS in a patient treated with epidermal growth factor receptor-tyrosine kinase inhibitor (EGFR-TKI) afatinib for EGFR-mutant pulmonary adenocarcinoma. This is a first DIHS case report caused by afatinib.
Case Report
An 83-year-old woman with a performance status 1, and a history of hypertension and hyperlipidemia had previously been treated with nifedipine and pitavastatin calcium. The patient had no smoking history or any known allergies. She was referred to our institution for consultation after presenting with a cough. Lung cancer in the lower left lung field was suspected from routine chest radiography. Computed tomography (CT)-guided biopsy, positron emission tomography (PET)-CT, and magnetic resonance imaging (MRI) were performed, revealing adenocarcinoma with multiple metastases at both lungs and for the liver and brain. She was diagnosed with primary pulmonary adenocarcinoma Stage IVB, harbouring an EGFR mutation (exon 19 deletion).
First-line treatment with 40 mg/day afatinib was initiated. On Day 17, the patient had grade 3 diarrhea and a grade 2 fever. Blood test findings showed no elevation of white blood cells (WBC) or eosinophils. However, grade 1 elevation of liver enzymes/lactate dehydrogenase (LDH), and high C-reactive protein (CRP) was seen [WBC 4,600/μL (Seg/Neutro 52%, Lympho 13.5%, Mono 5.5%, Eosino 6.5%, Atypical-lympho 0.5%), Aspartate aminotransferase (AST) 53 IU/L, Alanine aminotransferase (ALT) 45 IU/L, Alkaline phosphatase (ALP) 364 IU/L, LDH 259 IU/L, γ-glutamy transferase 49 IU/L, CRP 6.62 ng/mL]. A physical examination did not suggest infection, and influenza antigen was negative. Afatinib treatment was discontinued due to treatment-emergent adverse events. The oral administration of loperamide for diarrhea was initiated and the fever was followed-up. On Day 19, the WBC count remained stable, but the eosinophil counts had risen 10%. From Day 23, the results were higher, with grade 2 elevation of biliary enzymes, elevated eosinophils, and the emergence of atypical lymphocytes [WBC 10,400/μL (Seg/Neutro 47%, Lympho 20.0%, Mono 9.5%, Eosino 14.5%, Atypical-lympho 6.5%), AST 74 IU/L, ALT 60 IU/L, ALP 1,005 IU/L]. On Day 26, the patient displayed blepharedema and an exacerbation of multiple irregular erythema covering her entire body (Fig. 1). Due to this severe drug rash, DIHS due to afatinib was suspected. Since the rash worsened with the use of topical steroids, treatment with 30 mg/day prednisolone (PSL) (0.5 mg/kg) was initiated on Day 26 without performing a skin biopsy. After starting PSL, her erythema appeared to subside, and improvements in both liver function and fever were observed. Subsequently, the PSL dosage was gradually reduced. On Day 41, we tested for HHV-DNA, and the patient was discharged on Day 44. We strongly suspected DIHS since the patient experienced rapidly spreading erythema, a delay of at least 2 weeks after withdrawal of the causative drug, a fever of at least 38°C, abnormal liver function, an increase in atypical lymphocytes and eosinophil, and enlarged lymph nodes. HHV-DNA was found to be 250 times the reference level, and HHV-IgG measured at the same time was 640 times the reference. Moreover, paired sera measured approximately 3 weeks later was 640 times the reference. These points made it possible to make a definitive diagnosis of DIHS (Table) (3). The clinical course is shown in Fig. 2.
Figure 1. Blepharedema and erythema.
Table. Japanese Consensus Group Diagnostic Criteria for Drug-induced Hypersensitivity Syndrome (DIHS).
Main findings
1.Maculopapular rash develops 2~3 weeks after start of therapy with a limited number of drugs
2.Prolonged clinical symptoms 2 weeks after discontinuation of the suspected drug
3.Fever (>38°C)
4.Liver abnormalities or other organ involvement
5.Leukocyte abnormalities (at least one of the following)
a. Leukocytosis (>11,000/mm3)
b. Atypical lymphocytosis (>5%)
c. Eosinophilia (>1,500/mm3)
6. Lymphadenopathy
7. HHV-6 reactivation
Seven criteria needed for diagnosis of DIHS or the first five criteria required for diagnosis of atypical DIHS.
Figure 2. Clinical course.
Discussion
Outside Japan, DIHS is referred to as drug rash with eosinophilia and systemic symptoms (DRESS) (4). In 1998, Suzuki et al. and Tohyama et al. reported that anti-HHV-6 IgG levels become high 3 to 4 weeks after onset (5,6). The drugs causing DIHS trigger a marked decline in IgG, B cells, and natural killer (NK) cells, and the resulting immunosuppression has been reported to lead to HHV-6 reactivation of the organs in the early stages, followed by the reactivation of HHV-6 in the blood (2). However, the clinical pathology of DIHS is not yet fully understood. DIHS caused by Nivolumab and similar drugs, and the involvement of regulatory T-cells have also been reported (4,7). Furthermore, it has been reported that HHV-7, Epstein-Barr virus (EBV), and cytomegalovirus (CMV) reactivation can also cause DIHS (8). One report indicated between 40% and 70% of cases exhibit all four characteristics of DIHS, namely lymph node enlargement, atypical lymphocytes, eosinophilia, and viral reactivation, and that DIHS cannot be ruled out regardless of elevated HHV-6 IgG (9). In this present case, a definitive diagnosis was made since all the diagnostic criteria for DIHS were satisfied (3). Treatment requires systemic steroid administration to suppress hypersensitivity syndrome accompanying HHV-6 reactivation. The use of immunosuppressants like cyclosporine or gamma globulin preparations can also be considered (10). In this case, DIHS treatment was started with PSL 0.5 mg/kg/day, after which an improvement was observed. Subsequently, the steroid dose was gradually decreased. Unlike general drug rashes, a drug-induced lymphocyte stimulation test (DLST) results at 1 month after DIHS onset have been reported. However, we could not perform DLST because the rash had deteriorated after the PSL dose was reduced to 5 mg. CMV and EBV reactivation had been considered after blood test in this case. On day27, CMV-IgG was elevated to 37.7, however there was no increase seen for CMV-IgM. EBV nuclear antigen and EBV capsid antigen increased to 2.7 and 5.9, respectively. No increase was reported for EBV capsid antigen. On day 49, there was an increase of CMV-IgG to 34.8, but no increased IgM. We considered two reasons why afatinib caused DIHS. First is the time between administration of the drug causing DIHS and onset is thought to be around 2 to 8 weeks, which is clearly longer than the 5 to 14 days seen with other drug rashes. In this case, the rash appeared on Day 26 after afatinib administration. The timing of DIHS onset matches the clinical course for afatinib. In DIHS, fever and eruption do not always occur at the same time. Fever preceded erythema in this case. Second, typical eruptions caused by afatinib are different to erythema in this case. Common skin disorders caused by afatinib are acne (89%), perionychia (61%), dry skin (29%), and latching (18%) (11). On the other hand, blepharedema and erythema are uncommon. The blepharedema and erythema seen in this case are typical but severe drug eruptions. The frequency of skin rashes and flare-ups have been reported during DIHS treatment and occurred twice during the clinical course in our case. Therefore, we believe that this may be the DIHS case caused by afatinib. Anticonvulsants are well-known to cause DIHS. There have also been reports of DIHS caused by the multi-kinase inhibitor sorafenib and the BRAF inhibitor vemurafenib (12,13). As DIHS can be triggered by drugs used in the field of oncology, doctors should therefore include DIHS in the differential diagnosis and and select appropriate treatments when serious drug rashes occur.
The authors state that they have no Conflict of Interest (COI). | AFATINIB, NIFEDIPINE, PITAVASTATIN CALCIUM | DrugsGivenReaction | CC BY-NC-ND | 33518612 | 18,875,893 | 2021 |
Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Pyrexia'. | Drug-induced Hypersensitivity Syndrome by EGFR-TKI in a Patient with Lung Cancer.
An 83-years-old woman diagnosed with advanced Epidermal growth factor receptor (EGFR)-mutant lung adenocarcinoma was administered afatinib as a first-line treatment. On Day 17, the patient presented with grade 3 diarrhea and a blood test analysis showed an increased inflammatory response. Afatinib treatment was discontinued on the same day. On Day 26, the patient displayed blepharedema and multiple irregular erythema covering her entire body. Drug-induced hypersensitivity syndrome (DIHS) was suspected, and the systemic administration of 30 mg/day prednisolone was administered. The symptoms subsided thereafter. A blood test analysis 3 weeks after onset revealed a reactivation of Human herpesvirus 6 (HHV-6) and a diagnosis of DIHS due to afatinib therapy was confirmed.
Introduction
Drug-induced hypersensitivity syndrome (DIHS) is a severe drug allergy characterized by fever and a delayed severe rash that can result in multiple organ dysfunction. One main characteristic is the reactivation of human herpesvirus 6 (HHV-6) 10 to 30 days after onset, and in many cases, fever and hepatic impairment are observed with the viral reactivation (1). The drugs known to cause DIHS include; anticonvulsants carbamazepine, phenytoin, phenobarbital, and zonisamide, while occasional cases of antibacterial minocycline have been reported (2). We herein report a case of DIHS in a patient treated with epidermal growth factor receptor-tyrosine kinase inhibitor (EGFR-TKI) afatinib for EGFR-mutant pulmonary adenocarcinoma. This is a first DIHS case report caused by afatinib.
Case Report
An 83-year-old woman with a performance status 1, and a history of hypertension and hyperlipidemia had previously been treated with nifedipine and pitavastatin calcium. The patient had no smoking history or any known allergies. She was referred to our institution for consultation after presenting with a cough. Lung cancer in the lower left lung field was suspected from routine chest radiography. Computed tomography (CT)-guided biopsy, positron emission tomography (PET)-CT, and magnetic resonance imaging (MRI) were performed, revealing adenocarcinoma with multiple metastases at both lungs and for the liver and brain. She was diagnosed with primary pulmonary adenocarcinoma Stage IVB, harbouring an EGFR mutation (exon 19 deletion).
First-line treatment with 40 mg/day afatinib was initiated. On Day 17, the patient had grade 3 diarrhea and a grade 2 fever. Blood test findings showed no elevation of white blood cells (WBC) or eosinophils. However, grade 1 elevation of liver enzymes/lactate dehydrogenase (LDH), and high C-reactive protein (CRP) was seen [WBC 4,600/μL (Seg/Neutro 52%, Lympho 13.5%, Mono 5.5%, Eosino 6.5%, Atypical-lympho 0.5%), Aspartate aminotransferase (AST) 53 IU/L, Alanine aminotransferase (ALT) 45 IU/L, Alkaline phosphatase (ALP) 364 IU/L, LDH 259 IU/L, γ-glutamy transferase 49 IU/L, CRP 6.62 ng/mL]. A physical examination did not suggest infection, and influenza antigen was negative. Afatinib treatment was discontinued due to treatment-emergent adverse events. The oral administration of loperamide for diarrhea was initiated and the fever was followed-up. On Day 19, the WBC count remained stable, but the eosinophil counts had risen 10%. From Day 23, the results were higher, with grade 2 elevation of biliary enzymes, elevated eosinophils, and the emergence of atypical lymphocytes [WBC 10,400/μL (Seg/Neutro 47%, Lympho 20.0%, Mono 9.5%, Eosino 14.5%, Atypical-lympho 6.5%), AST 74 IU/L, ALT 60 IU/L, ALP 1,005 IU/L]. On Day 26, the patient displayed blepharedema and an exacerbation of multiple irregular erythema covering her entire body (Fig. 1). Due to this severe drug rash, DIHS due to afatinib was suspected. Since the rash worsened with the use of topical steroids, treatment with 30 mg/day prednisolone (PSL) (0.5 mg/kg) was initiated on Day 26 without performing a skin biopsy. After starting PSL, her erythema appeared to subside, and improvements in both liver function and fever were observed. Subsequently, the PSL dosage was gradually reduced. On Day 41, we tested for HHV-DNA, and the patient was discharged on Day 44. We strongly suspected DIHS since the patient experienced rapidly spreading erythema, a delay of at least 2 weeks after withdrawal of the causative drug, a fever of at least 38°C, abnormal liver function, an increase in atypical lymphocytes and eosinophil, and enlarged lymph nodes. HHV-DNA was found to be 250 times the reference level, and HHV-IgG measured at the same time was 640 times the reference. Moreover, paired sera measured approximately 3 weeks later was 640 times the reference. These points made it possible to make a definitive diagnosis of DIHS (Table) (3). The clinical course is shown in Fig. 2.
Figure 1. Blepharedema and erythema.
Table. Japanese Consensus Group Diagnostic Criteria for Drug-induced Hypersensitivity Syndrome (DIHS).
Main findings
1.Maculopapular rash develops 2~3 weeks after start of therapy with a limited number of drugs
2.Prolonged clinical symptoms 2 weeks after discontinuation of the suspected drug
3.Fever (>38°C)
4.Liver abnormalities or other organ involvement
5.Leukocyte abnormalities (at least one of the following)
a. Leukocytosis (>11,000/mm3)
b. Atypical lymphocytosis (>5%)
c. Eosinophilia (>1,500/mm3)
6. Lymphadenopathy
7. HHV-6 reactivation
Seven criteria needed for diagnosis of DIHS or the first five criteria required for diagnosis of atypical DIHS.
Figure 2. Clinical course.
Discussion
Outside Japan, DIHS is referred to as drug rash with eosinophilia and systemic symptoms (DRESS) (4). In 1998, Suzuki et al. and Tohyama et al. reported that anti-HHV-6 IgG levels become high 3 to 4 weeks after onset (5,6). The drugs causing DIHS trigger a marked decline in IgG, B cells, and natural killer (NK) cells, and the resulting immunosuppression has been reported to lead to HHV-6 reactivation of the organs in the early stages, followed by the reactivation of HHV-6 in the blood (2). However, the clinical pathology of DIHS is not yet fully understood. DIHS caused by Nivolumab and similar drugs, and the involvement of regulatory T-cells have also been reported (4,7). Furthermore, it has been reported that HHV-7, Epstein-Barr virus (EBV), and cytomegalovirus (CMV) reactivation can also cause DIHS (8). One report indicated between 40% and 70% of cases exhibit all four characteristics of DIHS, namely lymph node enlargement, atypical lymphocytes, eosinophilia, and viral reactivation, and that DIHS cannot be ruled out regardless of elevated HHV-6 IgG (9). In this present case, a definitive diagnosis was made since all the diagnostic criteria for DIHS were satisfied (3). Treatment requires systemic steroid administration to suppress hypersensitivity syndrome accompanying HHV-6 reactivation. The use of immunosuppressants like cyclosporine or gamma globulin preparations can also be considered (10). In this case, DIHS treatment was started with PSL 0.5 mg/kg/day, after which an improvement was observed. Subsequently, the steroid dose was gradually decreased. Unlike general drug rashes, a drug-induced lymphocyte stimulation test (DLST) results at 1 month after DIHS onset have been reported. However, we could not perform DLST because the rash had deteriorated after the PSL dose was reduced to 5 mg. CMV and EBV reactivation had been considered after blood test in this case. On day27, CMV-IgG was elevated to 37.7, however there was no increase seen for CMV-IgM. EBV nuclear antigen and EBV capsid antigen increased to 2.7 and 5.9, respectively. No increase was reported for EBV capsid antigen. On day 49, there was an increase of CMV-IgG to 34.8, but no increased IgM. We considered two reasons why afatinib caused DIHS. First is the time between administration of the drug causing DIHS and onset is thought to be around 2 to 8 weeks, which is clearly longer than the 5 to 14 days seen with other drug rashes. In this case, the rash appeared on Day 26 after afatinib administration. The timing of DIHS onset matches the clinical course for afatinib. In DIHS, fever and eruption do not always occur at the same time. Fever preceded erythema in this case. Second, typical eruptions caused by afatinib are different to erythema in this case. Common skin disorders caused by afatinib are acne (89%), perionychia (61%), dry skin (29%), and latching (18%) (11). On the other hand, blepharedema and erythema are uncommon. The blepharedema and erythema seen in this case are typical but severe drug eruptions. The frequency of skin rashes and flare-ups have been reported during DIHS treatment and occurred twice during the clinical course in our case. Therefore, we believe that this may be the DIHS case caused by afatinib. Anticonvulsants are well-known to cause DIHS. There have also been reports of DIHS caused by the multi-kinase inhibitor sorafenib and the BRAF inhibitor vemurafenib (12,13). As DIHS can be triggered by drugs used in the field of oncology, doctors should therefore include DIHS in the differential diagnosis and and select appropriate treatments when serious drug rashes occur.
The authors state that they have no Conflict of Interest (COI). | AFATINIB, NIFEDIPINE, PITAVASTATIN CALCIUM | DrugsGivenReaction | CC BY-NC-ND | 33518612 | 18,875,893 | 2021 |
What was the dosage of drug 'AFATINIB'? | Drug-induced Hypersensitivity Syndrome by EGFR-TKI in a Patient with Lung Cancer.
An 83-years-old woman diagnosed with advanced Epidermal growth factor receptor (EGFR)-mutant lung adenocarcinoma was administered afatinib as a first-line treatment. On Day 17, the patient presented with grade 3 diarrhea and a blood test analysis showed an increased inflammatory response. Afatinib treatment was discontinued on the same day. On Day 26, the patient displayed blepharedema and multiple irregular erythema covering her entire body. Drug-induced hypersensitivity syndrome (DIHS) was suspected, and the systemic administration of 30 mg/day prednisolone was administered. The symptoms subsided thereafter. A blood test analysis 3 weeks after onset revealed a reactivation of Human herpesvirus 6 (HHV-6) and a diagnosis of DIHS due to afatinib therapy was confirmed.
Introduction
Drug-induced hypersensitivity syndrome (DIHS) is a severe drug allergy characterized by fever and a delayed severe rash that can result in multiple organ dysfunction. One main characteristic is the reactivation of human herpesvirus 6 (HHV-6) 10 to 30 days after onset, and in many cases, fever and hepatic impairment are observed with the viral reactivation (1). The drugs known to cause DIHS include; anticonvulsants carbamazepine, phenytoin, phenobarbital, and zonisamide, while occasional cases of antibacterial minocycline have been reported (2). We herein report a case of DIHS in a patient treated with epidermal growth factor receptor-tyrosine kinase inhibitor (EGFR-TKI) afatinib for EGFR-mutant pulmonary adenocarcinoma. This is a first DIHS case report caused by afatinib.
Case Report
An 83-year-old woman with a performance status 1, and a history of hypertension and hyperlipidemia had previously been treated with nifedipine and pitavastatin calcium. The patient had no smoking history or any known allergies. She was referred to our institution for consultation after presenting with a cough. Lung cancer in the lower left lung field was suspected from routine chest radiography. Computed tomography (CT)-guided biopsy, positron emission tomography (PET)-CT, and magnetic resonance imaging (MRI) were performed, revealing adenocarcinoma with multiple metastases at both lungs and for the liver and brain. She was diagnosed with primary pulmonary adenocarcinoma Stage IVB, harbouring an EGFR mutation (exon 19 deletion).
First-line treatment with 40 mg/day afatinib was initiated. On Day 17, the patient had grade 3 diarrhea and a grade 2 fever. Blood test findings showed no elevation of white blood cells (WBC) or eosinophils. However, grade 1 elevation of liver enzymes/lactate dehydrogenase (LDH), and high C-reactive protein (CRP) was seen [WBC 4,600/μL (Seg/Neutro 52%, Lympho 13.5%, Mono 5.5%, Eosino 6.5%, Atypical-lympho 0.5%), Aspartate aminotransferase (AST) 53 IU/L, Alanine aminotransferase (ALT) 45 IU/L, Alkaline phosphatase (ALP) 364 IU/L, LDH 259 IU/L, γ-glutamy transferase 49 IU/L, CRP 6.62 ng/mL]. A physical examination did not suggest infection, and influenza antigen was negative. Afatinib treatment was discontinued due to treatment-emergent adverse events. The oral administration of loperamide for diarrhea was initiated and the fever was followed-up. On Day 19, the WBC count remained stable, but the eosinophil counts had risen 10%. From Day 23, the results were higher, with grade 2 elevation of biliary enzymes, elevated eosinophils, and the emergence of atypical lymphocytes [WBC 10,400/μL (Seg/Neutro 47%, Lympho 20.0%, Mono 9.5%, Eosino 14.5%, Atypical-lympho 6.5%), AST 74 IU/L, ALT 60 IU/L, ALP 1,005 IU/L]. On Day 26, the patient displayed blepharedema and an exacerbation of multiple irregular erythema covering her entire body (Fig. 1). Due to this severe drug rash, DIHS due to afatinib was suspected. Since the rash worsened with the use of topical steroids, treatment with 30 mg/day prednisolone (PSL) (0.5 mg/kg) was initiated on Day 26 without performing a skin biopsy. After starting PSL, her erythema appeared to subside, and improvements in both liver function and fever were observed. Subsequently, the PSL dosage was gradually reduced. On Day 41, we tested for HHV-DNA, and the patient was discharged on Day 44. We strongly suspected DIHS since the patient experienced rapidly spreading erythema, a delay of at least 2 weeks after withdrawal of the causative drug, a fever of at least 38°C, abnormal liver function, an increase in atypical lymphocytes and eosinophil, and enlarged lymph nodes. HHV-DNA was found to be 250 times the reference level, and HHV-IgG measured at the same time was 640 times the reference. Moreover, paired sera measured approximately 3 weeks later was 640 times the reference. These points made it possible to make a definitive diagnosis of DIHS (Table) (3). The clinical course is shown in Fig. 2.
Figure 1. Blepharedema and erythema.
Table. Japanese Consensus Group Diagnostic Criteria for Drug-induced Hypersensitivity Syndrome (DIHS).
Main findings
1.Maculopapular rash develops 2~3 weeks after start of therapy with a limited number of drugs
2.Prolonged clinical symptoms 2 weeks after discontinuation of the suspected drug
3.Fever (>38°C)
4.Liver abnormalities or other organ involvement
5.Leukocyte abnormalities (at least one of the following)
a. Leukocytosis (>11,000/mm3)
b. Atypical lymphocytosis (>5%)
c. Eosinophilia (>1,500/mm3)
6. Lymphadenopathy
7. HHV-6 reactivation
Seven criteria needed for diagnosis of DIHS or the first five criteria required for diagnosis of atypical DIHS.
Figure 2. Clinical course.
Discussion
Outside Japan, DIHS is referred to as drug rash with eosinophilia and systemic symptoms (DRESS) (4). In 1998, Suzuki et al. and Tohyama et al. reported that anti-HHV-6 IgG levels become high 3 to 4 weeks after onset (5,6). The drugs causing DIHS trigger a marked decline in IgG, B cells, and natural killer (NK) cells, and the resulting immunosuppression has been reported to lead to HHV-6 reactivation of the organs in the early stages, followed by the reactivation of HHV-6 in the blood (2). However, the clinical pathology of DIHS is not yet fully understood. DIHS caused by Nivolumab and similar drugs, and the involvement of regulatory T-cells have also been reported (4,7). Furthermore, it has been reported that HHV-7, Epstein-Barr virus (EBV), and cytomegalovirus (CMV) reactivation can also cause DIHS (8). One report indicated between 40% and 70% of cases exhibit all four characteristics of DIHS, namely lymph node enlargement, atypical lymphocytes, eosinophilia, and viral reactivation, and that DIHS cannot be ruled out regardless of elevated HHV-6 IgG (9). In this present case, a definitive diagnosis was made since all the diagnostic criteria for DIHS were satisfied (3). Treatment requires systemic steroid administration to suppress hypersensitivity syndrome accompanying HHV-6 reactivation. The use of immunosuppressants like cyclosporine or gamma globulin preparations can also be considered (10). In this case, DIHS treatment was started with PSL 0.5 mg/kg/day, after which an improvement was observed. Subsequently, the steroid dose was gradually decreased. Unlike general drug rashes, a drug-induced lymphocyte stimulation test (DLST) results at 1 month after DIHS onset have been reported. However, we could not perform DLST because the rash had deteriorated after the PSL dose was reduced to 5 mg. CMV and EBV reactivation had been considered after blood test in this case. On day27, CMV-IgG was elevated to 37.7, however there was no increase seen for CMV-IgM. EBV nuclear antigen and EBV capsid antigen increased to 2.7 and 5.9, respectively. No increase was reported for EBV capsid antigen. On day 49, there was an increase of CMV-IgG to 34.8, but no increased IgM. We considered two reasons why afatinib caused DIHS. First is the time between administration of the drug causing DIHS and onset is thought to be around 2 to 8 weeks, which is clearly longer than the 5 to 14 days seen with other drug rashes. In this case, the rash appeared on Day 26 after afatinib administration. The timing of DIHS onset matches the clinical course for afatinib. In DIHS, fever and eruption do not always occur at the same time. Fever preceded erythema in this case. Second, typical eruptions caused by afatinib are different to erythema in this case. Common skin disorders caused by afatinib are acne (89%), perionychia (61%), dry skin (29%), and latching (18%) (11). On the other hand, blepharedema and erythema are uncommon. The blepharedema and erythema seen in this case are typical but severe drug eruptions. The frequency of skin rashes and flare-ups have been reported during DIHS treatment and occurred twice during the clinical course in our case. Therefore, we believe that this may be the DIHS case caused by afatinib. Anticonvulsants are well-known to cause DIHS. There have also been reports of DIHS caused by the multi-kinase inhibitor sorafenib and the BRAF inhibitor vemurafenib (12,13). As DIHS can be triggered by drugs used in the field of oncology, doctors should therefore include DIHS in the differential diagnosis and and select appropriate treatments when serious drug rashes occur.
The authors state that they have no Conflict of Interest (COI). | 40 mg (milligrams). | DrugDosage | CC BY-NC-ND | 33518612 | 18,875,893 | 2021 |
What was the outcome of reaction 'Blood lactate dehydrogenase increased'? | Drug-induced Hypersensitivity Syndrome by EGFR-TKI in a Patient with Lung Cancer.
An 83-years-old woman diagnosed with advanced Epidermal growth factor receptor (EGFR)-mutant lung adenocarcinoma was administered afatinib as a first-line treatment. On Day 17, the patient presented with grade 3 diarrhea and a blood test analysis showed an increased inflammatory response. Afatinib treatment was discontinued on the same day. On Day 26, the patient displayed blepharedema and multiple irregular erythema covering her entire body. Drug-induced hypersensitivity syndrome (DIHS) was suspected, and the systemic administration of 30 mg/day prednisolone was administered. The symptoms subsided thereafter. A blood test analysis 3 weeks after onset revealed a reactivation of Human herpesvirus 6 (HHV-6) and a diagnosis of DIHS due to afatinib therapy was confirmed.
Introduction
Drug-induced hypersensitivity syndrome (DIHS) is a severe drug allergy characterized by fever and a delayed severe rash that can result in multiple organ dysfunction. One main characteristic is the reactivation of human herpesvirus 6 (HHV-6) 10 to 30 days after onset, and in many cases, fever and hepatic impairment are observed with the viral reactivation (1). The drugs known to cause DIHS include; anticonvulsants carbamazepine, phenytoin, phenobarbital, and zonisamide, while occasional cases of antibacterial minocycline have been reported (2). We herein report a case of DIHS in a patient treated with epidermal growth factor receptor-tyrosine kinase inhibitor (EGFR-TKI) afatinib for EGFR-mutant pulmonary adenocarcinoma. This is a first DIHS case report caused by afatinib.
Case Report
An 83-year-old woman with a performance status 1, and a history of hypertension and hyperlipidemia had previously been treated with nifedipine and pitavastatin calcium. The patient had no smoking history or any known allergies. She was referred to our institution for consultation after presenting with a cough. Lung cancer in the lower left lung field was suspected from routine chest radiography. Computed tomography (CT)-guided biopsy, positron emission tomography (PET)-CT, and magnetic resonance imaging (MRI) were performed, revealing adenocarcinoma with multiple metastases at both lungs and for the liver and brain. She was diagnosed with primary pulmonary adenocarcinoma Stage IVB, harbouring an EGFR mutation (exon 19 deletion).
First-line treatment with 40 mg/day afatinib was initiated. On Day 17, the patient had grade 3 diarrhea and a grade 2 fever. Blood test findings showed no elevation of white blood cells (WBC) or eosinophils. However, grade 1 elevation of liver enzymes/lactate dehydrogenase (LDH), and high C-reactive protein (CRP) was seen [WBC 4,600/μL (Seg/Neutro 52%, Lympho 13.5%, Mono 5.5%, Eosino 6.5%, Atypical-lympho 0.5%), Aspartate aminotransferase (AST) 53 IU/L, Alanine aminotransferase (ALT) 45 IU/L, Alkaline phosphatase (ALP) 364 IU/L, LDH 259 IU/L, γ-glutamy transferase 49 IU/L, CRP 6.62 ng/mL]. A physical examination did not suggest infection, and influenza antigen was negative. Afatinib treatment was discontinued due to treatment-emergent adverse events. The oral administration of loperamide for diarrhea was initiated and the fever was followed-up. On Day 19, the WBC count remained stable, but the eosinophil counts had risen 10%. From Day 23, the results were higher, with grade 2 elevation of biliary enzymes, elevated eosinophils, and the emergence of atypical lymphocytes [WBC 10,400/μL (Seg/Neutro 47%, Lympho 20.0%, Mono 9.5%, Eosino 14.5%, Atypical-lympho 6.5%), AST 74 IU/L, ALT 60 IU/L, ALP 1,005 IU/L]. On Day 26, the patient displayed blepharedema and an exacerbation of multiple irregular erythema covering her entire body (Fig. 1). Due to this severe drug rash, DIHS due to afatinib was suspected. Since the rash worsened with the use of topical steroids, treatment with 30 mg/day prednisolone (PSL) (0.5 mg/kg) was initiated on Day 26 without performing a skin biopsy. After starting PSL, her erythema appeared to subside, and improvements in both liver function and fever were observed. Subsequently, the PSL dosage was gradually reduced. On Day 41, we tested for HHV-DNA, and the patient was discharged on Day 44. We strongly suspected DIHS since the patient experienced rapidly spreading erythema, a delay of at least 2 weeks after withdrawal of the causative drug, a fever of at least 38°C, abnormal liver function, an increase in atypical lymphocytes and eosinophil, and enlarged lymph nodes. HHV-DNA was found to be 250 times the reference level, and HHV-IgG measured at the same time was 640 times the reference. Moreover, paired sera measured approximately 3 weeks later was 640 times the reference. These points made it possible to make a definitive diagnosis of DIHS (Table) (3). The clinical course is shown in Fig. 2.
Figure 1. Blepharedema and erythema.
Table. Japanese Consensus Group Diagnostic Criteria for Drug-induced Hypersensitivity Syndrome (DIHS).
Main findings
1.Maculopapular rash develops 2~3 weeks after start of therapy with a limited number of drugs
2.Prolonged clinical symptoms 2 weeks after discontinuation of the suspected drug
3.Fever (>38°C)
4.Liver abnormalities or other organ involvement
5.Leukocyte abnormalities (at least one of the following)
a. Leukocytosis (>11,000/mm3)
b. Atypical lymphocytosis (>5%)
c. Eosinophilia (>1,500/mm3)
6. Lymphadenopathy
7. HHV-6 reactivation
Seven criteria needed for diagnosis of DIHS or the first five criteria required for diagnosis of atypical DIHS.
Figure 2. Clinical course.
Discussion
Outside Japan, DIHS is referred to as drug rash with eosinophilia and systemic symptoms (DRESS) (4). In 1998, Suzuki et al. and Tohyama et al. reported that anti-HHV-6 IgG levels become high 3 to 4 weeks after onset (5,6). The drugs causing DIHS trigger a marked decline in IgG, B cells, and natural killer (NK) cells, and the resulting immunosuppression has been reported to lead to HHV-6 reactivation of the organs in the early stages, followed by the reactivation of HHV-6 in the blood (2). However, the clinical pathology of DIHS is not yet fully understood. DIHS caused by Nivolumab and similar drugs, and the involvement of regulatory T-cells have also been reported (4,7). Furthermore, it has been reported that HHV-7, Epstein-Barr virus (EBV), and cytomegalovirus (CMV) reactivation can also cause DIHS (8). One report indicated between 40% and 70% of cases exhibit all four characteristics of DIHS, namely lymph node enlargement, atypical lymphocytes, eosinophilia, and viral reactivation, and that DIHS cannot be ruled out regardless of elevated HHV-6 IgG (9). In this present case, a definitive diagnosis was made since all the diagnostic criteria for DIHS were satisfied (3). Treatment requires systemic steroid administration to suppress hypersensitivity syndrome accompanying HHV-6 reactivation. The use of immunosuppressants like cyclosporine or gamma globulin preparations can also be considered (10). In this case, DIHS treatment was started with PSL 0.5 mg/kg/day, after which an improvement was observed. Subsequently, the steroid dose was gradually decreased. Unlike general drug rashes, a drug-induced lymphocyte stimulation test (DLST) results at 1 month after DIHS onset have been reported. However, we could not perform DLST because the rash had deteriorated after the PSL dose was reduced to 5 mg. CMV and EBV reactivation had been considered after blood test in this case. On day27, CMV-IgG was elevated to 37.7, however there was no increase seen for CMV-IgM. EBV nuclear antigen and EBV capsid antigen increased to 2.7 and 5.9, respectively. No increase was reported for EBV capsid antigen. On day 49, there was an increase of CMV-IgG to 34.8, but no increased IgM. We considered two reasons why afatinib caused DIHS. First is the time between administration of the drug causing DIHS and onset is thought to be around 2 to 8 weeks, which is clearly longer than the 5 to 14 days seen with other drug rashes. In this case, the rash appeared on Day 26 after afatinib administration. The timing of DIHS onset matches the clinical course for afatinib. In DIHS, fever and eruption do not always occur at the same time. Fever preceded erythema in this case. Second, typical eruptions caused by afatinib are different to erythema in this case. Common skin disorders caused by afatinib are acne (89%), perionychia (61%), dry skin (29%), and latching (18%) (11). On the other hand, blepharedema and erythema are uncommon. The blepharedema and erythema seen in this case are typical but severe drug eruptions. The frequency of skin rashes and flare-ups have been reported during DIHS treatment and occurred twice during the clinical course in our case. Therefore, we believe that this may be the DIHS case caused by afatinib. Anticonvulsants are well-known to cause DIHS. There have also been reports of DIHS caused by the multi-kinase inhibitor sorafenib and the BRAF inhibitor vemurafenib (12,13). As DIHS can be triggered by drugs used in the field of oncology, doctors should therefore include DIHS in the differential diagnosis and and select appropriate treatments when serious drug rashes occur.
The authors state that they have no Conflict of Interest (COI). | Recovering | ReactionOutcome | CC BY-NC-ND | 33518612 | 18,875,893 | 2021 |
What was the outcome of reaction 'Drug reaction with eosinophilia and systemic symptoms'? | Drug-induced Hypersensitivity Syndrome by EGFR-TKI in a Patient with Lung Cancer.
An 83-years-old woman diagnosed with advanced Epidermal growth factor receptor (EGFR)-mutant lung adenocarcinoma was administered afatinib as a first-line treatment. On Day 17, the patient presented with grade 3 diarrhea and a blood test analysis showed an increased inflammatory response. Afatinib treatment was discontinued on the same day. On Day 26, the patient displayed blepharedema and multiple irregular erythema covering her entire body. Drug-induced hypersensitivity syndrome (DIHS) was suspected, and the systemic administration of 30 mg/day prednisolone was administered. The symptoms subsided thereafter. A blood test analysis 3 weeks after onset revealed a reactivation of Human herpesvirus 6 (HHV-6) and a diagnosis of DIHS due to afatinib therapy was confirmed.
Introduction
Drug-induced hypersensitivity syndrome (DIHS) is a severe drug allergy characterized by fever and a delayed severe rash that can result in multiple organ dysfunction. One main characteristic is the reactivation of human herpesvirus 6 (HHV-6) 10 to 30 days after onset, and in many cases, fever and hepatic impairment are observed with the viral reactivation (1). The drugs known to cause DIHS include; anticonvulsants carbamazepine, phenytoin, phenobarbital, and zonisamide, while occasional cases of antibacterial minocycline have been reported (2). We herein report a case of DIHS in a patient treated with epidermal growth factor receptor-tyrosine kinase inhibitor (EGFR-TKI) afatinib for EGFR-mutant pulmonary adenocarcinoma. This is a first DIHS case report caused by afatinib.
Case Report
An 83-year-old woman with a performance status 1, and a history of hypertension and hyperlipidemia had previously been treated with nifedipine and pitavastatin calcium. The patient had no smoking history or any known allergies. She was referred to our institution for consultation after presenting with a cough. Lung cancer in the lower left lung field was suspected from routine chest radiography. Computed tomography (CT)-guided biopsy, positron emission tomography (PET)-CT, and magnetic resonance imaging (MRI) were performed, revealing adenocarcinoma with multiple metastases at both lungs and for the liver and brain. She was diagnosed with primary pulmonary adenocarcinoma Stage IVB, harbouring an EGFR mutation (exon 19 deletion).
First-line treatment with 40 mg/day afatinib was initiated. On Day 17, the patient had grade 3 diarrhea and a grade 2 fever. Blood test findings showed no elevation of white blood cells (WBC) or eosinophils. However, grade 1 elevation of liver enzymes/lactate dehydrogenase (LDH), and high C-reactive protein (CRP) was seen [WBC 4,600/μL (Seg/Neutro 52%, Lympho 13.5%, Mono 5.5%, Eosino 6.5%, Atypical-lympho 0.5%), Aspartate aminotransferase (AST) 53 IU/L, Alanine aminotransferase (ALT) 45 IU/L, Alkaline phosphatase (ALP) 364 IU/L, LDH 259 IU/L, γ-glutamy transferase 49 IU/L, CRP 6.62 ng/mL]. A physical examination did not suggest infection, and influenza antigen was negative. Afatinib treatment was discontinued due to treatment-emergent adverse events. The oral administration of loperamide for diarrhea was initiated and the fever was followed-up. On Day 19, the WBC count remained stable, but the eosinophil counts had risen 10%. From Day 23, the results were higher, with grade 2 elevation of biliary enzymes, elevated eosinophils, and the emergence of atypical lymphocytes [WBC 10,400/μL (Seg/Neutro 47%, Lympho 20.0%, Mono 9.5%, Eosino 14.5%, Atypical-lympho 6.5%), AST 74 IU/L, ALT 60 IU/L, ALP 1,005 IU/L]. On Day 26, the patient displayed blepharedema and an exacerbation of multiple irregular erythema covering her entire body (Fig. 1). Due to this severe drug rash, DIHS due to afatinib was suspected. Since the rash worsened with the use of topical steroids, treatment with 30 mg/day prednisolone (PSL) (0.5 mg/kg) was initiated on Day 26 without performing a skin biopsy. After starting PSL, her erythema appeared to subside, and improvements in both liver function and fever were observed. Subsequently, the PSL dosage was gradually reduced. On Day 41, we tested for HHV-DNA, and the patient was discharged on Day 44. We strongly suspected DIHS since the patient experienced rapidly spreading erythema, a delay of at least 2 weeks after withdrawal of the causative drug, a fever of at least 38°C, abnormal liver function, an increase in atypical lymphocytes and eosinophil, and enlarged lymph nodes. HHV-DNA was found to be 250 times the reference level, and HHV-IgG measured at the same time was 640 times the reference. Moreover, paired sera measured approximately 3 weeks later was 640 times the reference. These points made it possible to make a definitive diagnosis of DIHS (Table) (3). The clinical course is shown in Fig. 2.
Figure 1. Blepharedema and erythema.
Table. Japanese Consensus Group Diagnostic Criteria for Drug-induced Hypersensitivity Syndrome (DIHS).
Main findings
1.Maculopapular rash develops 2~3 weeks after start of therapy with a limited number of drugs
2.Prolonged clinical symptoms 2 weeks after discontinuation of the suspected drug
3.Fever (>38°C)
4.Liver abnormalities or other organ involvement
5.Leukocyte abnormalities (at least one of the following)
a. Leukocytosis (>11,000/mm3)
b. Atypical lymphocytosis (>5%)
c. Eosinophilia (>1,500/mm3)
6. Lymphadenopathy
7. HHV-6 reactivation
Seven criteria needed for diagnosis of DIHS or the first five criteria required for diagnosis of atypical DIHS.
Figure 2. Clinical course.
Discussion
Outside Japan, DIHS is referred to as drug rash with eosinophilia and systemic symptoms (DRESS) (4). In 1998, Suzuki et al. and Tohyama et al. reported that anti-HHV-6 IgG levels become high 3 to 4 weeks after onset (5,6). The drugs causing DIHS trigger a marked decline in IgG, B cells, and natural killer (NK) cells, and the resulting immunosuppression has been reported to lead to HHV-6 reactivation of the organs in the early stages, followed by the reactivation of HHV-6 in the blood (2). However, the clinical pathology of DIHS is not yet fully understood. DIHS caused by Nivolumab and similar drugs, and the involvement of regulatory T-cells have also been reported (4,7). Furthermore, it has been reported that HHV-7, Epstein-Barr virus (EBV), and cytomegalovirus (CMV) reactivation can also cause DIHS (8). One report indicated between 40% and 70% of cases exhibit all four characteristics of DIHS, namely lymph node enlargement, atypical lymphocytes, eosinophilia, and viral reactivation, and that DIHS cannot be ruled out regardless of elevated HHV-6 IgG (9). In this present case, a definitive diagnosis was made since all the diagnostic criteria for DIHS were satisfied (3). Treatment requires systemic steroid administration to suppress hypersensitivity syndrome accompanying HHV-6 reactivation. The use of immunosuppressants like cyclosporine or gamma globulin preparations can also be considered (10). In this case, DIHS treatment was started with PSL 0.5 mg/kg/day, after which an improvement was observed. Subsequently, the steroid dose was gradually decreased. Unlike general drug rashes, a drug-induced lymphocyte stimulation test (DLST) results at 1 month after DIHS onset have been reported. However, we could not perform DLST because the rash had deteriorated after the PSL dose was reduced to 5 mg. CMV and EBV reactivation had been considered after blood test in this case. On day27, CMV-IgG was elevated to 37.7, however there was no increase seen for CMV-IgM. EBV nuclear antigen and EBV capsid antigen increased to 2.7 and 5.9, respectively. No increase was reported for EBV capsid antigen. On day 49, there was an increase of CMV-IgG to 34.8, but no increased IgM. We considered two reasons why afatinib caused DIHS. First is the time between administration of the drug causing DIHS and onset is thought to be around 2 to 8 weeks, which is clearly longer than the 5 to 14 days seen with other drug rashes. In this case, the rash appeared on Day 26 after afatinib administration. The timing of DIHS onset matches the clinical course for afatinib. In DIHS, fever and eruption do not always occur at the same time. Fever preceded erythema in this case. Second, typical eruptions caused by afatinib are different to erythema in this case. Common skin disorders caused by afatinib are acne (89%), perionychia (61%), dry skin (29%), and latching (18%) (11). On the other hand, blepharedema and erythema are uncommon. The blepharedema and erythema seen in this case are typical but severe drug eruptions. The frequency of skin rashes and flare-ups have been reported during DIHS treatment and occurred twice during the clinical course in our case. Therefore, we believe that this may be the DIHS case caused by afatinib. Anticonvulsants are well-known to cause DIHS. There have also been reports of DIHS caused by the multi-kinase inhibitor sorafenib and the BRAF inhibitor vemurafenib (12,13). As DIHS can be triggered by drugs used in the field of oncology, doctors should therefore include DIHS in the differential diagnosis and and select appropriate treatments when serious drug rashes occur.
The authors state that they have no Conflict of Interest (COI). | Recovering | ReactionOutcome | CC BY-NC-ND | 33518612 | 18,875,893 | 2021 |
What was the outcome of reaction 'Pyrexia'? | Drug-induced Hypersensitivity Syndrome by EGFR-TKI in a Patient with Lung Cancer.
An 83-years-old woman diagnosed with advanced Epidermal growth factor receptor (EGFR)-mutant lung adenocarcinoma was administered afatinib as a first-line treatment. On Day 17, the patient presented with grade 3 diarrhea and a blood test analysis showed an increased inflammatory response. Afatinib treatment was discontinued on the same day. On Day 26, the patient displayed blepharedema and multiple irregular erythema covering her entire body. Drug-induced hypersensitivity syndrome (DIHS) was suspected, and the systemic administration of 30 mg/day prednisolone was administered. The symptoms subsided thereafter. A blood test analysis 3 weeks after onset revealed a reactivation of Human herpesvirus 6 (HHV-6) and a diagnosis of DIHS due to afatinib therapy was confirmed.
Introduction
Drug-induced hypersensitivity syndrome (DIHS) is a severe drug allergy characterized by fever and a delayed severe rash that can result in multiple organ dysfunction. One main characteristic is the reactivation of human herpesvirus 6 (HHV-6) 10 to 30 days after onset, and in many cases, fever and hepatic impairment are observed with the viral reactivation (1). The drugs known to cause DIHS include; anticonvulsants carbamazepine, phenytoin, phenobarbital, and zonisamide, while occasional cases of antibacterial minocycline have been reported (2). We herein report a case of DIHS in a patient treated with epidermal growth factor receptor-tyrosine kinase inhibitor (EGFR-TKI) afatinib for EGFR-mutant pulmonary adenocarcinoma. This is a first DIHS case report caused by afatinib.
Case Report
An 83-year-old woman with a performance status 1, and a history of hypertension and hyperlipidemia had previously been treated with nifedipine and pitavastatin calcium. The patient had no smoking history or any known allergies. She was referred to our institution for consultation after presenting with a cough. Lung cancer in the lower left lung field was suspected from routine chest radiography. Computed tomography (CT)-guided biopsy, positron emission tomography (PET)-CT, and magnetic resonance imaging (MRI) were performed, revealing adenocarcinoma with multiple metastases at both lungs and for the liver and brain. She was diagnosed with primary pulmonary adenocarcinoma Stage IVB, harbouring an EGFR mutation (exon 19 deletion).
First-line treatment with 40 mg/day afatinib was initiated. On Day 17, the patient had grade 3 diarrhea and a grade 2 fever. Blood test findings showed no elevation of white blood cells (WBC) or eosinophils. However, grade 1 elevation of liver enzymes/lactate dehydrogenase (LDH), and high C-reactive protein (CRP) was seen [WBC 4,600/μL (Seg/Neutro 52%, Lympho 13.5%, Mono 5.5%, Eosino 6.5%, Atypical-lympho 0.5%), Aspartate aminotransferase (AST) 53 IU/L, Alanine aminotransferase (ALT) 45 IU/L, Alkaline phosphatase (ALP) 364 IU/L, LDH 259 IU/L, γ-glutamy transferase 49 IU/L, CRP 6.62 ng/mL]. A physical examination did not suggest infection, and influenza antigen was negative. Afatinib treatment was discontinued due to treatment-emergent adverse events. The oral administration of loperamide for diarrhea was initiated and the fever was followed-up. On Day 19, the WBC count remained stable, but the eosinophil counts had risen 10%. From Day 23, the results were higher, with grade 2 elevation of biliary enzymes, elevated eosinophils, and the emergence of atypical lymphocytes [WBC 10,400/μL (Seg/Neutro 47%, Lympho 20.0%, Mono 9.5%, Eosino 14.5%, Atypical-lympho 6.5%), AST 74 IU/L, ALT 60 IU/L, ALP 1,005 IU/L]. On Day 26, the patient displayed blepharedema and an exacerbation of multiple irregular erythema covering her entire body (Fig. 1). Due to this severe drug rash, DIHS due to afatinib was suspected. Since the rash worsened with the use of topical steroids, treatment with 30 mg/day prednisolone (PSL) (0.5 mg/kg) was initiated on Day 26 without performing a skin biopsy. After starting PSL, her erythema appeared to subside, and improvements in both liver function and fever were observed. Subsequently, the PSL dosage was gradually reduced. On Day 41, we tested for HHV-DNA, and the patient was discharged on Day 44. We strongly suspected DIHS since the patient experienced rapidly spreading erythema, a delay of at least 2 weeks after withdrawal of the causative drug, a fever of at least 38°C, abnormal liver function, an increase in atypical lymphocytes and eosinophil, and enlarged lymph nodes. HHV-DNA was found to be 250 times the reference level, and HHV-IgG measured at the same time was 640 times the reference. Moreover, paired sera measured approximately 3 weeks later was 640 times the reference. These points made it possible to make a definitive diagnosis of DIHS (Table) (3). The clinical course is shown in Fig. 2.
Figure 1. Blepharedema and erythema.
Table. Japanese Consensus Group Diagnostic Criteria for Drug-induced Hypersensitivity Syndrome (DIHS).
Main findings
1.Maculopapular rash develops 2~3 weeks after start of therapy with a limited number of drugs
2.Prolonged clinical symptoms 2 weeks after discontinuation of the suspected drug
3.Fever (>38°C)
4.Liver abnormalities or other organ involvement
5.Leukocyte abnormalities (at least one of the following)
a. Leukocytosis (>11,000/mm3)
b. Atypical lymphocytosis (>5%)
c. Eosinophilia (>1,500/mm3)
6. Lymphadenopathy
7. HHV-6 reactivation
Seven criteria needed for diagnosis of DIHS or the first five criteria required for diagnosis of atypical DIHS.
Figure 2. Clinical course.
Discussion
Outside Japan, DIHS is referred to as drug rash with eosinophilia and systemic symptoms (DRESS) (4). In 1998, Suzuki et al. and Tohyama et al. reported that anti-HHV-6 IgG levels become high 3 to 4 weeks after onset (5,6). The drugs causing DIHS trigger a marked decline in IgG, B cells, and natural killer (NK) cells, and the resulting immunosuppression has been reported to lead to HHV-6 reactivation of the organs in the early stages, followed by the reactivation of HHV-6 in the blood (2). However, the clinical pathology of DIHS is not yet fully understood. DIHS caused by Nivolumab and similar drugs, and the involvement of regulatory T-cells have also been reported (4,7). Furthermore, it has been reported that HHV-7, Epstein-Barr virus (EBV), and cytomegalovirus (CMV) reactivation can also cause DIHS (8). One report indicated between 40% and 70% of cases exhibit all four characteristics of DIHS, namely lymph node enlargement, atypical lymphocytes, eosinophilia, and viral reactivation, and that DIHS cannot be ruled out regardless of elevated HHV-6 IgG (9). In this present case, a definitive diagnosis was made since all the diagnostic criteria for DIHS were satisfied (3). Treatment requires systemic steroid administration to suppress hypersensitivity syndrome accompanying HHV-6 reactivation. The use of immunosuppressants like cyclosporine or gamma globulin preparations can also be considered (10). In this case, DIHS treatment was started with PSL 0.5 mg/kg/day, after which an improvement was observed. Subsequently, the steroid dose was gradually decreased. Unlike general drug rashes, a drug-induced lymphocyte stimulation test (DLST) results at 1 month after DIHS onset have been reported. However, we could not perform DLST because the rash had deteriorated after the PSL dose was reduced to 5 mg. CMV and EBV reactivation had been considered after blood test in this case. On day27, CMV-IgG was elevated to 37.7, however there was no increase seen for CMV-IgM. EBV nuclear antigen and EBV capsid antigen increased to 2.7 and 5.9, respectively. No increase was reported for EBV capsid antigen. On day 49, there was an increase of CMV-IgG to 34.8, but no increased IgM. We considered two reasons why afatinib caused DIHS. First is the time between administration of the drug causing DIHS and onset is thought to be around 2 to 8 weeks, which is clearly longer than the 5 to 14 days seen with other drug rashes. In this case, the rash appeared on Day 26 after afatinib administration. The timing of DIHS onset matches the clinical course for afatinib. In DIHS, fever and eruption do not always occur at the same time. Fever preceded erythema in this case. Second, typical eruptions caused by afatinib are different to erythema in this case. Common skin disorders caused by afatinib are acne (89%), perionychia (61%), dry skin (29%), and latching (18%) (11). On the other hand, blepharedema and erythema are uncommon. The blepharedema and erythema seen in this case are typical but severe drug eruptions. The frequency of skin rashes and flare-ups have been reported during DIHS treatment and occurred twice during the clinical course in our case. Therefore, we believe that this may be the DIHS case caused by afatinib. Anticonvulsants are well-known to cause DIHS. There have also been reports of DIHS caused by the multi-kinase inhibitor sorafenib and the BRAF inhibitor vemurafenib (12,13). As DIHS can be triggered by drugs used in the field of oncology, doctors should therefore include DIHS in the differential diagnosis and and select appropriate treatments when serious drug rashes occur.
The authors state that they have no Conflict of Interest (COI). | Recovering | ReactionOutcome | CC BY-NC-ND | 33518612 | 18,875,893 | 2021 |
Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Drug ineffective'. | Multiple Myeloma with Central Nervous System Relapse Early after Autologous Stem Cell Transplantation: A Case Report and Literature Review.
Few reports have so far described central nervous system (CNS) involvement in multiple myeloma (MM), which shows a poor prognosis owing to its resistance to several treatments. We herein describe a 45-year-old woman who had MM (diagnosed with IgA-κ type) with CNS relapse early after undergoing autologous hematopoietic stem cell transplantation. Because no standard treatment for CNS lesions of MM has been established, we conducted a literature review on the cerebrospinal fluid (CSF) transferability of drugs for MM, since it was considered to be a useful tool for CNS involvement. Immunomodulatory-drugs including pomalidomide exhibit a good CSF transfer ability, and, therefore, may be beneficial against the CNS involvement of MM.
Introduction
Previous studies have shown that the multiple myeloma (MM) genome is complex, and that MM patients have extremely diverse cytogenetic abnormalities with genomic heterogeneity (1). Thus, MM demonstrates a highly variable clinical course. Few reports have so far described neurologic complications arising from direct MM cell involvement in the central nervous system (CNS) (2-6). We herein present a case of an MM patient with an early relapse localized in the CNS early after autologous hematopoietic stem cell transplantation (ASCT). Because no standard treatment for CNS lesions of MM has yet been established (5,7) due to a lack of evidence, we conducted a literature review on the cerebrospinal fluid (CSF) transferablity of drugs for MM. The current case demonstrates that such a presentation of MM can be successfully treated with pomalidomide-dexamethasone (Pd) therapy together with whole-brain and craniospinal irradiation and intrathecal chemotherapy.
Case Report
A 45-year-old woman with M-proteinemia, anemia, and hypercalcemia was referred to our hospital. The patient had initially noticed general pain and consulted her physician. Other than her performance status being affected by general pain, the general and neurologic examination was unremarkable. A blood examination showed anemia, hypercalcemia, and elevated lactate dehydrogenase (LDH), and IgA-κ type M protein was detected by serum protein immunoelectrophoresis (Table 1). Bone marrow (BM) specimens revealed 25.7% of atypical plasma cells with the expression of CD38, CD56, and CD138, but no expression of CD19, CD20, MPC-1, CD45, or CD49e, which was compatible with a diagnosis of MM. Chromosome and fluorescence in situ hybridization cytogenic examinations of the BM showed complicated karyotypes, 72% IgH/FGFR3 fusion and 72% deletion 13q signal-positive cells, but no deletion of either 17p or IgH/MAF fusion. Diffusion-weighted whole-body imaging with background body signal suppression (DWIBS) detected diffuse abnormal signals in BM including in many vertebrae. From these findings, MM was diagnosed according to the Revised-International Staging System III (8).
Table 1. Hematologic Assessment of Patient.
WBC 6,400 /μL BUN 19 mg/dL LDH 561 U/L <Urine>
Neutro 67.0 % Cre 0.62 mg/dL CK 23 U/L gravity 1.010
Baso 0.0 % Na 142 mEq/L CRP 4.753 mg/dL WBC (-)
Eosino 0.5 % K 4.1 mEq/L urobilinogen normal
Lympho 14.0 % Cl 97 mEq/L APTT 33.7 s Uric protein (-)
Mono 9.5 % UA 5.1 mg/dL PT-INR 1.16 pH 5.5
Blast 1.0 % Ca 11.3 mg/dL IgG 245 mg/dL Uric blood (+/-)
Pro-myelo 0.0 % Tp 8.4 mg/dL IgA 2,381 mg/dL ketone (+/-)
Myelo 6.5 % ALB 3.6 g/dL IgM 31 mg/dL bilirubin (+/-)
Meta-myelo 1.5 % AST 31 U/L β2-MG 7.1 mg/L glucose (+/-)
RBC 295×104 /μL ALT 9 U/L IEP IgA-κ Bence Jones protein (+)
Hb 8.5 g/dL ChE 237 U/L FLC κ/λ 31.06
Hct 27.1 % T-Bil 0.6 mg/dL κ chain 61.5 mg/mL
Reticulo 0.4 % ALP 215 U/L λ chain 1.98 mg/mL
PLT 16.2×104 /μL γGTP 20 U/L
IEP: immunoelectrophoresis, FLC: free light chain, PT-INR: prothrombin time-international normalized ratio
Treatment with bortezomib-dexamethasone (Bd) therapy (1.3 mg/m2 bortezomib twice a week and 40 mg dexamethasone per week) was started, but it proved to be ineffective. The addition of lenalidomide administration [25 mg/day (on days 1-21)] with Bd transiently decreased the IgA levels. However, 1 week after the addition of lenalidomide, the right femoral diaphysis became fractured, and surgery was thus performed. After surgery, carfilzomib-lenalidomide-dexamethasone (CLd) therapy [with at a dose and schedule according to the ASPIRE protocol (9)] was started. After three courses of CLd therapy, a stringent complete response (sCR) was achieved. High-dose melphalan (200 mg/m2) therapy with ASCT was performed at 9 months after the initial diagnosis, and then the patient maintained an sCR after ASCT, which was confirmed by a BM biopsy and DWIBS. Lenalidomide maintenance therapy (10 mg orally) was then started. Approximately 2 months after ASCT, severe headache, nausea, and vomiting suddenly appeared, and the patient was hospitalized. A CSF examination revealed a marked increase in the total cell count (441/μL), completely consisting of abnormal plasma cells (Fig. 1A), and increased total protein (61 mg/dL) and decreased sugar levels (26 mg/dL). An examination of the plasma cell clonality of the CSF showed expression of CD38, CD56, and CD138 but not CD19, CD20, MPC-1, CD45 or CD49e (Fig. 1B), which was the same result found for the MM cells in BM at diagnosis. Bacterial culture, a tuberculosis PCR test, and viral gene PCR tests including herpes virus were all negative. Although no lesions could be detected by head computed tomography, magnetic resonance imaging (MRI) revealed patchy hyperintense regions on T2-weighted images (Fig. 2). These findings were indicative of MM involvement in the CNS. Blood examinations showed no anemia, renal dysfunction, or hypercalcemia. M-protein was not detected by serum protein immunoelectrophoresis. No abnormal increase in the plasma cells was observed, and no cells with IgH/FGFR3 fusion or a deletion of 13q signals were detected in BM specimens. No systemic lesions were detected on DWIBS. These findings indicate that the relapse was localized to the CNS.
Figure 1. Cerebrospinal fluid specimens showing a marked increase in the total cell count (441/μL), completely consisting of abnormal plasma cells. A: May-Giemsa staining ×400 and ×20 original magnification. B: A flow cytometric analysis of CD38-positive CSF cells. CSF: cerebrospinal fluid, SSC: side scatter
Figure 2. Magnetic resonance imaging showing patchy hyperintense on T2-weighted images.
Dexamethasone monotherapy was started, and the intrathecal injection of methotrexate (15 mg), cytarabine (40 mg), and dexamethasone (4 mg) was performed twice a week, four times in total. Thereafter, Pd therapy with 3 mg pomalidomide and 40 mg dexamethasone [performed on a schedule according to the MM-003 protocol (10)] with whole-brain/craniospinal irradiation (27 Gy/15 fr) was started. The number of myeloma cells in the CSF rapidly decreased, and the cells were observed to have disappeared at the end of irradiation. However, Pd therapy was transiently discontinued 10 days later because of myelosuppression and then was again resumed and continued after the completion of whole-brain/spinal irradiation. Thereafter, no further relapse was observed (Fig. 3).
Figure 3. Clinical course from the onset of central nervous system relapse. End of July (day1; day of hospitalization) (approximately 2 months after autologous stem cell transplantation), the patient experienced severe headache, nausea, and vomiting, and then dexamethasone monotherapy and intrathecal injection of methotrexate, cytarabine, and dexamethasone were started. Pomalidomide-dexamethasone (Pd) therapy and whole-brain/craniospinal irradiation were started on Day9 and Day17, respectively. Pd therapy was transiently discontinued because of myelosuppression and resumed on Day46. CSF: cerebrospinal fluid, LEN: lenalidomide, POM: pomalidomide, DEX dexamethasone, Pd: pomalidomide-dexamethasone, n.d.: not detected
Three months later, DWIBS revealed a mass lesion around the right kidney, which was indicative of extramedullary recurrence, but no relapse of the CNS lesions. Three courses of daratumumab-lenalidomide-dexamethasone therapy [with a dose and schedule according to the POLLUX protocol (11)] were performed, but no reductive effect on the abdominal tumor was observed. Thereafter, conventional chemotherapy [PACE (cisplatin, 10 mg/m2/day; doxorubicin, 10 mg/m2/day; cyclophosphamide, 400 mg/m2/day; and etoposide, 40 mg/m2/day from days 1 to 4)] was temporarily effective, but the tumor recurred, and the patient eventually died 12 months after the onset of CNS relapse (21 months after the diagnosis of MM). After the onset of the abdominal lesion, no relapse of the CNS lesions was observed.
Discussion
In MM, extramedullary lesions emerge in approximately 6-8% of cases at the time of diagnosis and in approximately 10-30% of cases in the advanced or relapse stage (12,13), but the frequency of CNS involvement is only approximately 1% (2-6). The clinical symptoms of CNS involvement in MM are diverse and uncharacteristic, including headache, nausea, vomiting, consciousness disorder, limb weakness, and convulsions (14). Because these symptoms are similar to those of hypercalcemia, uremia, and hyperviscosity syndrome or side effects caused by chemotherapy, a CSF examination to confirm the presence of MM cells in addition to MRI is crucial for making an accurate diagnosis (14). Moreover, the detection of abnormal free light chain in the CSF has great diagnostic significance (15), even if myeloma cells are absent in CSF. MRI may show high-intensity portions of the meninges and formation of solid tumors in the brain.
Although it is difficult to predict the CNS involvement of MM, features of CNS involvement include high-risk chromosomal abnormalities, high LDH levels, high β2 microglobulin levels, extramedullary lesions, and leukemic change (4,5). In particular, a high frequency of chromosomal deletion 17p or deletion 13q has been reported (16,17). The median age at the time of the initial diagnosis of MM patients, who develop CNS involvement during the clinical course, is 54-64 years (2-6), which is relatively younger than the age of onset of MM, as was seen in our case. The early onset of MM may be an important indicator of CNS involvement. Abdallah et al. reported that 42.9% of patients develop CNS involvement during the progression stage of relapsed MM, 48.6% of patients in the stable stage during treatment, and 8.6% of patients in the remission state (14). The average latency period from MM diagnosis to diagnosis of CNS involvement is 15 months, and the latency is 32.1 months in patients with ASCT, which is longer than that in patients without ASCT (8.3 months) (14). Our patient had a younger age, an aggressive disease course with resistance to bortezomib, and high-risk chromosomal abnormalities, thus suggesting a poor prognosis. Indeed, the latent period of between MM diagnosis and onset of CNS relapse was 11 months, which is very short. Furthermore, two months after ASCT, the tumor recurred only in the CNS despite hematologic remission. Thus, if unexplained neurological findings occur at any time during the disease course in patients with risk factors for CNS involvement, then either MRI or a CSF examination should be promptly performed for verification.
Although newly developed therapeutic agents have improved the prognosis of MM, no standard treatment for CNS involvement has yet been established, and the prognosis is very poor, with a median overall survival (OS) of less than 3-6 months (2-6). According to our literature review on CSF transfer of drugs for MM, immunomodulatory drugs (IMiDs) have CSF transferability (Table 2). Cases of successful treatment with thalidomide or lenalidomide have been reported (3,18-20). Thalidomide can be detected in CSF after an oral administration (18,21,22), and lenalidomide can cross the blood-brain barrier (BBB) (19,20,23). In particular, reports have shown that pomalidomide has good CSF transferability (24-26) and activity in extramedullary disease (27). In addition, Chen et al. reported that six of nine long-term survivors (median OS of 17.1 months) with CNS involvement received IMiDs-based therapy combined with intrathecal chemotherapy plus irradiation and/or systemic chemotherapy (28). Intrathecal chemotherapy is often effective against various hematological malignancies and CNS involvement of MM (15). Although a rapid therapeutic effect can be obtained, a long-term therapeutic effect of intrathecal chemotherapy is difficult to maintain. Thus, this therapy should be used as a bridge for subsequent systemic therapy. Moreover, MM cells are highly radiosensitive (29); thus, radiotherapy is also effective for CNS involvement and it is also more effective when combined with chemotherapy (3). In the present case, because of recurrence after CLd and lenalidomide maintenance therapy, pomalidomide was used instead of lenalidomide treatment. Because there was no recurrence in the CNS, combination therapy with pomalidomide, radiotherapy, and intrathecal chemotherapy was considered to be effective in our patient.
Table 2. Data of CSF Transferability and Efficacy of MM Drugs.
Drugs CSF transferability Cases for CNS involvement of MM
IMiDs Thalidomide good18, 23) effective18, 21, 22, 28)
Lenalidomide good19, 23) effective19, 20,28)
Pomalidomide good24) effective25, 26)
Proteasome inhibitors Bortezomib poor30) ineffective30)
Carfilzomib poor* no data
Ixazomib poor* no data
Antibody-drugs Daratumumab good32) effective32, 33, 34)
Isatuximab no data no data
Elotuzumab no data no data
*no experimental data exist.
One case report showed the inefficacy of bortezomib therapy for CNS involvement of MM because of its poor CSF transferability (30). In general, proteasome inhibitors such as carfilzomib and ixazomib have a good ability to permeate throughout the body tissues but cannot penetrate BBB (Table 2); thus, there are no data on the efficacy of carfilzomib and ixazomib for CNS lesions. However, the use of bortezomib has been reported to enhance radiosensitivity and chemosensitivity (31), and studies of CNS lesion treatment with combination therapy including bortezomib should be conducted in the future. To our knowledge, one report examined the CSF transferability of daratumumab (32), and two case reports described significant activity of daratumumab for CNS lesions of MM when concomitantly used with intrathecal chemotherapy (33,34). There are no current data of CSF transferability and the effectiveness of isatuximab and elotuzumab for CNS lesions.
It is possible that the induction of CLd followed by high-dose melphalan chemotherapy of ASCT might have insufficient CNS effects, because proteasome inhibitors carfilzomib has less CNS transferability and alkylating agents such as cyclophosphamide or melphalan can poorly penetrate the CSF (6). We speculated that the initial clones of MM in our case may have escaped into and grown locally in the CNS, where the drugs had not sufficiently penetrated, thus resulting in a local early relapse.
Conclusion
CNS involvement, as seen in our case, is an important consideration for patients with a younger disease onset and risk factors such as chromosomal abnormalities which predict a poor prognosis and high LDH levels. Regardless of hematological remission, when CNS symptoms develop, it is necessary to actively search for CNS lesions by a CSF examination and head MRI. MM patients with CNS lesions have a poor prognosis, but IMiDs such as pomalidomide may be effective because of their CSF transferability; thus, it may be beneficial to administer combination therapies including IMiDs, radiotherapy, and intrathecal chemotherapy against MM with CNS involvement. Crucial data are still sparse regarding treatment, and the accumulation of data from more cases is important to verify the choice of combination drugs for CNS lesions of MM.
Author's disclosure of potential Conflicts of Interest (COI).
Tomoki Ito: Honoraria, Celgene, Bristol-Myers Squibb and Takeda.
Acknowledgement
We thank Lisa Kreiner, PhD, for editing a draft of this manuscript. | DEXAMETHASONE, POMALIDOMIDE | DrugsGivenReaction | CC BY-NC-ND | 33518613 | 19,441,866 | 2021 |
What was the administration route of drug 'CYTARABINE'? | Multiple Myeloma with Central Nervous System Relapse Early after Autologous Stem Cell Transplantation: A Case Report and Literature Review.
Few reports have so far described central nervous system (CNS) involvement in multiple myeloma (MM), which shows a poor prognosis owing to its resistance to several treatments. We herein describe a 45-year-old woman who had MM (diagnosed with IgA-κ type) with CNS relapse early after undergoing autologous hematopoietic stem cell transplantation. Because no standard treatment for CNS lesions of MM has been established, we conducted a literature review on the cerebrospinal fluid (CSF) transferability of drugs for MM, since it was considered to be a useful tool for CNS involvement. Immunomodulatory-drugs including pomalidomide exhibit a good CSF transfer ability, and, therefore, may be beneficial against the CNS involvement of MM.
Introduction
Previous studies have shown that the multiple myeloma (MM) genome is complex, and that MM patients have extremely diverse cytogenetic abnormalities with genomic heterogeneity (1). Thus, MM demonstrates a highly variable clinical course. Few reports have so far described neurologic complications arising from direct MM cell involvement in the central nervous system (CNS) (2-6). We herein present a case of an MM patient with an early relapse localized in the CNS early after autologous hematopoietic stem cell transplantation (ASCT). Because no standard treatment for CNS lesions of MM has yet been established (5,7) due to a lack of evidence, we conducted a literature review on the cerebrospinal fluid (CSF) transferablity of drugs for MM. The current case demonstrates that such a presentation of MM can be successfully treated with pomalidomide-dexamethasone (Pd) therapy together with whole-brain and craniospinal irradiation and intrathecal chemotherapy.
Case Report
A 45-year-old woman with M-proteinemia, anemia, and hypercalcemia was referred to our hospital. The patient had initially noticed general pain and consulted her physician. Other than her performance status being affected by general pain, the general and neurologic examination was unremarkable. A blood examination showed anemia, hypercalcemia, and elevated lactate dehydrogenase (LDH), and IgA-κ type M protein was detected by serum protein immunoelectrophoresis (Table 1). Bone marrow (BM) specimens revealed 25.7% of atypical plasma cells with the expression of CD38, CD56, and CD138, but no expression of CD19, CD20, MPC-1, CD45, or CD49e, which was compatible with a diagnosis of MM. Chromosome and fluorescence in situ hybridization cytogenic examinations of the BM showed complicated karyotypes, 72% IgH/FGFR3 fusion and 72% deletion 13q signal-positive cells, but no deletion of either 17p or IgH/MAF fusion. Diffusion-weighted whole-body imaging with background body signal suppression (DWIBS) detected diffuse abnormal signals in BM including in many vertebrae. From these findings, MM was diagnosed according to the Revised-International Staging System III (8).
Table 1. Hematologic Assessment of Patient.
WBC 6,400 /μL BUN 19 mg/dL LDH 561 U/L <Urine>
Neutro 67.0 % Cre 0.62 mg/dL CK 23 U/L gravity 1.010
Baso 0.0 % Na 142 mEq/L CRP 4.753 mg/dL WBC (-)
Eosino 0.5 % K 4.1 mEq/L urobilinogen normal
Lympho 14.0 % Cl 97 mEq/L APTT 33.7 s Uric protein (-)
Mono 9.5 % UA 5.1 mg/dL PT-INR 1.16 pH 5.5
Blast 1.0 % Ca 11.3 mg/dL IgG 245 mg/dL Uric blood (+/-)
Pro-myelo 0.0 % Tp 8.4 mg/dL IgA 2,381 mg/dL ketone (+/-)
Myelo 6.5 % ALB 3.6 g/dL IgM 31 mg/dL bilirubin (+/-)
Meta-myelo 1.5 % AST 31 U/L β2-MG 7.1 mg/L glucose (+/-)
RBC 295×104 /μL ALT 9 U/L IEP IgA-κ Bence Jones protein (+)
Hb 8.5 g/dL ChE 237 U/L FLC κ/λ 31.06
Hct 27.1 % T-Bil 0.6 mg/dL κ chain 61.5 mg/mL
Reticulo 0.4 % ALP 215 U/L λ chain 1.98 mg/mL
PLT 16.2×104 /μL γGTP 20 U/L
IEP: immunoelectrophoresis, FLC: free light chain, PT-INR: prothrombin time-international normalized ratio
Treatment with bortezomib-dexamethasone (Bd) therapy (1.3 mg/m2 bortezomib twice a week and 40 mg dexamethasone per week) was started, but it proved to be ineffective. The addition of lenalidomide administration [25 mg/day (on days 1-21)] with Bd transiently decreased the IgA levels. However, 1 week after the addition of lenalidomide, the right femoral diaphysis became fractured, and surgery was thus performed. After surgery, carfilzomib-lenalidomide-dexamethasone (CLd) therapy [with at a dose and schedule according to the ASPIRE protocol (9)] was started. After three courses of CLd therapy, a stringent complete response (sCR) was achieved. High-dose melphalan (200 mg/m2) therapy with ASCT was performed at 9 months after the initial diagnosis, and then the patient maintained an sCR after ASCT, which was confirmed by a BM biopsy and DWIBS. Lenalidomide maintenance therapy (10 mg orally) was then started. Approximately 2 months after ASCT, severe headache, nausea, and vomiting suddenly appeared, and the patient was hospitalized. A CSF examination revealed a marked increase in the total cell count (441/μL), completely consisting of abnormal plasma cells (Fig. 1A), and increased total protein (61 mg/dL) and decreased sugar levels (26 mg/dL). An examination of the plasma cell clonality of the CSF showed expression of CD38, CD56, and CD138 but not CD19, CD20, MPC-1, CD45 or CD49e (Fig. 1B), which was the same result found for the MM cells in BM at diagnosis. Bacterial culture, a tuberculosis PCR test, and viral gene PCR tests including herpes virus were all negative. Although no lesions could be detected by head computed tomography, magnetic resonance imaging (MRI) revealed patchy hyperintense regions on T2-weighted images (Fig. 2). These findings were indicative of MM involvement in the CNS. Blood examinations showed no anemia, renal dysfunction, or hypercalcemia. M-protein was not detected by serum protein immunoelectrophoresis. No abnormal increase in the plasma cells was observed, and no cells with IgH/FGFR3 fusion or a deletion of 13q signals were detected in BM specimens. No systemic lesions were detected on DWIBS. These findings indicate that the relapse was localized to the CNS.
Figure 1. Cerebrospinal fluid specimens showing a marked increase in the total cell count (441/μL), completely consisting of abnormal plasma cells. A: May-Giemsa staining ×400 and ×20 original magnification. B: A flow cytometric analysis of CD38-positive CSF cells. CSF: cerebrospinal fluid, SSC: side scatter
Figure 2. Magnetic resonance imaging showing patchy hyperintense on T2-weighted images.
Dexamethasone monotherapy was started, and the intrathecal injection of methotrexate (15 mg), cytarabine (40 mg), and dexamethasone (4 mg) was performed twice a week, four times in total. Thereafter, Pd therapy with 3 mg pomalidomide and 40 mg dexamethasone [performed on a schedule according to the MM-003 protocol (10)] with whole-brain/craniospinal irradiation (27 Gy/15 fr) was started. The number of myeloma cells in the CSF rapidly decreased, and the cells were observed to have disappeared at the end of irradiation. However, Pd therapy was transiently discontinued 10 days later because of myelosuppression and then was again resumed and continued after the completion of whole-brain/spinal irradiation. Thereafter, no further relapse was observed (Fig. 3).
Figure 3. Clinical course from the onset of central nervous system relapse. End of July (day1; day of hospitalization) (approximately 2 months after autologous stem cell transplantation), the patient experienced severe headache, nausea, and vomiting, and then dexamethasone monotherapy and intrathecal injection of methotrexate, cytarabine, and dexamethasone were started. Pomalidomide-dexamethasone (Pd) therapy and whole-brain/craniospinal irradiation were started on Day9 and Day17, respectively. Pd therapy was transiently discontinued because of myelosuppression and resumed on Day46. CSF: cerebrospinal fluid, LEN: lenalidomide, POM: pomalidomide, DEX dexamethasone, Pd: pomalidomide-dexamethasone, n.d.: not detected
Three months later, DWIBS revealed a mass lesion around the right kidney, which was indicative of extramedullary recurrence, but no relapse of the CNS lesions. Three courses of daratumumab-lenalidomide-dexamethasone therapy [with a dose and schedule according to the POLLUX protocol (11)] were performed, but no reductive effect on the abdominal tumor was observed. Thereafter, conventional chemotherapy [PACE (cisplatin, 10 mg/m2/day; doxorubicin, 10 mg/m2/day; cyclophosphamide, 400 mg/m2/day; and etoposide, 40 mg/m2/day from days 1 to 4)] was temporarily effective, but the tumor recurred, and the patient eventually died 12 months after the onset of CNS relapse (21 months after the diagnosis of MM). After the onset of the abdominal lesion, no relapse of the CNS lesions was observed.
Discussion
In MM, extramedullary lesions emerge in approximately 6-8% of cases at the time of diagnosis and in approximately 10-30% of cases in the advanced or relapse stage (12,13), but the frequency of CNS involvement is only approximately 1% (2-6). The clinical symptoms of CNS involvement in MM are diverse and uncharacteristic, including headache, nausea, vomiting, consciousness disorder, limb weakness, and convulsions (14). Because these symptoms are similar to those of hypercalcemia, uremia, and hyperviscosity syndrome or side effects caused by chemotherapy, a CSF examination to confirm the presence of MM cells in addition to MRI is crucial for making an accurate diagnosis (14). Moreover, the detection of abnormal free light chain in the CSF has great diagnostic significance (15), even if myeloma cells are absent in CSF. MRI may show high-intensity portions of the meninges and formation of solid tumors in the brain.
Although it is difficult to predict the CNS involvement of MM, features of CNS involvement include high-risk chromosomal abnormalities, high LDH levels, high β2 microglobulin levels, extramedullary lesions, and leukemic change (4,5). In particular, a high frequency of chromosomal deletion 17p or deletion 13q has been reported (16,17). The median age at the time of the initial diagnosis of MM patients, who develop CNS involvement during the clinical course, is 54-64 years (2-6), which is relatively younger than the age of onset of MM, as was seen in our case. The early onset of MM may be an important indicator of CNS involvement. Abdallah et al. reported that 42.9% of patients develop CNS involvement during the progression stage of relapsed MM, 48.6% of patients in the stable stage during treatment, and 8.6% of patients in the remission state (14). The average latency period from MM diagnosis to diagnosis of CNS involvement is 15 months, and the latency is 32.1 months in patients with ASCT, which is longer than that in patients without ASCT (8.3 months) (14). Our patient had a younger age, an aggressive disease course with resistance to bortezomib, and high-risk chromosomal abnormalities, thus suggesting a poor prognosis. Indeed, the latent period of between MM diagnosis and onset of CNS relapse was 11 months, which is very short. Furthermore, two months after ASCT, the tumor recurred only in the CNS despite hematologic remission. Thus, if unexplained neurological findings occur at any time during the disease course in patients with risk factors for CNS involvement, then either MRI or a CSF examination should be promptly performed for verification.
Although newly developed therapeutic agents have improved the prognosis of MM, no standard treatment for CNS involvement has yet been established, and the prognosis is very poor, with a median overall survival (OS) of less than 3-6 months (2-6). According to our literature review on CSF transfer of drugs for MM, immunomodulatory drugs (IMiDs) have CSF transferability (Table 2). Cases of successful treatment with thalidomide or lenalidomide have been reported (3,18-20). Thalidomide can be detected in CSF after an oral administration (18,21,22), and lenalidomide can cross the blood-brain barrier (BBB) (19,20,23). In particular, reports have shown that pomalidomide has good CSF transferability (24-26) and activity in extramedullary disease (27). In addition, Chen et al. reported that six of nine long-term survivors (median OS of 17.1 months) with CNS involvement received IMiDs-based therapy combined with intrathecal chemotherapy plus irradiation and/or systemic chemotherapy (28). Intrathecal chemotherapy is often effective against various hematological malignancies and CNS involvement of MM (15). Although a rapid therapeutic effect can be obtained, a long-term therapeutic effect of intrathecal chemotherapy is difficult to maintain. Thus, this therapy should be used as a bridge for subsequent systemic therapy. Moreover, MM cells are highly radiosensitive (29); thus, radiotherapy is also effective for CNS involvement and it is also more effective when combined with chemotherapy (3). In the present case, because of recurrence after CLd and lenalidomide maintenance therapy, pomalidomide was used instead of lenalidomide treatment. Because there was no recurrence in the CNS, combination therapy with pomalidomide, radiotherapy, and intrathecal chemotherapy was considered to be effective in our patient.
Table 2. Data of CSF Transferability and Efficacy of MM Drugs.
Drugs CSF transferability Cases for CNS involvement of MM
IMiDs Thalidomide good18, 23) effective18, 21, 22, 28)
Lenalidomide good19, 23) effective19, 20,28)
Pomalidomide good24) effective25, 26)
Proteasome inhibitors Bortezomib poor30) ineffective30)
Carfilzomib poor* no data
Ixazomib poor* no data
Antibody-drugs Daratumumab good32) effective32, 33, 34)
Isatuximab no data no data
Elotuzumab no data no data
*no experimental data exist.
One case report showed the inefficacy of bortezomib therapy for CNS involvement of MM because of its poor CSF transferability (30). In general, proteasome inhibitors such as carfilzomib and ixazomib have a good ability to permeate throughout the body tissues but cannot penetrate BBB (Table 2); thus, there are no data on the efficacy of carfilzomib and ixazomib for CNS lesions. However, the use of bortezomib has been reported to enhance radiosensitivity and chemosensitivity (31), and studies of CNS lesion treatment with combination therapy including bortezomib should be conducted in the future. To our knowledge, one report examined the CSF transferability of daratumumab (32), and two case reports described significant activity of daratumumab for CNS lesions of MM when concomitantly used with intrathecal chemotherapy (33,34). There are no current data of CSF transferability and the effectiveness of isatuximab and elotuzumab for CNS lesions.
It is possible that the induction of CLd followed by high-dose melphalan chemotherapy of ASCT might have insufficient CNS effects, because proteasome inhibitors carfilzomib has less CNS transferability and alkylating agents such as cyclophosphamide or melphalan can poorly penetrate the CSF (6). We speculated that the initial clones of MM in our case may have escaped into and grown locally in the CNS, where the drugs had not sufficiently penetrated, thus resulting in a local early relapse.
Conclusion
CNS involvement, as seen in our case, is an important consideration for patients with a younger disease onset and risk factors such as chromosomal abnormalities which predict a poor prognosis and high LDH levels. Regardless of hematological remission, when CNS symptoms develop, it is necessary to actively search for CNS lesions by a CSF examination and head MRI. MM patients with CNS lesions have a poor prognosis, but IMiDs such as pomalidomide may be effective because of their CSF transferability; thus, it may be beneficial to administer combination therapies including IMiDs, radiotherapy, and intrathecal chemotherapy against MM with CNS involvement. Crucial data are still sparse regarding treatment, and the accumulation of data from more cases is important to verify the choice of combination drugs for CNS lesions of MM.
Author's disclosure of potential Conflicts of Interest (COI).
Tomoki Ito: Honoraria, Celgene, Bristol-Myers Squibb and Takeda.
Acknowledgement
We thank Lisa Kreiner, PhD, for editing a draft of this manuscript. | Intrathecal | DrugAdministrationRoute | CC BY-NC-ND | 33518613 | 18,905,511 | 2021 |
What was the administration route of drug 'METHOTREXATE'? | Multiple Myeloma with Central Nervous System Relapse Early after Autologous Stem Cell Transplantation: A Case Report and Literature Review.
Few reports have so far described central nervous system (CNS) involvement in multiple myeloma (MM), which shows a poor prognosis owing to its resistance to several treatments. We herein describe a 45-year-old woman who had MM (diagnosed with IgA-κ type) with CNS relapse early after undergoing autologous hematopoietic stem cell transplantation. Because no standard treatment for CNS lesions of MM has been established, we conducted a literature review on the cerebrospinal fluid (CSF) transferability of drugs for MM, since it was considered to be a useful tool for CNS involvement. Immunomodulatory-drugs including pomalidomide exhibit a good CSF transfer ability, and, therefore, may be beneficial against the CNS involvement of MM.
Introduction
Previous studies have shown that the multiple myeloma (MM) genome is complex, and that MM patients have extremely diverse cytogenetic abnormalities with genomic heterogeneity (1). Thus, MM demonstrates a highly variable clinical course. Few reports have so far described neurologic complications arising from direct MM cell involvement in the central nervous system (CNS) (2-6). We herein present a case of an MM patient with an early relapse localized in the CNS early after autologous hematopoietic stem cell transplantation (ASCT). Because no standard treatment for CNS lesions of MM has yet been established (5,7) due to a lack of evidence, we conducted a literature review on the cerebrospinal fluid (CSF) transferablity of drugs for MM. The current case demonstrates that such a presentation of MM can be successfully treated with pomalidomide-dexamethasone (Pd) therapy together with whole-brain and craniospinal irradiation and intrathecal chemotherapy.
Case Report
A 45-year-old woman with M-proteinemia, anemia, and hypercalcemia was referred to our hospital. The patient had initially noticed general pain and consulted her physician. Other than her performance status being affected by general pain, the general and neurologic examination was unremarkable. A blood examination showed anemia, hypercalcemia, and elevated lactate dehydrogenase (LDH), and IgA-κ type M protein was detected by serum protein immunoelectrophoresis (Table 1). Bone marrow (BM) specimens revealed 25.7% of atypical plasma cells with the expression of CD38, CD56, and CD138, but no expression of CD19, CD20, MPC-1, CD45, or CD49e, which was compatible with a diagnosis of MM. Chromosome and fluorescence in situ hybridization cytogenic examinations of the BM showed complicated karyotypes, 72% IgH/FGFR3 fusion and 72% deletion 13q signal-positive cells, but no deletion of either 17p or IgH/MAF fusion. Diffusion-weighted whole-body imaging with background body signal suppression (DWIBS) detected diffuse abnormal signals in BM including in many vertebrae. From these findings, MM was diagnosed according to the Revised-International Staging System III (8).
Table 1. Hematologic Assessment of Patient.
WBC 6,400 /μL BUN 19 mg/dL LDH 561 U/L <Urine>
Neutro 67.0 % Cre 0.62 mg/dL CK 23 U/L gravity 1.010
Baso 0.0 % Na 142 mEq/L CRP 4.753 mg/dL WBC (-)
Eosino 0.5 % K 4.1 mEq/L urobilinogen normal
Lympho 14.0 % Cl 97 mEq/L APTT 33.7 s Uric protein (-)
Mono 9.5 % UA 5.1 mg/dL PT-INR 1.16 pH 5.5
Blast 1.0 % Ca 11.3 mg/dL IgG 245 mg/dL Uric blood (+/-)
Pro-myelo 0.0 % Tp 8.4 mg/dL IgA 2,381 mg/dL ketone (+/-)
Myelo 6.5 % ALB 3.6 g/dL IgM 31 mg/dL bilirubin (+/-)
Meta-myelo 1.5 % AST 31 U/L β2-MG 7.1 mg/L glucose (+/-)
RBC 295×104 /μL ALT 9 U/L IEP IgA-κ Bence Jones protein (+)
Hb 8.5 g/dL ChE 237 U/L FLC κ/λ 31.06
Hct 27.1 % T-Bil 0.6 mg/dL κ chain 61.5 mg/mL
Reticulo 0.4 % ALP 215 U/L λ chain 1.98 mg/mL
PLT 16.2×104 /μL γGTP 20 U/L
IEP: immunoelectrophoresis, FLC: free light chain, PT-INR: prothrombin time-international normalized ratio
Treatment with bortezomib-dexamethasone (Bd) therapy (1.3 mg/m2 bortezomib twice a week and 40 mg dexamethasone per week) was started, but it proved to be ineffective. The addition of lenalidomide administration [25 mg/day (on days 1-21)] with Bd transiently decreased the IgA levels. However, 1 week after the addition of lenalidomide, the right femoral diaphysis became fractured, and surgery was thus performed. After surgery, carfilzomib-lenalidomide-dexamethasone (CLd) therapy [with at a dose and schedule according to the ASPIRE protocol (9)] was started. After three courses of CLd therapy, a stringent complete response (sCR) was achieved. High-dose melphalan (200 mg/m2) therapy with ASCT was performed at 9 months after the initial diagnosis, and then the patient maintained an sCR after ASCT, which was confirmed by a BM biopsy and DWIBS. Lenalidomide maintenance therapy (10 mg orally) was then started. Approximately 2 months after ASCT, severe headache, nausea, and vomiting suddenly appeared, and the patient was hospitalized. A CSF examination revealed a marked increase in the total cell count (441/μL), completely consisting of abnormal plasma cells (Fig. 1A), and increased total protein (61 mg/dL) and decreased sugar levels (26 mg/dL). An examination of the plasma cell clonality of the CSF showed expression of CD38, CD56, and CD138 but not CD19, CD20, MPC-1, CD45 or CD49e (Fig. 1B), which was the same result found for the MM cells in BM at diagnosis. Bacterial culture, a tuberculosis PCR test, and viral gene PCR tests including herpes virus were all negative. Although no lesions could be detected by head computed tomography, magnetic resonance imaging (MRI) revealed patchy hyperintense regions on T2-weighted images (Fig. 2). These findings were indicative of MM involvement in the CNS. Blood examinations showed no anemia, renal dysfunction, or hypercalcemia. M-protein was not detected by serum protein immunoelectrophoresis. No abnormal increase in the plasma cells was observed, and no cells with IgH/FGFR3 fusion or a deletion of 13q signals were detected in BM specimens. No systemic lesions were detected on DWIBS. These findings indicate that the relapse was localized to the CNS.
Figure 1. Cerebrospinal fluid specimens showing a marked increase in the total cell count (441/μL), completely consisting of abnormal plasma cells. A: May-Giemsa staining ×400 and ×20 original magnification. B: A flow cytometric analysis of CD38-positive CSF cells. CSF: cerebrospinal fluid, SSC: side scatter
Figure 2. Magnetic resonance imaging showing patchy hyperintense on T2-weighted images.
Dexamethasone monotherapy was started, and the intrathecal injection of methotrexate (15 mg), cytarabine (40 mg), and dexamethasone (4 mg) was performed twice a week, four times in total. Thereafter, Pd therapy with 3 mg pomalidomide and 40 mg dexamethasone [performed on a schedule according to the MM-003 protocol (10)] with whole-brain/craniospinal irradiation (27 Gy/15 fr) was started. The number of myeloma cells in the CSF rapidly decreased, and the cells were observed to have disappeared at the end of irradiation. However, Pd therapy was transiently discontinued 10 days later because of myelosuppression and then was again resumed and continued after the completion of whole-brain/spinal irradiation. Thereafter, no further relapse was observed (Fig. 3).
Figure 3. Clinical course from the onset of central nervous system relapse. End of July (day1; day of hospitalization) (approximately 2 months after autologous stem cell transplantation), the patient experienced severe headache, nausea, and vomiting, and then dexamethasone monotherapy and intrathecal injection of methotrexate, cytarabine, and dexamethasone were started. Pomalidomide-dexamethasone (Pd) therapy and whole-brain/craniospinal irradiation were started on Day9 and Day17, respectively. Pd therapy was transiently discontinued because of myelosuppression and resumed on Day46. CSF: cerebrospinal fluid, LEN: lenalidomide, POM: pomalidomide, DEX dexamethasone, Pd: pomalidomide-dexamethasone, n.d.: not detected
Three months later, DWIBS revealed a mass lesion around the right kidney, which was indicative of extramedullary recurrence, but no relapse of the CNS lesions. Three courses of daratumumab-lenalidomide-dexamethasone therapy [with a dose and schedule according to the POLLUX protocol (11)] were performed, but no reductive effect on the abdominal tumor was observed. Thereafter, conventional chemotherapy [PACE (cisplatin, 10 mg/m2/day; doxorubicin, 10 mg/m2/day; cyclophosphamide, 400 mg/m2/day; and etoposide, 40 mg/m2/day from days 1 to 4)] was temporarily effective, but the tumor recurred, and the patient eventually died 12 months after the onset of CNS relapse (21 months after the diagnosis of MM). After the onset of the abdominal lesion, no relapse of the CNS lesions was observed.
Discussion
In MM, extramedullary lesions emerge in approximately 6-8% of cases at the time of diagnosis and in approximately 10-30% of cases in the advanced or relapse stage (12,13), but the frequency of CNS involvement is only approximately 1% (2-6). The clinical symptoms of CNS involvement in MM are diverse and uncharacteristic, including headache, nausea, vomiting, consciousness disorder, limb weakness, and convulsions (14). Because these symptoms are similar to those of hypercalcemia, uremia, and hyperviscosity syndrome or side effects caused by chemotherapy, a CSF examination to confirm the presence of MM cells in addition to MRI is crucial for making an accurate diagnosis (14). Moreover, the detection of abnormal free light chain in the CSF has great diagnostic significance (15), even if myeloma cells are absent in CSF. MRI may show high-intensity portions of the meninges and formation of solid tumors in the brain.
Although it is difficult to predict the CNS involvement of MM, features of CNS involvement include high-risk chromosomal abnormalities, high LDH levels, high β2 microglobulin levels, extramedullary lesions, and leukemic change (4,5). In particular, a high frequency of chromosomal deletion 17p or deletion 13q has been reported (16,17). The median age at the time of the initial diagnosis of MM patients, who develop CNS involvement during the clinical course, is 54-64 years (2-6), which is relatively younger than the age of onset of MM, as was seen in our case. The early onset of MM may be an important indicator of CNS involvement. Abdallah et al. reported that 42.9% of patients develop CNS involvement during the progression stage of relapsed MM, 48.6% of patients in the stable stage during treatment, and 8.6% of patients in the remission state (14). The average latency period from MM diagnosis to diagnosis of CNS involvement is 15 months, and the latency is 32.1 months in patients with ASCT, which is longer than that in patients without ASCT (8.3 months) (14). Our patient had a younger age, an aggressive disease course with resistance to bortezomib, and high-risk chromosomal abnormalities, thus suggesting a poor prognosis. Indeed, the latent period of between MM diagnosis and onset of CNS relapse was 11 months, which is very short. Furthermore, two months after ASCT, the tumor recurred only in the CNS despite hematologic remission. Thus, if unexplained neurological findings occur at any time during the disease course in patients with risk factors for CNS involvement, then either MRI or a CSF examination should be promptly performed for verification.
Although newly developed therapeutic agents have improved the prognosis of MM, no standard treatment for CNS involvement has yet been established, and the prognosis is very poor, with a median overall survival (OS) of less than 3-6 months (2-6). According to our literature review on CSF transfer of drugs for MM, immunomodulatory drugs (IMiDs) have CSF transferability (Table 2). Cases of successful treatment with thalidomide or lenalidomide have been reported (3,18-20). Thalidomide can be detected in CSF after an oral administration (18,21,22), and lenalidomide can cross the blood-brain barrier (BBB) (19,20,23). In particular, reports have shown that pomalidomide has good CSF transferability (24-26) and activity in extramedullary disease (27). In addition, Chen et al. reported that six of nine long-term survivors (median OS of 17.1 months) with CNS involvement received IMiDs-based therapy combined with intrathecal chemotherapy plus irradiation and/or systemic chemotherapy (28). Intrathecal chemotherapy is often effective against various hematological malignancies and CNS involvement of MM (15). Although a rapid therapeutic effect can be obtained, a long-term therapeutic effect of intrathecal chemotherapy is difficult to maintain. Thus, this therapy should be used as a bridge for subsequent systemic therapy. Moreover, MM cells are highly radiosensitive (29); thus, radiotherapy is also effective for CNS involvement and it is also more effective when combined with chemotherapy (3). In the present case, because of recurrence after CLd and lenalidomide maintenance therapy, pomalidomide was used instead of lenalidomide treatment. Because there was no recurrence in the CNS, combination therapy with pomalidomide, radiotherapy, and intrathecal chemotherapy was considered to be effective in our patient.
Table 2. Data of CSF Transferability and Efficacy of MM Drugs.
Drugs CSF transferability Cases for CNS involvement of MM
IMiDs Thalidomide good18, 23) effective18, 21, 22, 28)
Lenalidomide good19, 23) effective19, 20,28)
Pomalidomide good24) effective25, 26)
Proteasome inhibitors Bortezomib poor30) ineffective30)
Carfilzomib poor* no data
Ixazomib poor* no data
Antibody-drugs Daratumumab good32) effective32, 33, 34)
Isatuximab no data no data
Elotuzumab no data no data
*no experimental data exist.
One case report showed the inefficacy of bortezomib therapy for CNS involvement of MM because of its poor CSF transferability (30). In general, proteasome inhibitors such as carfilzomib and ixazomib have a good ability to permeate throughout the body tissues but cannot penetrate BBB (Table 2); thus, there are no data on the efficacy of carfilzomib and ixazomib for CNS lesions. However, the use of bortezomib has been reported to enhance radiosensitivity and chemosensitivity (31), and studies of CNS lesion treatment with combination therapy including bortezomib should be conducted in the future. To our knowledge, one report examined the CSF transferability of daratumumab (32), and two case reports described significant activity of daratumumab for CNS lesions of MM when concomitantly used with intrathecal chemotherapy (33,34). There are no current data of CSF transferability and the effectiveness of isatuximab and elotuzumab for CNS lesions.
It is possible that the induction of CLd followed by high-dose melphalan chemotherapy of ASCT might have insufficient CNS effects, because proteasome inhibitors carfilzomib has less CNS transferability and alkylating agents such as cyclophosphamide or melphalan can poorly penetrate the CSF (6). We speculated that the initial clones of MM in our case may have escaped into and grown locally in the CNS, where the drugs had not sufficiently penetrated, thus resulting in a local early relapse.
Conclusion
CNS involvement, as seen in our case, is an important consideration for patients with a younger disease onset and risk factors such as chromosomal abnormalities which predict a poor prognosis and high LDH levels. Regardless of hematological remission, when CNS symptoms develop, it is necessary to actively search for CNS lesions by a CSF examination and head MRI. MM patients with CNS lesions have a poor prognosis, but IMiDs such as pomalidomide may be effective because of their CSF transferability; thus, it may be beneficial to administer combination therapies including IMiDs, radiotherapy, and intrathecal chemotherapy against MM with CNS involvement. Crucial data are still sparse regarding treatment, and the accumulation of data from more cases is important to verify the choice of combination drugs for CNS lesions of MM.
Author's disclosure of potential Conflicts of Interest (COI).
Tomoki Ito: Honoraria, Celgene, Bristol-Myers Squibb and Takeda.
Acknowledgement
We thank Lisa Kreiner, PhD, for editing a draft of this manuscript. | Intrathecal | DrugAdministrationRoute | CC BY-NC-ND | 33518613 | 18,905,511 | 2021 |
What was the administration route of drug 'POMALIDOMIDE'? | Multiple Myeloma with Central Nervous System Relapse Early after Autologous Stem Cell Transplantation: A Case Report and Literature Review.
Few reports have so far described central nervous system (CNS) involvement in multiple myeloma (MM), which shows a poor prognosis owing to its resistance to several treatments. We herein describe a 45-year-old woman who had MM (diagnosed with IgA-κ type) with CNS relapse early after undergoing autologous hematopoietic stem cell transplantation. Because no standard treatment for CNS lesions of MM has been established, we conducted a literature review on the cerebrospinal fluid (CSF) transferability of drugs for MM, since it was considered to be a useful tool for CNS involvement. Immunomodulatory-drugs including pomalidomide exhibit a good CSF transfer ability, and, therefore, may be beneficial against the CNS involvement of MM.
Introduction
Previous studies have shown that the multiple myeloma (MM) genome is complex, and that MM patients have extremely diverse cytogenetic abnormalities with genomic heterogeneity (1). Thus, MM demonstrates a highly variable clinical course. Few reports have so far described neurologic complications arising from direct MM cell involvement in the central nervous system (CNS) (2-6). We herein present a case of an MM patient with an early relapse localized in the CNS early after autologous hematopoietic stem cell transplantation (ASCT). Because no standard treatment for CNS lesions of MM has yet been established (5,7) due to a lack of evidence, we conducted a literature review on the cerebrospinal fluid (CSF) transferablity of drugs for MM. The current case demonstrates that such a presentation of MM can be successfully treated with pomalidomide-dexamethasone (Pd) therapy together with whole-brain and craniospinal irradiation and intrathecal chemotherapy.
Case Report
A 45-year-old woman with M-proteinemia, anemia, and hypercalcemia was referred to our hospital. The patient had initially noticed general pain and consulted her physician. Other than her performance status being affected by general pain, the general and neurologic examination was unremarkable. A blood examination showed anemia, hypercalcemia, and elevated lactate dehydrogenase (LDH), and IgA-κ type M protein was detected by serum protein immunoelectrophoresis (Table 1). Bone marrow (BM) specimens revealed 25.7% of atypical plasma cells with the expression of CD38, CD56, and CD138, but no expression of CD19, CD20, MPC-1, CD45, or CD49e, which was compatible with a diagnosis of MM. Chromosome and fluorescence in situ hybridization cytogenic examinations of the BM showed complicated karyotypes, 72% IgH/FGFR3 fusion and 72% deletion 13q signal-positive cells, but no deletion of either 17p or IgH/MAF fusion. Diffusion-weighted whole-body imaging with background body signal suppression (DWIBS) detected diffuse abnormal signals in BM including in many vertebrae. From these findings, MM was diagnosed according to the Revised-International Staging System III (8).
Table 1. Hematologic Assessment of Patient.
WBC 6,400 /μL BUN 19 mg/dL LDH 561 U/L <Urine>
Neutro 67.0 % Cre 0.62 mg/dL CK 23 U/L gravity 1.010
Baso 0.0 % Na 142 mEq/L CRP 4.753 mg/dL WBC (-)
Eosino 0.5 % K 4.1 mEq/L urobilinogen normal
Lympho 14.0 % Cl 97 mEq/L APTT 33.7 s Uric protein (-)
Mono 9.5 % UA 5.1 mg/dL PT-INR 1.16 pH 5.5
Blast 1.0 % Ca 11.3 mg/dL IgG 245 mg/dL Uric blood (+/-)
Pro-myelo 0.0 % Tp 8.4 mg/dL IgA 2,381 mg/dL ketone (+/-)
Myelo 6.5 % ALB 3.6 g/dL IgM 31 mg/dL bilirubin (+/-)
Meta-myelo 1.5 % AST 31 U/L β2-MG 7.1 mg/L glucose (+/-)
RBC 295×104 /μL ALT 9 U/L IEP IgA-κ Bence Jones protein (+)
Hb 8.5 g/dL ChE 237 U/L FLC κ/λ 31.06
Hct 27.1 % T-Bil 0.6 mg/dL κ chain 61.5 mg/mL
Reticulo 0.4 % ALP 215 U/L λ chain 1.98 mg/mL
PLT 16.2×104 /μL γGTP 20 U/L
IEP: immunoelectrophoresis, FLC: free light chain, PT-INR: prothrombin time-international normalized ratio
Treatment with bortezomib-dexamethasone (Bd) therapy (1.3 mg/m2 bortezomib twice a week and 40 mg dexamethasone per week) was started, but it proved to be ineffective. The addition of lenalidomide administration [25 mg/day (on days 1-21)] with Bd transiently decreased the IgA levels. However, 1 week after the addition of lenalidomide, the right femoral diaphysis became fractured, and surgery was thus performed. After surgery, carfilzomib-lenalidomide-dexamethasone (CLd) therapy [with at a dose and schedule according to the ASPIRE protocol (9)] was started. After three courses of CLd therapy, a stringent complete response (sCR) was achieved. High-dose melphalan (200 mg/m2) therapy with ASCT was performed at 9 months after the initial diagnosis, and then the patient maintained an sCR after ASCT, which was confirmed by a BM biopsy and DWIBS. Lenalidomide maintenance therapy (10 mg orally) was then started. Approximately 2 months after ASCT, severe headache, nausea, and vomiting suddenly appeared, and the patient was hospitalized. A CSF examination revealed a marked increase in the total cell count (441/μL), completely consisting of abnormal plasma cells (Fig. 1A), and increased total protein (61 mg/dL) and decreased sugar levels (26 mg/dL). An examination of the plasma cell clonality of the CSF showed expression of CD38, CD56, and CD138 but not CD19, CD20, MPC-1, CD45 or CD49e (Fig. 1B), which was the same result found for the MM cells in BM at diagnosis. Bacterial culture, a tuberculosis PCR test, and viral gene PCR tests including herpes virus were all negative. Although no lesions could be detected by head computed tomography, magnetic resonance imaging (MRI) revealed patchy hyperintense regions on T2-weighted images (Fig. 2). These findings were indicative of MM involvement in the CNS. Blood examinations showed no anemia, renal dysfunction, or hypercalcemia. M-protein was not detected by serum protein immunoelectrophoresis. No abnormal increase in the plasma cells was observed, and no cells with IgH/FGFR3 fusion or a deletion of 13q signals were detected in BM specimens. No systemic lesions were detected on DWIBS. These findings indicate that the relapse was localized to the CNS.
Figure 1. Cerebrospinal fluid specimens showing a marked increase in the total cell count (441/μL), completely consisting of abnormal plasma cells. A: May-Giemsa staining ×400 and ×20 original magnification. B: A flow cytometric analysis of CD38-positive CSF cells. CSF: cerebrospinal fluid, SSC: side scatter
Figure 2. Magnetic resonance imaging showing patchy hyperintense on T2-weighted images.
Dexamethasone monotherapy was started, and the intrathecal injection of methotrexate (15 mg), cytarabine (40 mg), and dexamethasone (4 mg) was performed twice a week, four times in total. Thereafter, Pd therapy with 3 mg pomalidomide and 40 mg dexamethasone [performed on a schedule according to the MM-003 protocol (10)] with whole-brain/craniospinal irradiation (27 Gy/15 fr) was started. The number of myeloma cells in the CSF rapidly decreased, and the cells were observed to have disappeared at the end of irradiation. However, Pd therapy was transiently discontinued 10 days later because of myelosuppression and then was again resumed and continued after the completion of whole-brain/spinal irradiation. Thereafter, no further relapse was observed (Fig. 3).
Figure 3. Clinical course from the onset of central nervous system relapse. End of July (day1; day of hospitalization) (approximately 2 months after autologous stem cell transplantation), the patient experienced severe headache, nausea, and vomiting, and then dexamethasone monotherapy and intrathecal injection of methotrexate, cytarabine, and dexamethasone were started. Pomalidomide-dexamethasone (Pd) therapy and whole-brain/craniospinal irradiation were started on Day9 and Day17, respectively. Pd therapy was transiently discontinued because of myelosuppression and resumed on Day46. CSF: cerebrospinal fluid, LEN: lenalidomide, POM: pomalidomide, DEX dexamethasone, Pd: pomalidomide-dexamethasone, n.d.: not detected
Three months later, DWIBS revealed a mass lesion around the right kidney, which was indicative of extramedullary recurrence, but no relapse of the CNS lesions. Three courses of daratumumab-lenalidomide-dexamethasone therapy [with a dose and schedule according to the POLLUX protocol (11)] were performed, but no reductive effect on the abdominal tumor was observed. Thereafter, conventional chemotherapy [PACE (cisplatin, 10 mg/m2/day; doxorubicin, 10 mg/m2/day; cyclophosphamide, 400 mg/m2/day; and etoposide, 40 mg/m2/day from days 1 to 4)] was temporarily effective, but the tumor recurred, and the patient eventually died 12 months after the onset of CNS relapse (21 months after the diagnosis of MM). After the onset of the abdominal lesion, no relapse of the CNS lesions was observed.
Discussion
In MM, extramedullary lesions emerge in approximately 6-8% of cases at the time of diagnosis and in approximately 10-30% of cases in the advanced or relapse stage (12,13), but the frequency of CNS involvement is only approximately 1% (2-6). The clinical symptoms of CNS involvement in MM are diverse and uncharacteristic, including headache, nausea, vomiting, consciousness disorder, limb weakness, and convulsions (14). Because these symptoms are similar to those of hypercalcemia, uremia, and hyperviscosity syndrome or side effects caused by chemotherapy, a CSF examination to confirm the presence of MM cells in addition to MRI is crucial for making an accurate diagnosis (14). Moreover, the detection of abnormal free light chain in the CSF has great diagnostic significance (15), even if myeloma cells are absent in CSF. MRI may show high-intensity portions of the meninges and formation of solid tumors in the brain.
Although it is difficult to predict the CNS involvement of MM, features of CNS involvement include high-risk chromosomal abnormalities, high LDH levels, high β2 microglobulin levels, extramedullary lesions, and leukemic change (4,5). In particular, a high frequency of chromosomal deletion 17p or deletion 13q has been reported (16,17). The median age at the time of the initial diagnosis of MM patients, who develop CNS involvement during the clinical course, is 54-64 years (2-6), which is relatively younger than the age of onset of MM, as was seen in our case. The early onset of MM may be an important indicator of CNS involvement. Abdallah et al. reported that 42.9% of patients develop CNS involvement during the progression stage of relapsed MM, 48.6% of patients in the stable stage during treatment, and 8.6% of patients in the remission state (14). The average latency period from MM diagnosis to diagnosis of CNS involvement is 15 months, and the latency is 32.1 months in patients with ASCT, which is longer than that in patients without ASCT (8.3 months) (14). Our patient had a younger age, an aggressive disease course with resistance to bortezomib, and high-risk chromosomal abnormalities, thus suggesting a poor prognosis. Indeed, the latent period of between MM diagnosis and onset of CNS relapse was 11 months, which is very short. Furthermore, two months after ASCT, the tumor recurred only in the CNS despite hematologic remission. Thus, if unexplained neurological findings occur at any time during the disease course in patients with risk factors for CNS involvement, then either MRI or a CSF examination should be promptly performed for verification.
Although newly developed therapeutic agents have improved the prognosis of MM, no standard treatment for CNS involvement has yet been established, and the prognosis is very poor, with a median overall survival (OS) of less than 3-6 months (2-6). According to our literature review on CSF transfer of drugs for MM, immunomodulatory drugs (IMiDs) have CSF transferability (Table 2). Cases of successful treatment with thalidomide or lenalidomide have been reported (3,18-20). Thalidomide can be detected in CSF after an oral administration (18,21,22), and lenalidomide can cross the blood-brain barrier (BBB) (19,20,23). In particular, reports have shown that pomalidomide has good CSF transferability (24-26) and activity in extramedullary disease (27). In addition, Chen et al. reported that six of nine long-term survivors (median OS of 17.1 months) with CNS involvement received IMiDs-based therapy combined with intrathecal chemotherapy plus irradiation and/or systemic chemotherapy (28). Intrathecal chemotherapy is often effective against various hematological malignancies and CNS involvement of MM (15). Although a rapid therapeutic effect can be obtained, a long-term therapeutic effect of intrathecal chemotherapy is difficult to maintain. Thus, this therapy should be used as a bridge for subsequent systemic therapy. Moreover, MM cells are highly radiosensitive (29); thus, radiotherapy is also effective for CNS involvement and it is also more effective when combined with chemotherapy (3). In the present case, because of recurrence after CLd and lenalidomide maintenance therapy, pomalidomide was used instead of lenalidomide treatment. Because there was no recurrence in the CNS, combination therapy with pomalidomide, radiotherapy, and intrathecal chemotherapy was considered to be effective in our patient.
Table 2. Data of CSF Transferability and Efficacy of MM Drugs.
Drugs CSF transferability Cases for CNS involvement of MM
IMiDs Thalidomide good18, 23) effective18, 21, 22, 28)
Lenalidomide good19, 23) effective19, 20,28)
Pomalidomide good24) effective25, 26)
Proteasome inhibitors Bortezomib poor30) ineffective30)
Carfilzomib poor* no data
Ixazomib poor* no data
Antibody-drugs Daratumumab good32) effective32, 33, 34)
Isatuximab no data no data
Elotuzumab no data no data
*no experimental data exist.
One case report showed the inefficacy of bortezomib therapy for CNS involvement of MM because of its poor CSF transferability (30). In general, proteasome inhibitors such as carfilzomib and ixazomib have a good ability to permeate throughout the body tissues but cannot penetrate BBB (Table 2); thus, there are no data on the efficacy of carfilzomib and ixazomib for CNS lesions. However, the use of bortezomib has been reported to enhance radiosensitivity and chemosensitivity (31), and studies of CNS lesion treatment with combination therapy including bortezomib should be conducted in the future. To our knowledge, one report examined the CSF transferability of daratumumab (32), and two case reports described significant activity of daratumumab for CNS lesions of MM when concomitantly used with intrathecal chemotherapy (33,34). There are no current data of CSF transferability and the effectiveness of isatuximab and elotuzumab for CNS lesions.
It is possible that the induction of CLd followed by high-dose melphalan chemotherapy of ASCT might have insufficient CNS effects, because proteasome inhibitors carfilzomib has less CNS transferability and alkylating agents such as cyclophosphamide or melphalan can poorly penetrate the CSF (6). We speculated that the initial clones of MM in our case may have escaped into and grown locally in the CNS, where the drugs had not sufficiently penetrated, thus resulting in a local early relapse.
Conclusion
CNS involvement, as seen in our case, is an important consideration for patients with a younger disease onset and risk factors such as chromosomal abnormalities which predict a poor prognosis and high LDH levels. Regardless of hematological remission, when CNS symptoms develop, it is necessary to actively search for CNS lesions by a CSF examination and head MRI. MM patients with CNS lesions have a poor prognosis, but IMiDs such as pomalidomide may be effective because of their CSF transferability; thus, it may be beneficial to administer combination therapies including IMiDs, radiotherapy, and intrathecal chemotherapy against MM with CNS involvement. Crucial data are still sparse regarding treatment, and the accumulation of data from more cases is important to verify the choice of combination drugs for CNS lesions of MM.
Author's disclosure of potential Conflicts of Interest (COI).
Tomoki Ito: Honoraria, Celgene, Bristol-Myers Squibb and Takeda.
Acknowledgement
We thank Lisa Kreiner, PhD, for editing a draft of this manuscript. | Oral | DrugAdministrationRoute | CC BY-NC-ND | 33518613 | 18,905,511 | 2021 |
What was the dosage of drug 'CYTARABINE'? | Multiple Myeloma with Central Nervous System Relapse Early after Autologous Stem Cell Transplantation: A Case Report and Literature Review.
Few reports have so far described central nervous system (CNS) involvement in multiple myeloma (MM), which shows a poor prognosis owing to its resistance to several treatments. We herein describe a 45-year-old woman who had MM (diagnosed with IgA-κ type) with CNS relapse early after undergoing autologous hematopoietic stem cell transplantation. Because no standard treatment for CNS lesions of MM has been established, we conducted a literature review on the cerebrospinal fluid (CSF) transferability of drugs for MM, since it was considered to be a useful tool for CNS involvement. Immunomodulatory-drugs including pomalidomide exhibit a good CSF transfer ability, and, therefore, may be beneficial against the CNS involvement of MM.
Introduction
Previous studies have shown that the multiple myeloma (MM) genome is complex, and that MM patients have extremely diverse cytogenetic abnormalities with genomic heterogeneity (1). Thus, MM demonstrates a highly variable clinical course. Few reports have so far described neurologic complications arising from direct MM cell involvement in the central nervous system (CNS) (2-6). We herein present a case of an MM patient with an early relapse localized in the CNS early after autologous hematopoietic stem cell transplantation (ASCT). Because no standard treatment for CNS lesions of MM has yet been established (5,7) due to a lack of evidence, we conducted a literature review on the cerebrospinal fluid (CSF) transferablity of drugs for MM. The current case demonstrates that such a presentation of MM can be successfully treated with pomalidomide-dexamethasone (Pd) therapy together with whole-brain and craniospinal irradiation and intrathecal chemotherapy.
Case Report
A 45-year-old woman with M-proteinemia, anemia, and hypercalcemia was referred to our hospital. The patient had initially noticed general pain and consulted her physician. Other than her performance status being affected by general pain, the general and neurologic examination was unremarkable. A blood examination showed anemia, hypercalcemia, and elevated lactate dehydrogenase (LDH), and IgA-κ type M protein was detected by serum protein immunoelectrophoresis (Table 1). Bone marrow (BM) specimens revealed 25.7% of atypical plasma cells with the expression of CD38, CD56, and CD138, but no expression of CD19, CD20, MPC-1, CD45, or CD49e, which was compatible with a diagnosis of MM. Chromosome and fluorescence in situ hybridization cytogenic examinations of the BM showed complicated karyotypes, 72% IgH/FGFR3 fusion and 72% deletion 13q signal-positive cells, but no deletion of either 17p or IgH/MAF fusion. Diffusion-weighted whole-body imaging with background body signal suppression (DWIBS) detected diffuse abnormal signals in BM including in many vertebrae. From these findings, MM was diagnosed according to the Revised-International Staging System III (8).
Table 1. Hematologic Assessment of Patient.
WBC 6,400 /μL BUN 19 mg/dL LDH 561 U/L <Urine>
Neutro 67.0 % Cre 0.62 mg/dL CK 23 U/L gravity 1.010
Baso 0.0 % Na 142 mEq/L CRP 4.753 mg/dL WBC (-)
Eosino 0.5 % K 4.1 mEq/L urobilinogen normal
Lympho 14.0 % Cl 97 mEq/L APTT 33.7 s Uric protein (-)
Mono 9.5 % UA 5.1 mg/dL PT-INR 1.16 pH 5.5
Blast 1.0 % Ca 11.3 mg/dL IgG 245 mg/dL Uric blood (+/-)
Pro-myelo 0.0 % Tp 8.4 mg/dL IgA 2,381 mg/dL ketone (+/-)
Myelo 6.5 % ALB 3.6 g/dL IgM 31 mg/dL bilirubin (+/-)
Meta-myelo 1.5 % AST 31 U/L β2-MG 7.1 mg/L glucose (+/-)
RBC 295×104 /μL ALT 9 U/L IEP IgA-κ Bence Jones protein (+)
Hb 8.5 g/dL ChE 237 U/L FLC κ/λ 31.06
Hct 27.1 % T-Bil 0.6 mg/dL κ chain 61.5 mg/mL
Reticulo 0.4 % ALP 215 U/L λ chain 1.98 mg/mL
PLT 16.2×104 /μL γGTP 20 U/L
IEP: immunoelectrophoresis, FLC: free light chain, PT-INR: prothrombin time-international normalized ratio
Treatment with bortezomib-dexamethasone (Bd) therapy (1.3 mg/m2 bortezomib twice a week and 40 mg dexamethasone per week) was started, but it proved to be ineffective. The addition of lenalidomide administration [25 mg/day (on days 1-21)] with Bd transiently decreased the IgA levels. However, 1 week after the addition of lenalidomide, the right femoral diaphysis became fractured, and surgery was thus performed. After surgery, carfilzomib-lenalidomide-dexamethasone (CLd) therapy [with at a dose and schedule according to the ASPIRE protocol (9)] was started. After three courses of CLd therapy, a stringent complete response (sCR) was achieved. High-dose melphalan (200 mg/m2) therapy with ASCT was performed at 9 months after the initial diagnosis, and then the patient maintained an sCR after ASCT, which was confirmed by a BM biopsy and DWIBS. Lenalidomide maintenance therapy (10 mg orally) was then started. Approximately 2 months after ASCT, severe headache, nausea, and vomiting suddenly appeared, and the patient was hospitalized. A CSF examination revealed a marked increase in the total cell count (441/μL), completely consisting of abnormal plasma cells (Fig. 1A), and increased total protein (61 mg/dL) and decreased sugar levels (26 mg/dL). An examination of the plasma cell clonality of the CSF showed expression of CD38, CD56, and CD138 but not CD19, CD20, MPC-1, CD45 or CD49e (Fig. 1B), which was the same result found for the MM cells in BM at diagnosis. Bacterial culture, a tuberculosis PCR test, and viral gene PCR tests including herpes virus were all negative. Although no lesions could be detected by head computed tomography, magnetic resonance imaging (MRI) revealed patchy hyperintense regions on T2-weighted images (Fig. 2). These findings were indicative of MM involvement in the CNS. Blood examinations showed no anemia, renal dysfunction, or hypercalcemia. M-protein was not detected by serum protein immunoelectrophoresis. No abnormal increase in the plasma cells was observed, and no cells with IgH/FGFR3 fusion or a deletion of 13q signals were detected in BM specimens. No systemic lesions were detected on DWIBS. These findings indicate that the relapse was localized to the CNS.
Figure 1. Cerebrospinal fluid specimens showing a marked increase in the total cell count (441/μL), completely consisting of abnormal plasma cells. A: May-Giemsa staining ×400 and ×20 original magnification. B: A flow cytometric analysis of CD38-positive CSF cells. CSF: cerebrospinal fluid, SSC: side scatter
Figure 2. Magnetic resonance imaging showing patchy hyperintense on T2-weighted images.
Dexamethasone monotherapy was started, and the intrathecal injection of methotrexate (15 mg), cytarabine (40 mg), and dexamethasone (4 mg) was performed twice a week, four times in total. Thereafter, Pd therapy with 3 mg pomalidomide and 40 mg dexamethasone [performed on a schedule according to the MM-003 protocol (10)] with whole-brain/craniospinal irradiation (27 Gy/15 fr) was started. The number of myeloma cells in the CSF rapidly decreased, and the cells were observed to have disappeared at the end of irradiation. However, Pd therapy was transiently discontinued 10 days later because of myelosuppression and then was again resumed and continued after the completion of whole-brain/spinal irradiation. Thereafter, no further relapse was observed (Fig. 3).
Figure 3. Clinical course from the onset of central nervous system relapse. End of July (day1; day of hospitalization) (approximately 2 months after autologous stem cell transplantation), the patient experienced severe headache, nausea, and vomiting, and then dexamethasone monotherapy and intrathecal injection of methotrexate, cytarabine, and dexamethasone were started. Pomalidomide-dexamethasone (Pd) therapy and whole-brain/craniospinal irradiation were started on Day9 and Day17, respectively. Pd therapy was transiently discontinued because of myelosuppression and resumed on Day46. CSF: cerebrospinal fluid, LEN: lenalidomide, POM: pomalidomide, DEX dexamethasone, Pd: pomalidomide-dexamethasone, n.d.: not detected
Three months later, DWIBS revealed a mass lesion around the right kidney, which was indicative of extramedullary recurrence, but no relapse of the CNS lesions. Three courses of daratumumab-lenalidomide-dexamethasone therapy [with a dose and schedule according to the POLLUX protocol (11)] were performed, but no reductive effect on the abdominal tumor was observed. Thereafter, conventional chemotherapy [PACE (cisplatin, 10 mg/m2/day; doxorubicin, 10 mg/m2/day; cyclophosphamide, 400 mg/m2/day; and etoposide, 40 mg/m2/day from days 1 to 4)] was temporarily effective, but the tumor recurred, and the patient eventually died 12 months after the onset of CNS relapse (21 months after the diagnosis of MM). After the onset of the abdominal lesion, no relapse of the CNS lesions was observed.
Discussion
In MM, extramedullary lesions emerge in approximately 6-8% of cases at the time of diagnosis and in approximately 10-30% of cases in the advanced or relapse stage (12,13), but the frequency of CNS involvement is only approximately 1% (2-6). The clinical symptoms of CNS involvement in MM are diverse and uncharacteristic, including headache, nausea, vomiting, consciousness disorder, limb weakness, and convulsions (14). Because these symptoms are similar to those of hypercalcemia, uremia, and hyperviscosity syndrome or side effects caused by chemotherapy, a CSF examination to confirm the presence of MM cells in addition to MRI is crucial for making an accurate diagnosis (14). Moreover, the detection of abnormal free light chain in the CSF has great diagnostic significance (15), even if myeloma cells are absent in CSF. MRI may show high-intensity portions of the meninges and formation of solid tumors in the brain.
Although it is difficult to predict the CNS involvement of MM, features of CNS involvement include high-risk chromosomal abnormalities, high LDH levels, high β2 microglobulin levels, extramedullary lesions, and leukemic change (4,5). In particular, a high frequency of chromosomal deletion 17p or deletion 13q has been reported (16,17). The median age at the time of the initial diagnosis of MM patients, who develop CNS involvement during the clinical course, is 54-64 years (2-6), which is relatively younger than the age of onset of MM, as was seen in our case. The early onset of MM may be an important indicator of CNS involvement. Abdallah et al. reported that 42.9% of patients develop CNS involvement during the progression stage of relapsed MM, 48.6% of patients in the stable stage during treatment, and 8.6% of patients in the remission state (14). The average latency period from MM diagnosis to diagnosis of CNS involvement is 15 months, and the latency is 32.1 months in patients with ASCT, which is longer than that in patients without ASCT (8.3 months) (14). Our patient had a younger age, an aggressive disease course with resistance to bortezomib, and high-risk chromosomal abnormalities, thus suggesting a poor prognosis. Indeed, the latent period of between MM diagnosis and onset of CNS relapse was 11 months, which is very short. Furthermore, two months after ASCT, the tumor recurred only in the CNS despite hematologic remission. Thus, if unexplained neurological findings occur at any time during the disease course in patients with risk factors for CNS involvement, then either MRI or a CSF examination should be promptly performed for verification.
Although newly developed therapeutic agents have improved the prognosis of MM, no standard treatment for CNS involvement has yet been established, and the prognosis is very poor, with a median overall survival (OS) of less than 3-6 months (2-6). According to our literature review on CSF transfer of drugs for MM, immunomodulatory drugs (IMiDs) have CSF transferability (Table 2). Cases of successful treatment with thalidomide or lenalidomide have been reported (3,18-20). Thalidomide can be detected in CSF after an oral administration (18,21,22), and lenalidomide can cross the blood-brain barrier (BBB) (19,20,23). In particular, reports have shown that pomalidomide has good CSF transferability (24-26) and activity in extramedullary disease (27). In addition, Chen et al. reported that six of nine long-term survivors (median OS of 17.1 months) with CNS involvement received IMiDs-based therapy combined with intrathecal chemotherapy plus irradiation and/or systemic chemotherapy (28). Intrathecal chemotherapy is often effective against various hematological malignancies and CNS involvement of MM (15). Although a rapid therapeutic effect can be obtained, a long-term therapeutic effect of intrathecal chemotherapy is difficult to maintain. Thus, this therapy should be used as a bridge for subsequent systemic therapy. Moreover, MM cells are highly radiosensitive (29); thus, radiotherapy is also effective for CNS involvement and it is also more effective when combined with chemotherapy (3). In the present case, because of recurrence after CLd and lenalidomide maintenance therapy, pomalidomide was used instead of lenalidomide treatment. Because there was no recurrence in the CNS, combination therapy with pomalidomide, radiotherapy, and intrathecal chemotherapy was considered to be effective in our patient.
Table 2. Data of CSF Transferability and Efficacy of MM Drugs.
Drugs CSF transferability Cases for CNS involvement of MM
IMiDs Thalidomide good18, 23) effective18, 21, 22, 28)
Lenalidomide good19, 23) effective19, 20,28)
Pomalidomide good24) effective25, 26)
Proteasome inhibitors Bortezomib poor30) ineffective30)
Carfilzomib poor* no data
Ixazomib poor* no data
Antibody-drugs Daratumumab good32) effective32, 33, 34)
Isatuximab no data no data
Elotuzumab no data no data
*no experimental data exist.
One case report showed the inefficacy of bortezomib therapy for CNS involvement of MM because of its poor CSF transferability (30). In general, proteasome inhibitors such as carfilzomib and ixazomib have a good ability to permeate throughout the body tissues but cannot penetrate BBB (Table 2); thus, there are no data on the efficacy of carfilzomib and ixazomib for CNS lesions. However, the use of bortezomib has been reported to enhance radiosensitivity and chemosensitivity (31), and studies of CNS lesion treatment with combination therapy including bortezomib should be conducted in the future. To our knowledge, one report examined the CSF transferability of daratumumab (32), and two case reports described significant activity of daratumumab for CNS lesions of MM when concomitantly used with intrathecal chemotherapy (33,34). There are no current data of CSF transferability and the effectiveness of isatuximab and elotuzumab for CNS lesions.
It is possible that the induction of CLd followed by high-dose melphalan chemotherapy of ASCT might have insufficient CNS effects, because proteasome inhibitors carfilzomib has less CNS transferability and alkylating agents such as cyclophosphamide or melphalan can poorly penetrate the CSF (6). We speculated that the initial clones of MM in our case may have escaped into and grown locally in the CNS, where the drugs had not sufficiently penetrated, thus resulting in a local early relapse.
Conclusion
CNS involvement, as seen in our case, is an important consideration for patients with a younger disease onset and risk factors such as chromosomal abnormalities which predict a poor prognosis and high LDH levels. Regardless of hematological remission, when CNS symptoms develop, it is necessary to actively search for CNS lesions by a CSF examination and head MRI. MM patients with CNS lesions have a poor prognosis, but IMiDs such as pomalidomide may be effective because of their CSF transferability; thus, it may be beneficial to administer combination therapies including IMiDs, radiotherapy, and intrathecal chemotherapy against MM with CNS involvement. Crucial data are still sparse regarding treatment, and the accumulation of data from more cases is important to verify the choice of combination drugs for CNS lesions of MM.
Author's disclosure of potential Conflicts of Interest (COI).
Tomoki Ito: Honoraria, Celgene, Bristol-Myers Squibb and Takeda.
Acknowledgement
We thank Lisa Kreiner, PhD, for editing a draft of this manuscript. | 40 mg (milligrams). | DrugDosage | CC BY-NC-ND | 33518613 | 18,905,511 | 2021 |
What was the dosage of drug 'METHOTREXATE'? | Multiple Myeloma with Central Nervous System Relapse Early after Autologous Stem Cell Transplantation: A Case Report and Literature Review.
Few reports have so far described central nervous system (CNS) involvement in multiple myeloma (MM), which shows a poor prognosis owing to its resistance to several treatments. We herein describe a 45-year-old woman who had MM (diagnosed with IgA-κ type) with CNS relapse early after undergoing autologous hematopoietic stem cell transplantation. Because no standard treatment for CNS lesions of MM has been established, we conducted a literature review on the cerebrospinal fluid (CSF) transferability of drugs for MM, since it was considered to be a useful tool for CNS involvement. Immunomodulatory-drugs including pomalidomide exhibit a good CSF transfer ability, and, therefore, may be beneficial against the CNS involvement of MM.
Introduction
Previous studies have shown that the multiple myeloma (MM) genome is complex, and that MM patients have extremely diverse cytogenetic abnormalities with genomic heterogeneity (1). Thus, MM demonstrates a highly variable clinical course. Few reports have so far described neurologic complications arising from direct MM cell involvement in the central nervous system (CNS) (2-6). We herein present a case of an MM patient with an early relapse localized in the CNS early after autologous hematopoietic stem cell transplantation (ASCT). Because no standard treatment for CNS lesions of MM has yet been established (5,7) due to a lack of evidence, we conducted a literature review on the cerebrospinal fluid (CSF) transferablity of drugs for MM. The current case demonstrates that such a presentation of MM can be successfully treated with pomalidomide-dexamethasone (Pd) therapy together with whole-brain and craniospinal irradiation and intrathecal chemotherapy.
Case Report
A 45-year-old woman with M-proteinemia, anemia, and hypercalcemia was referred to our hospital. The patient had initially noticed general pain and consulted her physician. Other than her performance status being affected by general pain, the general and neurologic examination was unremarkable. A blood examination showed anemia, hypercalcemia, and elevated lactate dehydrogenase (LDH), and IgA-κ type M protein was detected by serum protein immunoelectrophoresis (Table 1). Bone marrow (BM) specimens revealed 25.7% of atypical plasma cells with the expression of CD38, CD56, and CD138, but no expression of CD19, CD20, MPC-1, CD45, or CD49e, which was compatible with a diagnosis of MM. Chromosome and fluorescence in situ hybridization cytogenic examinations of the BM showed complicated karyotypes, 72% IgH/FGFR3 fusion and 72% deletion 13q signal-positive cells, but no deletion of either 17p or IgH/MAF fusion. Diffusion-weighted whole-body imaging with background body signal suppression (DWIBS) detected diffuse abnormal signals in BM including in many vertebrae. From these findings, MM was diagnosed according to the Revised-International Staging System III (8).
Table 1. Hematologic Assessment of Patient.
WBC 6,400 /μL BUN 19 mg/dL LDH 561 U/L <Urine>
Neutro 67.0 % Cre 0.62 mg/dL CK 23 U/L gravity 1.010
Baso 0.0 % Na 142 mEq/L CRP 4.753 mg/dL WBC (-)
Eosino 0.5 % K 4.1 mEq/L urobilinogen normal
Lympho 14.0 % Cl 97 mEq/L APTT 33.7 s Uric protein (-)
Mono 9.5 % UA 5.1 mg/dL PT-INR 1.16 pH 5.5
Blast 1.0 % Ca 11.3 mg/dL IgG 245 mg/dL Uric blood (+/-)
Pro-myelo 0.0 % Tp 8.4 mg/dL IgA 2,381 mg/dL ketone (+/-)
Myelo 6.5 % ALB 3.6 g/dL IgM 31 mg/dL bilirubin (+/-)
Meta-myelo 1.5 % AST 31 U/L β2-MG 7.1 mg/L glucose (+/-)
RBC 295×104 /μL ALT 9 U/L IEP IgA-κ Bence Jones protein (+)
Hb 8.5 g/dL ChE 237 U/L FLC κ/λ 31.06
Hct 27.1 % T-Bil 0.6 mg/dL κ chain 61.5 mg/mL
Reticulo 0.4 % ALP 215 U/L λ chain 1.98 mg/mL
PLT 16.2×104 /μL γGTP 20 U/L
IEP: immunoelectrophoresis, FLC: free light chain, PT-INR: prothrombin time-international normalized ratio
Treatment with bortezomib-dexamethasone (Bd) therapy (1.3 mg/m2 bortezomib twice a week and 40 mg dexamethasone per week) was started, but it proved to be ineffective. The addition of lenalidomide administration [25 mg/day (on days 1-21)] with Bd transiently decreased the IgA levels. However, 1 week after the addition of lenalidomide, the right femoral diaphysis became fractured, and surgery was thus performed. After surgery, carfilzomib-lenalidomide-dexamethasone (CLd) therapy [with at a dose and schedule according to the ASPIRE protocol (9)] was started. After three courses of CLd therapy, a stringent complete response (sCR) was achieved. High-dose melphalan (200 mg/m2) therapy with ASCT was performed at 9 months after the initial diagnosis, and then the patient maintained an sCR after ASCT, which was confirmed by a BM biopsy and DWIBS. Lenalidomide maintenance therapy (10 mg orally) was then started. Approximately 2 months after ASCT, severe headache, nausea, and vomiting suddenly appeared, and the patient was hospitalized. A CSF examination revealed a marked increase in the total cell count (441/μL), completely consisting of abnormal plasma cells (Fig. 1A), and increased total protein (61 mg/dL) and decreased sugar levels (26 mg/dL). An examination of the plasma cell clonality of the CSF showed expression of CD38, CD56, and CD138 but not CD19, CD20, MPC-1, CD45 or CD49e (Fig. 1B), which was the same result found for the MM cells in BM at diagnosis. Bacterial culture, a tuberculosis PCR test, and viral gene PCR tests including herpes virus were all negative. Although no lesions could be detected by head computed tomography, magnetic resonance imaging (MRI) revealed patchy hyperintense regions on T2-weighted images (Fig. 2). These findings were indicative of MM involvement in the CNS. Blood examinations showed no anemia, renal dysfunction, or hypercalcemia. M-protein was not detected by serum protein immunoelectrophoresis. No abnormal increase in the plasma cells was observed, and no cells with IgH/FGFR3 fusion or a deletion of 13q signals were detected in BM specimens. No systemic lesions were detected on DWIBS. These findings indicate that the relapse was localized to the CNS.
Figure 1. Cerebrospinal fluid specimens showing a marked increase in the total cell count (441/μL), completely consisting of abnormal plasma cells. A: May-Giemsa staining ×400 and ×20 original magnification. B: A flow cytometric analysis of CD38-positive CSF cells. CSF: cerebrospinal fluid, SSC: side scatter
Figure 2. Magnetic resonance imaging showing patchy hyperintense on T2-weighted images.
Dexamethasone monotherapy was started, and the intrathecal injection of methotrexate (15 mg), cytarabine (40 mg), and dexamethasone (4 mg) was performed twice a week, four times in total. Thereafter, Pd therapy with 3 mg pomalidomide and 40 mg dexamethasone [performed on a schedule according to the MM-003 protocol (10)] with whole-brain/craniospinal irradiation (27 Gy/15 fr) was started. The number of myeloma cells in the CSF rapidly decreased, and the cells were observed to have disappeared at the end of irradiation. However, Pd therapy was transiently discontinued 10 days later because of myelosuppression and then was again resumed and continued after the completion of whole-brain/spinal irradiation. Thereafter, no further relapse was observed (Fig. 3).
Figure 3. Clinical course from the onset of central nervous system relapse. End of July (day1; day of hospitalization) (approximately 2 months after autologous stem cell transplantation), the patient experienced severe headache, nausea, and vomiting, and then dexamethasone monotherapy and intrathecal injection of methotrexate, cytarabine, and dexamethasone were started. Pomalidomide-dexamethasone (Pd) therapy and whole-brain/craniospinal irradiation were started on Day9 and Day17, respectively. Pd therapy was transiently discontinued because of myelosuppression and resumed on Day46. CSF: cerebrospinal fluid, LEN: lenalidomide, POM: pomalidomide, DEX dexamethasone, Pd: pomalidomide-dexamethasone, n.d.: not detected
Three months later, DWIBS revealed a mass lesion around the right kidney, which was indicative of extramedullary recurrence, but no relapse of the CNS lesions. Three courses of daratumumab-lenalidomide-dexamethasone therapy [with a dose and schedule according to the POLLUX protocol (11)] were performed, but no reductive effect on the abdominal tumor was observed. Thereafter, conventional chemotherapy [PACE (cisplatin, 10 mg/m2/day; doxorubicin, 10 mg/m2/day; cyclophosphamide, 400 mg/m2/day; and etoposide, 40 mg/m2/day from days 1 to 4)] was temporarily effective, but the tumor recurred, and the patient eventually died 12 months after the onset of CNS relapse (21 months after the diagnosis of MM). After the onset of the abdominal lesion, no relapse of the CNS lesions was observed.
Discussion
In MM, extramedullary lesions emerge in approximately 6-8% of cases at the time of diagnosis and in approximately 10-30% of cases in the advanced or relapse stage (12,13), but the frequency of CNS involvement is only approximately 1% (2-6). The clinical symptoms of CNS involvement in MM are diverse and uncharacteristic, including headache, nausea, vomiting, consciousness disorder, limb weakness, and convulsions (14). Because these symptoms are similar to those of hypercalcemia, uremia, and hyperviscosity syndrome or side effects caused by chemotherapy, a CSF examination to confirm the presence of MM cells in addition to MRI is crucial for making an accurate diagnosis (14). Moreover, the detection of abnormal free light chain in the CSF has great diagnostic significance (15), even if myeloma cells are absent in CSF. MRI may show high-intensity portions of the meninges and formation of solid tumors in the brain.
Although it is difficult to predict the CNS involvement of MM, features of CNS involvement include high-risk chromosomal abnormalities, high LDH levels, high β2 microglobulin levels, extramedullary lesions, and leukemic change (4,5). In particular, a high frequency of chromosomal deletion 17p or deletion 13q has been reported (16,17). The median age at the time of the initial diagnosis of MM patients, who develop CNS involvement during the clinical course, is 54-64 years (2-6), which is relatively younger than the age of onset of MM, as was seen in our case. The early onset of MM may be an important indicator of CNS involvement. Abdallah et al. reported that 42.9% of patients develop CNS involvement during the progression stage of relapsed MM, 48.6% of patients in the stable stage during treatment, and 8.6% of patients in the remission state (14). The average latency period from MM diagnosis to diagnosis of CNS involvement is 15 months, and the latency is 32.1 months in patients with ASCT, which is longer than that in patients without ASCT (8.3 months) (14). Our patient had a younger age, an aggressive disease course with resistance to bortezomib, and high-risk chromosomal abnormalities, thus suggesting a poor prognosis. Indeed, the latent period of between MM diagnosis and onset of CNS relapse was 11 months, which is very short. Furthermore, two months after ASCT, the tumor recurred only in the CNS despite hematologic remission. Thus, if unexplained neurological findings occur at any time during the disease course in patients with risk factors for CNS involvement, then either MRI or a CSF examination should be promptly performed for verification.
Although newly developed therapeutic agents have improved the prognosis of MM, no standard treatment for CNS involvement has yet been established, and the prognosis is very poor, with a median overall survival (OS) of less than 3-6 months (2-6). According to our literature review on CSF transfer of drugs for MM, immunomodulatory drugs (IMiDs) have CSF transferability (Table 2). Cases of successful treatment with thalidomide or lenalidomide have been reported (3,18-20). Thalidomide can be detected in CSF after an oral administration (18,21,22), and lenalidomide can cross the blood-brain barrier (BBB) (19,20,23). In particular, reports have shown that pomalidomide has good CSF transferability (24-26) and activity in extramedullary disease (27). In addition, Chen et al. reported that six of nine long-term survivors (median OS of 17.1 months) with CNS involvement received IMiDs-based therapy combined with intrathecal chemotherapy plus irradiation and/or systemic chemotherapy (28). Intrathecal chemotherapy is often effective against various hematological malignancies and CNS involvement of MM (15). Although a rapid therapeutic effect can be obtained, a long-term therapeutic effect of intrathecal chemotherapy is difficult to maintain. Thus, this therapy should be used as a bridge for subsequent systemic therapy. Moreover, MM cells are highly radiosensitive (29); thus, radiotherapy is also effective for CNS involvement and it is also more effective when combined with chemotherapy (3). In the present case, because of recurrence after CLd and lenalidomide maintenance therapy, pomalidomide was used instead of lenalidomide treatment. Because there was no recurrence in the CNS, combination therapy with pomalidomide, radiotherapy, and intrathecal chemotherapy was considered to be effective in our patient.
Table 2. Data of CSF Transferability and Efficacy of MM Drugs.
Drugs CSF transferability Cases for CNS involvement of MM
IMiDs Thalidomide good18, 23) effective18, 21, 22, 28)
Lenalidomide good19, 23) effective19, 20,28)
Pomalidomide good24) effective25, 26)
Proteasome inhibitors Bortezomib poor30) ineffective30)
Carfilzomib poor* no data
Ixazomib poor* no data
Antibody-drugs Daratumumab good32) effective32, 33, 34)
Isatuximab no data no data
Elotuzumab no data no data
*no experimental data exist.
One case report showed the inefficacy of bortezomib therapy for CNS involvement of MM because of its poor CSF transferability (30). In general, proteasome inhibitors such as carfilzomib and ixazomib have a good ability to permeate throughout the body tissues but cannot penetrate BBB (Table 2); thus, there are no data on the efficacy of carfilzomib and ixazomib for CNS lesions. However, the use of bortezomib has been reported to enhance radiosensitivity and chemosensitivity (31), and studies of CNS lesion treatment with combination therapy including bortezomib should be conducted in the future. To our knowledge, one report examined the CSF transferability of daratumumab (32), and two case reports described significant activity of daratumumab for CNS lesions of MM when concomitantly used with intrathecal chemotherapy (33,34). There are no current data of CSF transferability and the effectiveness of isatuximab and elotuzumab for CNS lesions.
It is possible that the induction of CLd followed by high-dose melphalan chemotherapy of ASCT might have insufficient CNS effects, because proteasome inhibitors carfilzomib has less CNS transferability and alkylating agents such as cyclophosphamide or melphalan can poorly penetrate the CSF (6). We speculated that the initial clones of MM in our case may have escaped into and grown locally in the CNS, where the drugs had not sufficiently penetrated, thus resulting in a local early relapse.
Conclusion
CNS involvement, as seen in our case, is an important consideration for patients with a younger disease onset and risk factors such as chromosomal abnormalities which predict a poor prognosis and high LDH levels. Regardless of hematological remission, when CNS symptoms develop, it is necessary to actively search for CNS lesions by a CSF examination and head MRI. MM patients with CNS lesions have a poor prognosis, but IMiDs such as pomalidomide may be effective because of their CSF transferability; thus, it may be beneficial to administer combination therapies including IMiDs, radiotherapy, and intrathecal chemotherapy against MM with CNS involvement. Crucial data are still sparse regarding treatment, and the accumulation of data from more cases is important to verify the choice of combination drugs for CNS lesions of MM.
Author's disclosure of potential Conflicts of Interest (COI).
Tomoki Ito: Honoraria, Celgene, Bristol-Myers Squibb and Takeda.
Acknowledgement
We thank Lisa Kreiner, PhD, for editing a draft of this manuscript. | 15 mg (milligrams). | DrugDosage | CC BY-NC-ND | 33518613 | 18,905,511 | 2021 |
Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Orbital myositis'. | Standardized diagnostic algorithm for spitzoid lesions aids clinical decision-making and management: a case series from a Swiss reference center.
OBJECTIVE
Spitzoid lesions are a group of melanocytic tumors characterized by spindle-like or epithelioid cells with variable malignant potential. While some spitzoid lesions are classified as evidently benign or malignant by clinic and histology, others present with unclear clinical and histological characteristics and are categorized as lesions of intermediate biologic potential. These lesions represent a challenge for pathologists and clinicians alike. No consensus on ancillary diagnostics and clinical management exists. Prediction of their clinical course is difficult. The implementation of ancillary diagnostics is currently subject of extensive discussions.
METHODS
We report three cases of spitzoid lesions in three young female patients (3-, 15- and 17 years old) from a single reference center with different clinical and histological manifestations. In each case, uncertain clinical and histological presentation led to the stepwise application of additional diagnostics using immunohistochemistry and a custom next generation sequencing panel optimized for melanocytic lesions (MelArray). Combining ancillary diagnostics helped determine clinical management in all cases by characterizing the biology of these lesions.
CONCLUSIONS
We illustrate how clinical, histological and molecular features contribute to an optimized management plan in these critical situations and present a possible algorithm for the assessment of spitzoid neoplasms.
INTRODUCTION
Spitzoid lesions are a diverse group of rapid-growing melanocytic tumors characterized by spindle-like or epithelioid cells. Certain spitzoid lesions show evidently benign or malignant clinic and histology, while others present with unclear characteristics and are therefore categorized as lesions of intermediate biologic potential [1]. These lesions are a challenge for pathologists and clinicians, as there is no consensus on ancillary diagnostics or clinical management [2]. As patients are typically young [2, 3], prediction of the clinical outcome is essential to determine if adjuvant treatment is necessary.
The implementation of ancillary diagnostics such as immunohistochemistry (IHC), comparative genomic hybridization (CGH) and next generation sequencing (NGS) is currently subject of extensive discussions.
The usefulness of IHC in these cases is widely accepted, although there is no consensus on which markers to apply [1, 2, 4]. Garola et al. suggest the use of a panel combining p16, HMB45 and Ki67 stainings [5]. Current research further suggests a stepwise implementation of additional diagnostics including CGH or NGS. However, for all diagnostics, no cut-offs or standardized panel recommendations exist [2].
MelArray is a customized NGS panel optimized for melanocytic lesions that focuses on 190 genes previously reported in melanoma [6].
We use three cases to present the interplay between clinical presentation, pathology and molecular biology and illustrate how this currently influences clinical management.
CLINICAL CASES
Patient 1
A 3-year-old female presented with a quickly developing lesion on the right calf. The parents had first noticed a flat, reddish macula at 29 months of age. Within 4 months, it had grown in size and elevation and developed a verrucous aspect. Due to unclear clinical features, the lesion was totally excised in April 2019. Histology, IHC and MelArray were performed (see Figure 1).
Figure 1 Diagnostics in benign spitzoid lesion.
Clinical manifestation of lesion in January 2019 (A) and April 2019 (B) showing progression from small erythematous macula to verrucous papule. Histologically, the lesion showed pronounced verrucous hyperplasia of the epidermis. In the dermis there is a well demarcated dense infiltration of epitheloid cells with extensive cytoplasm presenting mild mitotic activity (H&E, original magnification 100×) (C) and (H&E, original magnification 40×) (D). p16 was homogenously positive in melanocytic cells (P16 staining, original magnification 40×) (E) and HMB45 was negative in the dermal compartment (H&E, original magnification 40×) (F). Ki67 was widely expressed in the dermal-epidermal junction in keratinocytes and some melanocytic cells (Ki67 staining, original magnification 40×) (G). Denoised copy ratio depicts the ratio of copy numbers of the tissue analyzed compared to normal tissue gained from the same FFPE block. In this case, no CNVs were seen (H). No non-synonymous mutations were detected in the genes included in the MelArray panel.
Considering atypical clinical presentation and histology with inconspicuous molecular characteristics, clinical follow-ups were recommended after total excision. The patient has been followed up for 9 months without relapse.
Patient 2
A 15-year-old female presented with a 13 × 18 mm dome-shaped, pinkish papule on the lower right back. Right inguinal lymphadenopathy was detected concomitantly. The patient reported to have first noticed the skin lesion in October 2017 and an inguinal swelling in February 2019. A biopsy of the skin was taken in March 2019. Histology, IHC and MelArray were performed (see Figure 2).
Figure 2 Diagnostics in intermediate spitzoid lesion.
Clinical presentation of the lesion in March 2019 (A). Conventional histology showed a lesion with nevoid architecture with an acanthotic epithelial reaction pattern. In the dermis there are abundant preferentially spindle cell shaped melanocytic cells presenting disconcerting deep infiltration as well as pleomorphic nuclei and mitotic activity. (H&E, original magnification 40×) (B) (H&E, original magnification 100×) (C). p16 immunoreactivity was seen as far as the deep dermis (P16 staining, original magnification 40×) (D). Ki67 staining confirmed an increased fraction of cells undergoing mitotic proliferation. (Ki67 staining, original magnification 100×) (E). HMB45 staining was negative in tumor cells (HMB45 staining, original magnification 40×) (F). CNV analysis showed no alterations in MelArray genes (G). 7 non-synonymous mutations (11 mut/Mb) were detected in MelArray genes. MelArray also showed a variant in the RASA2 gene (c876_877delinsTT) (H).
Based on this diagnostic constellation, a re-excision with 1 cm safety margin was carried out shortly after.
Fine needle aspiration of the enlarged right inguinal lymph node with a diameter of 1 cm and thereafter a modified lymphadenectomy was performed in April 2019.
Histology and IHC of the lymphadenectomy sample showed locoregional spreading.
A PET/CT performed before the operation showed no further manifestations of disease.
The family was informed about the uncertain prognostic outcome. We recommended a close follow-up regimen with clinical assessments every 6 weeks and imaging every 3 months, alternating ultrasound and PET/CT scans and no adjuvant therapy. After 9 months, no relapses have occurred.
Patient 3
A female was referred to our clinic in April 2017 at the age of 14. The girl initially presented with a 15 mm, asymmetrically pigmented lesion on her back. The lesion had been present for years but had increased in size and thickness. Upon biopsy, a distinctly malignant histology and IHC features were seen; MelArray was performed to assess mutational status (see Figure 3, Supplementary Figures 1 and 2).
Figure 3 Diagnostics in malignant spitzoid lesion.
Clinical presentation of primary not available. Conventional histology showed a polypoid, asymmetrical lesion with irregular shouldering (H&E, original original magnification 40×). (A) Melanocytic nests and mutiple single cells, focally lining up in the junction zone present in the atrophic epidermis with slight hyperkeratosis, spindle-like cells with polymorphic nuclei and pagetoid epidermal spread and lack of maturation in the dermis lead to the diagnosis of melanoma with a Breslow depth of 1.9 mm (H&E, original magnification 100×). (B) Denoised copy ratio and CNV analysis showed a high number of CNVs (1938 CNVs). (C) 11 non-synonymous mutations (17.5 mut/Mb) were seen. A BRAF p.V600E (D) mutation as well as alterations in several other melanoma-relevant genes were detected. These included amplifications (such as CCND1 (chromosome 11)) and heterozygous losses (such as loss of CDKN2A (chromosome 9)) (see Supplementary Materials).
The clinical management followed current melanoma guidelines: a re-excision with 2 cm safety margin and sentinel lymph node biopsy (SLNB) were performed. The SLNB showed a 2.5 mm metastasis. Adjusted lymphadenectomy was carried out in a peripheral center and was tumor-free. The patient was treated with adjuvant Ipilimumab without complications from August to November 2017. Follow-ups took place every 3 months and showed no recurrence until February 2019, when multiple lymph node, lung and brain metastases were detected during routine diagnostics. The biggest brain metastasis was excised and irradiated stereotactically. Systemic immunotherapy with Ipilimumab and Nivolumab was initiated in March 2019. The patient had to discontinue immunotherapy due to progressive disease and myositis of the ocular muscles after her second and third infusions.
The patient is now undergoing targeted therapy with Dabrafenib and Trametinib since May 2019. She is followed up clinically every month, with imaging every 3 months.
The last PET/CT performed in December 2019 showed complete response of all extracranial lesions and cMRI showed stable disease.
DISCUSSION AND CONCLUSIONS
Variability of histologic classification [3, 7, 8] and the absence of standardized ancillary diagnostic or therapeutic algorithms [2] create insecurity concerning clinical management and prognosis of patients with spitzoid lesions [1, 9].
In our first patient, unremarkable IHC and molecular patterns lead us to believe that the biology of the lesion was most likely benign and a loose regimen with regular clinical follow-ups was chosen.
The lesion in our second patient showed regular nevus architecture with large cells in conventional histology. Focal Ki-67 activity raised concern. Additionally, NGS showed a variant in the RASA2 gene, a tumor-suppressor for which inactivating mutations are described in 5% of melanomas [10]. To our best knowledge, there are no published reports showing RASA2 alterations in spitzoid lesions, hence the significance of the variant documented in this lesion is unknown.
The frequency of non-synonymous coding mutations suggested an intermediate genetic instability. The constellation of clinical presentation of primary lesion, histology, IHC and NGS, lead us to postulate an intermediate biologic instability of the lesion. Although the tumor had already developed lymph node spreading, we expect a low risk of developing further metastases.
In cases like hers, where prognosis is unpredictable, counseling of patients is crucial. A close follow-up regimen was chosen in agreement with the family, with close clinical follow-ups and frequent imaging. Adjuvant immunotherapy was not recommended.
In our third patient, IHC corroborated with histology, showing distinct signs of malignancy. NGS showed BRAF (p.V600E) mutation as well as a variety of other mutations (see Supplementary Materials) and a high amount of copy number variants (CNVs) in the genes analyzed by MelArray. All technologies pointed towards high potential for malignant course of disease, supporting the clinicians’ decision to proceed according to melanoma guidelines including adjuvant immunotherapy. Our primary goal was to define the dignity of these lesions and find a suitable therapeutic strategy, rather than classify them by nomenclature. Nevertheless, we would like to note that, since Spitz nevi only rarely present BRAF (p.V600E) mutations [2, 11], whereas common melanocytic nevi often do [12], we decided to classify this lesion as spitzoid melanoma rather than Spitz melanoma. Hence, we would like to underline that, by using NGS as a part of a standardized diagnostic algorithm, we were able to differentiate between a lesion with traits typical for Spitz tumors versus other types of melanoma by analyzing it’s genetic hallmarks in a clinically and histologically malignant lesion with spitzoid traits.
The combination of specific IHC-staining and NGS gave valuable insight on lesion biology in all cases. As NGS accessibility increases, it is conceivable that it will play a role in routine assessment of biologic potential of spitzoid lesions in the near future. Although the mutational landscape of Spitz tumors differs from cutaneous melanoma [2, 4, 12], many of previously mentioned genetic alterations found in Spitz tumors [2, 11, 13] are mutations, amplifications and losses that are detectable by MelArray (as HRAS mutations, BAP1 mutations, TERTp mutations. see Supplementary Materials). A weakness of the use of this customized NGS panel for characterization of Spitz tumors is the lack of detectability of fusions, which make up a significant part of their genetic landscape [2, 11, 13].
However, information on mutational burden and CNV analysis allows us to estimate the genomic alteration burden that might reflect malignant potential, as multiple mutations and CNVs tend to be more common in lesions with higher malignancy [4, 14, 15].
We are confident that a standardized classification system, which routinely includes IHC and NGS, will give more clarity on spitzoid lesions in the near future [2, 16].
For centers rarely confronted with spitzoid lesions and technologies such as NGS are not readily available, we suggest cases be referred to reference centers for further assessment [2].
With these cases we portray three different clinical, histological and molecular manifestations of spitzoid lesions. All the information gained impacted the clinical management plan. Here we present a possible algorithm for the classification of biologic potential of spitzoid lesions (Figure 4).
Figure 4 Proposed diagnostic and therapeutic algorithm [2].
IHC combining proliferative and melanocytic markers (for example Ki67, p16, HMB45). If lesion seems benign in histology and IHC, then further analysis might not be needed. If lesion shows unclear or malignant characteristics, MelArray should be performed. Management: probably benign lesions should be totally excised and followed up clinically, intermediate lesions should be excised with a safety margin and potentially receive SLNB, although this is still subject of fierce debate. Malignant lesions should be managed according to melanoma guidelines.
Larger, multi-center validation studies and registries with long-term follow-up are needed to evaluate feasibility and clinical relevance of routine implementation.
Author contributions
RD conceived the algorithm. MLH coordinated and documented patient information. RBW and RD contributed to collecting cases. MLH wrote manuscript with input from all authors. All authors discussed and contributed to the final manuscript.
CONFLICTS OF INTEREST
MLH, RBW, BM and SNF have no conflicts of interests. JM has intermittent project focused consultant or advisory relationships with Merck/Pfizer, Merck Sharp & Dohme, Amgen, Novartis and Pierre Fabre and has received travel support from Ultrasun, L’Oréal, Merck Sharp & Dohme, Bristol Myers and Squibb und Pierre Fabre outside of the submitted work. RD has intermittent, project focused consulting and/or advisory relationships with Novartis, Merck Sharp & Dhome (MSD), Bristol-Myers Squibb (BMS), Roche, Amgen, Takeda, Pierre Fabre, Sun Pharma, Sanofi, Catalym, Second Genome outside the submitted work.
FUNDING
This research did not receive any specific grant from funding agencies in the public, commercial, or not-for-profit sectors.
SUPPLEMENTARY MATERIALS | IPILIMUMAB, NIVOLUMAB | DrugsGivenReaction | CC BY | 33520116 | 19,076,274 | 2021-01-19 |
Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Aspergillus infection'. | Tocilizumab administration in COVID-19 patients: Water on the fire or gasoline?
Tocilizumab is widely being used to treat COVID-19. Although reducing systemic inflammation, it also increases the risk for secondary infections as a result of the immunosuppression produced. We report the case of a 69-year-old patient admitted to the ICU with severe respiratory distress caused by COVID-19 pneumonia who developed pulmonary aspergillosis. On the basis of these findings, we suggest early testing for pulmonary aspergillosis in COVID-19 patients treated with tocilizumab.
1 Introduction
Aspergillus is an opportunistic fungus mainly affecting immunocompromised patients. A high rate of invasive pulmonary aspergillosis has been demonstrated among critically ill patients admitted to the ICU with severe influenza, which may contribute to their high odds of mortality [1]. In the early days of the Sars-CoV-2 pandemic, several case reports emerged from Wuhan of COVID-19-associated pulmonary aspergillosis (CAPA) [2]. Many risk factors for CAPA were recognized among critically ill COVID-19 patients, including lymphopenia, high levels of systemic pro-inflammatory cytokines, and the use of steroids [3].
Tocilizumab is a recombinant humanized monoclonal antibody against the interleukin-6 receptor. Initially, it showed promising results in reducing the severity of COVID-19 infection in critically ill patients. It dramatically reduces the potent inflammatory effects of IL-6 responsible for causing the lung damage and eventual multiorgan failure associated with COVID-19 [4]. A large retrospective study found that tocilizumab reduced the risk of death and the odds of needing mechanical ventilation in severe COVID-19 pneumonia [5]. However, subsequent findings from large randomized controlled trials raised doubts regarding these findings.
Here, we report the case of a critically ill patient who developed CAPA following tocilizumab administration.
2 Case
A 69-year-old man was admitted to the emergency department (ED) with fever and a cough which he had had for two days. His medical history included HBV-related liver cirrhosis, arterial hypertension and mild obesity (Body Mass Index 32). The man was calm and cooperative during his ED visit. His vital signs were: ABP 160/100 mmHg, SpO2 97% while breathing room air (PaO2/FIO2=303 mmHg), HR 75/min, and body temperature 36.7 °C. His white blood cell count was 3849/mm3, platelets were 62,000/mm3 (abnormal), and lymphocytes were 2140/mm3. C-reactive protein was 1.48 mg/L, procalcitonin (PCT) was 0.04 ng/ml, pro-adrenomedullin (pro-ADM) was 0.69 nMol/L, and IL-6 was 27.0 pg/mL (abnormal). A real-time PCR nasal swab tested positive for SARS-COV2.
The patient was then admitted to the infectious diseases ward (day 0) where he was treated with dexamethasone intravenously 6 mg per day. Given his worsening clinical situation, which necessitated increasing levels of oxygen provided by non-invasive ventilation using a full face mask, he was finally admitted to the ICU (day 8). In the ICU, the patient required immediate endotracheal intubation and invasive mechanical ventilation due to worsening dyspnoea associated with a PaO2/FIO2 of 135 mmHg. On his second day in the ICU (day 10), the patient's IL-6 levels reached 223.0 pg/mL (abnormal), thus the decision to administer tocilizumab that same day was taken (the patient was also being treated with entecavir for HBV-related cirrhosis).
Following tocilizumab administration, pre-emptive ceftobiprole treatment was started, 500 mg intravenously every 8 hours according to our internal protocol (day 10 until day 19). On day 15, the patient underwent an early percutaneous tracheostomy, as per our routine practice in COVID-19 patients, in order to facilitate easier weaning from mechanical ventilation.
On day 23, acyclovir (10 mg/kg BW) was administered intravenously every 8 hours to treat Herpes reactivation (HSV1-DNA detected in blood: 5197 copies/mL, abnormal). The same day, liposomal amphotericin B (3 mg/kg BW that was stopped after 30 days of therapy) was also given despite the absence of microbiological findings due to the suspicion of CAPA as suggested by the patient's high serum levels of β–D glucan (86.9 pg/ml, abnormal).
Aspergillus fumigatus was finally isolated from the bronchial aspirate on day 37, 22 days after tocilizumab administration and 12 days after the first positive result for serum β–D glucan.
Galactomannan levels in serum and alveolar fluid were tested on day 17, 20, 26 and 32. In the same days bronchoalveolar lavage fluid was also investigated through standard bacterial and fungal cultures and multiplex PCR filmarray. All these tests resulted negative for Aspergillus.
Repeated CT scans of the thorax showed the development over time of a cavity in the lung parenchyma, supporting our suspicion of pulmonary Aspergillus infection (see Fig. 1, Fig. 2, Fig. 3).Fig. 1 CT scan of the thorax at hospital admission (day 0) demonstrates diffuse subpleural ground-glass opacity.
Fig. 1
Fig. 2 CT scan of the thorax taken on day 14 demonstrates the appearance of consolidation in the upper left pulmonary lobe (blue arrow), extended ground-glass opacity and the crazy-paving pattern associated with posterior lung consolidation. (For interpretation of the references to colour in this figure legend, the reader is referred to the Web version of this article.)
Fig. 2
Fig. 3 CT scan (day 28) demonstrating a large septated cavity in the lung parenchyma suspected to be an Aspergillus lesion (blue arrow). (For interpretation of the references to colour in this figure legend, the reader is referred to the Web version of this article.)
Fig. 3
On day 43, the patient was discharged from the ICU to the Pneumology Unit with spontaneous breathing through the tracheostomy, which was removed on day 58. He went to rehabilitation unit in good condition after 68 days of hospitalization.
3 Discussion
The COVID-19 pandemic raises important questions regarding the treatment of coronaviruses. To the best of our knowledge, no single drug has been demonstrated to be effective in critically ill patients, and more evidence is required [6,7]. Many drugs and treatments (e.g. hydroxychloroquine, lopinavir/ritonavir, darunavir/cobicistat, etc.) have been proposed for the treatment of critically ill COVID-19 patients. One goal of these treatments is to reduce viral spread and replication. Another is to limit hyperinflammation and the triggering of a systemic response during the later phase of an infection which could lead to multiorgan dysfunction [8].
Steroids constitute the cornerstone treatment for COVID-19. The aim of steroid treatment is to modulate the inflammatory response, being recognized as a standard of care in the latest WHO guidelines [9]. Other drugs have also been proposed and tested for their capacity to limit the hyperinflammation that characterizes the later stages of COVID-19. These include inhibitors of the IL-1β and IL-6 receptor, of which anakinra and tocilizumab are the most commonly used. It is worth noting here that IL-6 also promotes viral and bacterial clearance. However, excessive inflammation could increase vascular permeability, inducing acute respiratory distress syndrome (ARDS), cardiac arrhythmia and other negative consequences [10].
From a theoretical perspective, tocilizumab therapy is currently considered the most appropriate. Its overall goal is to prevent multiorgan dysfunction caused by a cytokine storm. However, the associated consequences of immunosuppression must also be taken into account. Warnings about the increased risk of bacterial and fungal infections following immunosuppressant therapy have become more numerous over the last year [11]. Lymphopenia is present in a high percentage of COVID-19 patients. The additional use of steroids and other immunosuppressive drugs thus increases the risk for fungal infections, especially Aspergillus sp. In the case described, HBV-related cirrhosis was an additional risk factor for fungal infection. Indeed, evidence suggests there to be more secondary infections in COVID-19 patients treated with tocilizumab than in those not receiving the drug [12]. Moreover, it is difficult to confirm suspected infections using standard laboratory tests for infection, such as C-reactive protein or procalcitonin. These markers rapidly decrease after tocilizumab administration, with very low values persisting for many days. As a consequence, doctors are unlikely to suspect an infection.
Some authors recommend empirical antibiotic prophylaxis, including antifungal drugs. Indeed, the difficulty and time involved in isolating Aspergillus from bronchoalveolar lavage fluid further support the adoption of an empirical antifungal approach to COVID-19 therapy in critically ill patients [13]. In fact, in the case herein described, following our initial suspicion of CAPA due to the significant increase in β–D glucan levels (on day 23), the first microbiological specimen testing positive for Aspergillus was not obtained until 12 days later.
Diagnosis of invasive pulmonary aspergillosis (IPA) in the ICU remains challenging. For this reason, the European Organization for Research and Treatment of Cancer/Mycoses Study Group (EORTC/MSG) criteria have been supplemented with a specific algorithm in critically ill patients [14]. Although biomarkers of Aspergillus infection, such as serum galactomannan or β–D glucan, are generally deemed to be unsensitive, testing for their presence in serum and bronchoalveolar lavage fluid was recently added to the EORTC/MSG criteria to aid the identification of IPA in influenza patients admitted to ICU. In our case, in addition to the patient's risk factors for IPA, the sudden increase in β–D glucan levels was enough for us to deem therapy with a broad spectrum antifungal necessary. Curiously, although the patient tested positive for β–D glucan, he remained negative for galactomannan.
In the present case, tocilizumab may have favoured CAPA, although this remains to be proven.
Many questions remain unanswered regarding the role of tocilizumab therapy in COVID-19. Physicians generally prescribe it believing that they are damping down the fire … however, in some cases, it might be better likened to adding gasoline and not water!
Declaration of competing interest
The authors have no conflicts of interest to declare.
Acknowledgements
The authors do not wish to make any specific acknowledgements. | CEFTOBIPROLE, DEXAMETHASONE, TOCILIZUMAB | DrugsGivenReaction | CC BY | 33520634 | 19,154,715 | 2021-03 |
Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Bronchopulmonary aspergillosis'. | Tocilizumab administration in COVID-19 patients: Water on the fire or gasoline?
Tocilizumab is widely being used to treat COVID-19. Although reducing systemic inflammation, it also increases the risk for secondary infections as a result of the immunosuppression produced. We report the case of a 69-year-old patient admitted to the ICU with severe respiratory distress caused by COVID-19 pneumonia who developed pulmonary aspergillosis. On the basis of these findings, we suggest early testing for pulmonary aspergillosis in COVID-19 patients treated with tocilizumab.
1 Introduction
Aspergillus is an opportunistic fungus mainly affecting immunocompromised patients. A high rate of invasive pulmonary aspergillosis has been demonstrated among critically ill patients admitted to the ICU with severe influenza, which may contribute to their high odds of mortality [1]. In the early days of the Sars-CoV-2 pandemic, several case reports emerged from Wuhan of COVID-19-associated pulmonary aspergillosis (CAPA) [2]. Many risk factors for CAPA were recognized among critically ill COVID-19 patients, including lymphopenia, high levels of systemic pro-inflammatory cytokines, and the use of steroids [3].
Tocilizumab is a recombinant humanized monoclonal antibody against the interleukin-6 receptor. Initially, it showed promising results in reducing the severity of COVID-19 infection in critically ill patients. It dramatically reduces the potent inflammatory effects of IL-6 responsible for causing the lung damage and eventual multiorgan failure associated with COVID-19 [4]. A large retrospective study found that tocilizumab reduced the risk of death and the odds of needing mechanical ventilation in severe COVID-19 pneumonia [5]. However, subsequent findings from large randomized controlled trials raised doubts regarding these findings.
Here, we report the case of a critically ill patient who developed CAPA following tocilizumab administration.
2 Case
A 69-year-old man was admitted to the emergency department (ED) with fever and a cough which he had had for two days. His medical history included HBV-related liver cirrhosis, arterial hypertension and mild obesity (Body Mass Index 32). The man was calm and cooperative during his ED visit. His vital signs were: ABP 160/100 mmHg, SpO2 97% while breathing room air (PaO2/FIO2=303 mmHg), HR 75/min, and body temperature 36.7 °C. His white blood cell count was 3849/mm3, platelets were 62,000/mm3 (abnormal), and lymphocytes were 2140/mm3. C-reactive protein was 1.48 mg/L, procalcitonin (PCT) was 0.04 ng/ml, pro-adrenomedullin (pro-ADM) was 0.69 nMol/L, and IL-6 was 27.0 pg/mL (abnormal). A real-time PCR nasal swab tested positive for SARS-COV2.
The patient was then admitted to the infectious diseases ward (day 0) where he was treated with dexamethasone intravenously 6 mg per day. Given his worsening clinical situation, which necessitated increasing levels of oxygen provided by non-invasive ventilation using a full face mask, he was finally admitted to the ICU (day 8). In the ICU, the patient required immediate endotracheal intubation and invasive mechanical ventilation due to worsening dyspnoea associated with a PaO2/FIO2 of 135 mmHg. On his second day in the ICU (day 10), the patient's IL-6 levels reached 223.0 pg/mL (abnormal), thus the decision to administer tocilizumab that same day was taken (the patient was also being treated with entecavir for HBV-related cirrhosis).
Following tocilizumab administration, pre-emptive ceftobiprole treatment was started, 500 mg intravenously every 8 hours according to our internal protocol (day 10 until day 19). On day 15, the patient underwent an early percutaneous tracheostomy, as per our routine practice in COVID-19 patients, in order to facilitate easier weaning from mechanical ventilation.
On day 23, acyclovir (10 mg/kg BW) was administered intravenously every 8 hours to treat Herpes reactivation (HSV1-DNA detected in blood: 5197 copies/mL, abnormal). The same day, liposomal amphotericin B (3 mg/kg BW that was stopped after 30 days of therapy) was also given despite the absence of microbiological findings due to the suspicion of CAPA as suggested by the patient's high serum levels of β–D glucan (86.9 pg/ml, abnormal).
Aspergillus fumigatus was finally isolated from the bronchial aspirate on day 37, 22 days after tocilizumab administration and 12 days after the first positive result for serum β–D glucan.
Galactomannan levels in serum and alveolar fluid were tested on day 17, 20, 26 and 32. In the same days bronchoalveolar lavage fluid was also investigated through standard bacterial and fungal cultures and multiplex PCR filmarray. All these tests resulted negative for Aspergillus.
Repeated CT scans of the thorax showed the development over time of a cavity in the lung parenchyma, supporting our suspicion of pulmonary Aspergillus infection (see Fig. 1, Fig. 2, Fig. 3).Fig. 1 CT scan of the thorax at hospital admission (day 0) demonstrates diffuse subpleural ground-glass opacity.
Fig. 1
Fig. 2 CT scan of the thorax taken on day 14 demonstrates the appearance of consolidation in the upper left pulmonary lobe (blue arrow), extended ground-glass opacity and the crazy-paving pattern associated with posterior lung consolidation. (For interpretation of the references to colour in this figure legend, the reader is referred to the Web version of this article.)
Fig. 2
Fig. 3 CT scan (day 28) demonstrating a large septated cavity in the lung parenchyma suspected to be an Aspergillus lesion (blue arrow). (For interpretation of the references to colour in this figure legend, the reader is referred to the Web version of this article.)
Fig. 3
On day 43, the patient was discharged from the ICU to the Pneumology Unit with spontaneous breathing through the tracheostomy, which was removed on day 58. He went to rehabilitation unit in good condition after 68 days of hospitalization.
3 Discussion
The COVID-19 pandemic raises important questions regarding the treatment of coronaviruses. To the best of our knowledge, no single drug has been demonstrated to be effective in critically ill patients, and more evidence is required [6,7]. Many drugs and treatments (e.g. hydroxychloroquine, lopinavir/ritonavir, darunavir/cobicistat, etc.) have been proposed for the treatment of critically ill COVID-19 patients. One goal of these treatments is to reduce viral spread and replication. Another is to limit hyperinflammation and the triggering of a systemic response during the later phase of an infection which could lead to multiorgan dysfunction [8].
Steroids constitute the cornerstone treatment for COVID-19. The aim of steroid treatment is to modulate the inflammatory response, being recognized as a standard of care in the latest WHO guidelines [9]. Other drugs have also been proposed and tested for their capacity to limit the hyperinflammation that characterizes the later stages of COVID-19. These include inhibitors of the IL-1β and IL-6 receptor, of which anakinra and tocilizumab are the most commonly used. It is worth noting here that IL-6 also promotes viral and bacterial clearance. However, excessive inflammation could increase vascular permeability, inducing acute respiratory distress syndrome (ARDS), cardiac arrhythmia and other negative consequences [10].
From a theoretical perspective, tocilizumab therapy is currently considered the most appropriate. Its overall goal is to prevent multiorgan dysfunction caused by a cytokine storm. However, the associated consequences of immunosuppression must also be taken into account. Warnings about the increased risk of bacterial and fungal infections following immunosuppressant therapy have become more numerous over the last year [11]. Lymphopenia is present in a high percentage of COVID-19 patients. The additional use of steroids and other immunosuppressive drugs thus increases the risk for fungal infections, especially Aspergillus sp. In the case described, HBV-related cirrhosis was an additional risk factor for fungal infection. Indeed, evidence suggests there to be more secondary infections in COVID-19 patients treated with tocilizumab than in those not receiving the drug [12]. Moreover, it is difficult to confirm suspected infections using standard laboratory tests for infection, such as C-reactive protein or procalcitonin. These markers rapidly decrease after tocilizumab administration, with very low values persisting for many days. As a consequence, doctors are unlikely to suspect an infection.
Some authors recommend empirical antibiotic prophylaxis, including antifungal drugs. Indeed, the difficulty and time involved in isolating Aspergillus from bronchoalveolar lavage fluid further support the adoption of an empirical antifungal approach to COVID-19 therapy in critically ill patients [13]. In fact, in the case herein described, following our initial suspicion of CAPA due to the significant increase in β–D glucan levels (on day 23), the first microbiological specimen testing positive for Aspergillus was not obtained until 12 days later.
Diagnosis of invasive pulmonary aspergillosis (IPA) in the ICU remains challenging. For this reason, the European Organization for Research and Treatment of Cancer/Mycoses Study Group (EORTC/MSG) criteria have been supplemented with a specific algorithm in critically ill patients [14]. Although biomarkers of Aspergillus infection, such as serum galactomannan or β–D glucan, are generally deemed to be unsensitive, testing for their presence in serum and bronchoalveolar lavage fluid was recently added to the EORTC/MSG criteria to aid the identification of IPA in influenza patients admitted to ICU. In our case, in addition to the patient's risk factors for IPA, the sudden increase in β–D glucan levels was enough for us to deem therapy with a broad spectrum antifungal necessary. Curiously, although the patient tested positive for β–D glucan, he remained negative for galactomannan.
In the present case, tocilizumab may have favoured CAPA, although this remains to be proven.
Many questions remain unanswered regarding the role of tocilizumab therapy in COVID-19. Physicians generally prescribe it believing that they are damping down the fire … however, in some cases, it might be better likened to adding gasoline and not water!
Declaration of competing interest
The authors have no conflicts of interest to declare.
Acknowledgements
The authors do not wish to make any specific acknowledgements. | CEFTOBIPROLE, DEXAMETHASONE, ENTECAVIR, TOCILIZUMAB | DrugsGivenReaction | CC BY | 33520634 | 18,923,578 | 2021-03 |
Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Herpes virus infection'. | Tocilizumab administration in COVID-19 patients: Water on the fire or gasoline?
Tocilizumab is widely being used to treat COVID-19. Although reducing systemic inflammation, it also increases the risk for secondary infections as a result of the immunosuppression produced. We report the case of a 69-year-old patient admitted to the ICU with severe respiratory distress caused by COVID-19 pneumonia who developed pulmonary aspergillosis. On the basis of these findings, we suggest early testing for pulmonary aspergillosis in COVID-19 patients treated with tocilizumab.
1 Introduction
Aspergillus is an opportunistic fungus mainly affecting immunocompromised patients. A high rate of invasive pulmonary aspergillosis has been demonstrated among critically ill patients admitted to the ICU with severe influenza, which may contribute to their high odds of mortality [1]. In the early days of the Sars-CoV-2 pandemic, several case reports emerged from Wuhan of COVID-19-associated pulmonary aspergillosis (CAPA) [2]. Many risk factors for CAPA were recognized among critically ill COVID-19 patients, including lymphopenia, high levels of systemic pro-inflammatory cytokines, and the use of steroids [3].
Tocilizumab is a recombinant humanized monoclonal antibody against the interleukin-6 receptor. Initially, it showed promising results in reducing the severity of COVID-19 infection in critically ill patients. It dramatically reduces the potent inflammatory effects of IL-6 responsible for causing the lung damage and eventual multiorgan failure associated with COVID-19 [4]. A large retrospective study found that tocilizumab reduced the risk of death and the odds of needing mechanical ventilation in severe COVID-19 pneumonia [5]. However, subsequent findings from large randomized controlled trials raised doubts regarding these findings.
Here, we report the case of a critically ill patient who developed CAPA following tocilizumab administration.
2 Case
A 69-year-old man was admitted to the emergency department (ED) with fever and a cough which he had had for two days. His medical history included HBV-related liver cirrhosis, arterial hypertension and mild obesity (Body Mass Index 32). The man was calm and cooperative during his ED visit. His vital signs were: ABP 160/100 mmHg, SpO2 97% while breathing room air (PaO2/FIO2=303 mmHg), HR 75/min, and body temperature 36.7 °C. His white blood cell count was 3849/mm3, platelets were 62,000/mm3 (abnormal), and lymphocytes were 2140/mm3. C-reactive protein was 1.48 mg/L, procalcitonin (PCT) was 0.04 ng/ml, pro-adrenomedullin (pro-ADM) was 0.69 nMol/L, and IL-6 was 27.0 pg/mL (abnormal). A real-time PCR nasal swab tested positive for SARS-COV2.
The patient was then admitted to the infectious diseases ward (day 0) where he was treated with dexamethasone intravenously 6 mg per day. Given his worsening clinical situation, which necessitated increasing levels of oxygen provided by non-invasive ventilation using a full face mask, he was finally admitted to the ICU (day 8). In the ICU, the patient required immediate endotracheal intubation and invasive mechanical ventilation due to worsening dyspnoea associated with a PaO2/FIO2 of 135 mmHg. On his second day in the ICU (day 10), the patient's IL-6 levels reached 223.0 pg/mL (abnormal), thus the decision to administer tocilizumab that same day was taken (the patient was also being treated with entecavir for HBV-related cirrhosis).
Following tocilizumab administration, pre-emptive ceftobiprole treatment was started, 500 mg intravenously every 8 hours according to our internal protocol (day 10 until day 19). On day 15, the patient underwent an early percutaneous tracheostomy, as per our routine practice in COVID-19 patients, in order to facilitate easier weaning from mechanical ventilation.
On day 23, acyclovir (10 mg/kg BW) was administered intravenously every 8 hours to treat Herpes reactivation (HSV1-DNA detected in blood: 5197 copies/mL, abnormal). The same day, liposomal amphotericin B (3 mg/kg BW that was stopped after 30 days of therapy) was also given despite the absence of microbiological findings due to the suspicion of CAPA as suggested by the patient's high serum levels of β–D glucan (86.9 pg/ml, abnormal).
Aspergillus fumigatus was finally isolated from the bronchial aspirate on day 37, 22 days after tocilizumab administration and 12 days after the first positive result for serum β–D glucan.
Galactomannan levels in serum and alveolar fluid were tested on day 17, 20, 26 and 32. In the same days bronchoalveolar lavage fluid was also investigated through standard bacterial and fungal cultures and multiplex PCR filmarray. All these tests resulted negative for Aspergillus.
Repeated CT scans of the thorax showed the development over time of a cavity in the lung parenchyma, supporting our suspicion of pulmonary Aspergillus infection (see Fig. 1, Fig. 2, Fig. 3).Fig. 1 CT scan of the thorax at hospital admission (day 0) demonstrates diffuse subpleural ground-glass opacity.
Fig. 1
Fig. 2 CT scan of the thorax taken on day 14 demonstrates the appearance of consolidation in the upper left pulmonary lobe (blue arrow), extended ground-glass opacity and the crazy-paving pattern associated with posterior lung consolidation. (For interpretation of the references to colour in this figure legend, the reader is referred to the Web version of this article.)
Fig. 2
Fig. 3 CT scan (day 28) demonstrating a large septated cavity in the lung parenchyma suspected to be an Aspergillus lesion (blue arrow). (For interpretation of the references to colour in this figure legend, the reader is referred to the Web version of this article.)
Fig. 3
On day 43, the patient was discharged from the ICU to the Pneumology Unit with spontaneous breathing through the tracheostomy, which was removed on day 58. He went to rehabilitation unit in good condition after 68 days of hospitalization.
3 Discussion
The COVID-19 pandemic raises important questions regarding the treatment of coronaviruses. To the best of our knowledge, no single drug has been demonstrated to be effective in critically ill patients, and more evidence is required [6,7]. Many drugs and treatments (e.g. hydroxychloroquine, lopinavir/ritonavir, darunavir/cobicistat, etc.) have been proposed for the treatment of critically ill COVID-19 patients. One goal of these treatments is to reduce viral spread and replication. Another is to limit hyperinflammation and the triggering of a systemic response during the later phase of an infection which could lead to multiorgan dysfunction [8].
Steroids constitute the cornerstone treatment for COVID-19. The aim of steroid treatment is to modulate the inflammatory response, being recognized as a standard of care in the latest WHO guidelines [9]. Other drugs have also been proposed and tested for their capacity to limit the hyperinflammation that characterizes the later stages of COVID-19. These include inhibitors of the IL-1β and IL-6 receptor, of which anakinra and tocilizumab are the most commonly used. It is worth noting here that IL-6 also promotes viral and bacterial clearance. However, excessive inflammation could increase vascular permeability, inducing acute respiratory distress syndrome (ARDS), cardiac arrhythmia and other negative consequences [10].
From a theoretical perspective, tocilizumab therapy is currently considered the most appropriate. Its overall goal is to prevent multiorgan dysfunction caused by a cytokine storm. However, the associated consequences of immunosuppression must also be taken into account. Warnings about the increased risk of bacterial and fungal infections following immunosuppressant therapy have become more numerous over the last year [11]. Lymphopenia is present in a high percentage of COVID-19 patients. The additional use of steroids and other immunosuppressive drugs thus increases the risk for fungal infections, especially Aspergillus sp. In the case described, HBV-related cirrhosis was an additional risk factor for fungal infection. Indeed, evidence suggests there to be more secondary infections in COVID-19 patients treated with tocilizumab than in those not receiving the drug [12]. Moreover, it is difficult to confirm suspected infections using standard laboratory tests for infection, such as C-reactive protein or procalcitonin. These markers rapidly decrease after tocilizumab administration, with very low values persisting for many days. As a consequence, doctors are unlikely to suspect an infection.
Some authors recommend empirical antibiotic prophylaxis, including antifungal drugs. Indeed, the difficulty and time involved in isolating Aspergillus from bronchoalveolar lavage fluid further support the adoption of an empirical antifungal approach to COVID-19 therapy in critically ill patients [13]. In fact, in the case herein described, following our initial suspicion of CAPA due to the significant increase in β–D glucan levels (on day 23), the first microbiological specimen testing positive for Aspergillus was not obtained until 12 days later.
Diagnosis of invasive pulmonary aspergillosis (IPA) in the ICU remains challenging. For this reason, the European Organization for Research and Treatment of Cancer/Mycoses Study Group (EORTC/MSG) criteria have been supplemented with a specific algorithm in critically ill patients [14]. Although biomarkers of Aspergillus infection, such as serum galactomannan or β–D glucan, are generally deemed to be unsensitive, testing for their presence in serum and bronchoalveolar lavage fluid was recently added to the EORTC/MSG criteria to aid the identification of IPA in influenza patients admitted to ICU. In our case, in addition to the patient's risk factors for IPA, the sudden increase in β–D glucan levels was enough for us to deem therapy with a broad spectrum antifungal necessary. Curiously, although the patient tested positive for β–D glucan, he remained negative for galactomannan.
In the present case, tocilizumab may have favoured CAPA, although this remains to be proven.
Many questions remain unanswered regarding the role of tocilizumab therapy in COVID-19. Physicians generally prescribe it believing that they are damping down the fire … however, in some cases, it might be better likened to adding gasoline and not water!
Declaration of competing interest
The authors have no conflicts of interest to declare.
Acknowledgements
The authors do not wish to make any specific acknowledgements. | CEFTOBIPROLE, DEXAMETHASONE, ENTECAVIR, TOCILIZUMAB | DrugsGivenReaction | CC BY | 33520634 | 18,923,578 | 2021-03 |
Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Intentional product use issue'. | Tocilizumab administration in COVID-19 patients: Water on the fire or gasoline?
Tocilizumab is widely being used to treat COVID-19. Although reducing systemic inflammation, it also increases the risk for secondary infections as a result of the immunosuppression produced. We report the case of a 69-year-old patient admitted to the ICU with severe respiratory distress caused by COVID-19 pneumonia who developed pulmonary aspergillosis. On the basis of these findings, we suggest early testing for pulmonary aspergillosis in COVID-19 patients treated with tocilizumab.
1 Introduction
Aspergillus is an opportunistic fungus mainly affecting immunocompromised patients. A high rate of invasive pulmonary aspergillosis has been demonstrated among critically ill patients admitted to the ICU with severe influenza, which may contribute to their high odds of mortality [1]. In the early days of the Sars-CoV-2 pandemic, several case reports emerged from Wuhan of COVID-19-associated pulmonary aspergillosis (CAPA) [2]. Many risk factors for CAPA were recognized among critically ill COVID-19 patients, including lymphopenia, high levels of systemic pro-inflammatory cytokines, and the use of steroids [3].
Tocilizumab is a recombinant humanized monoclonal antibody against the interleukin-6 receptor. Initially, it showed promising results in reducing the severity of COVID-19 infection in critically ill patients. It dramatically reduces the potent inflammatory effects of IL-6 responsible for causing the lung damage and eventual multiorgan failure associated with COVID-19 [4]. A large retrospective study found that tocilizumab reduced the risk of death and the odds of needing mechanical ventilation in severe COVID-19 pneumonia [5]. However, subsequent findings from large randomized controlled trials raised doubts regarding these findings.
Here, we report the case of a critically ill patient who developed CAPA following tocilizumab administration.
2 Case
A 69-year-old man was admitted to the emergency department (ED) with fever and a cough which he had had for two days. His medical history included HBV-related liver cirrhosis, arterial hypertension and mild obesity (Body Mass Index 32). The man was calm and cooperative during his ED visit. His vital signs were: ABP 160/100 mmHg, SpO2 97% while breathing room air (PaO2/FIO2=303 mmHg), HR 75/min, and body temperature 36.7 °C. His white blood cell count was 3849/mm3, platelets were 62,000/mm3 (abnormal), and lymphocytes were 2140/mm3. C-reactive protein was 1.48 mg/L, procalcitonin (PCT) was 0.04 ng/ml, pro-adrenomedullin (pro-ADM) was 0.69 nMol/L, and IL-6 was 27.0 pg/mL (abnormal). A real-time PCR nasal swab tested positive for SARS-COV2.
The patient was then admitted to the infectious diseases ward (day 0) where he was treated with dexamethasone intravenously 6 mg per day. Given his worsening clinical situation, which necessitated increasing levels of oxygen provided by non-invasive ventilation using a full face mask, he was finally admitted to the ICU (day 8). In the ICU, the patient required immediate endotracheal intubation and invasive mechanical ventilation due to worsening dyspnoea associated with a PaO2/FIO2 of 135 mmHg. On his second day in the ICU (day 10), the patient's IL-6 levels reached 223.0 pg/mL (abnormal), thus the decision to administer tocilizumab that same day was taken (the patient was also being treated with entecavir for HBV-related cirrhosis).
Following tocilizumab administration, pre-emptive ceftobiprole treatment was started, 500 mg intravenously every 8 hours according to our internal protocol (day 10 until day 19). On day 15, the patient underwent an early percutaneous tracheostomy, as per our routine practice in COVID-19 patients, in order to facilitate easier weaning from mechanical ventilation.
On day 23, acyclovir (10 mg/kg BW) was administered intravenously every 8 hours to treat Herpes reactivation (HSV1-DNA detected in blood: 5197 copies/mL, abnormal). The same day, liposomal amphotericin B (3 mg/kg BW that was stopped after 30 days of therapy) was also given despite the absence of microbiological findings due to the suspicion of CAPA as suggested by the patient's high serum levels of β–D glucan (86.9 pg/ml, abnormal).
Aspergillus fumigatus was finally isolated from the bronchial aspirate on day 37, 22 days after tocilizumab administration and 12 days after the first positive result for serum β–D glucan.
Galactomannan levels in serum and alveolar fluid were tested on day 17, 20, 26 and 32. In the same days bronchoalveolar lavage fluid was also investigated through standard bacterial and fungal cultures and multiplex PCR filmarray. All these tests resulted negative for Aspergillus.
Repeated CT scans of the thorax showed the development over time of a cavity in the lung parenchyma, supporting our suspicion of pulmonary Aspergillus infection (see Fig. 1, Fig. 2, Fig. 3).Fig. 1 CT scan of the thorax at hospital admission (day 0) demonstrates diffuse subpleural ground-glass opacity.
Fig. 1
Fig. 2 CT scan of the thorax taken on day 14 demonstrates the appearance of consolidation in the upper left pulmonary lobe (blue arrow), extended ground-glass opacity and the crazy-paving pattern associated with posterior lung consolidation. (For interpretation of the references to colour in this figure legend, the reader is referred to the Web version of this article.)
Fig. 2
Fig. 3 CT scan (day 28) demonstrating a large septated cavity in the lung parenchyma suspected to be an Aspergillus lesion (blue arrow). (For interpretation of the references to colour in this figure legend, the reader is referred to the Web version of this article.)
Fig. 3
On day 43, the patient was discharged from the ICU to the Pneumology Unit with spontaneous breathing through the tracheostomy, which was removed on day 58. He went to rehabilitation unit in good condition after 68 days of hospitalization.
3 Discussion
The COVID-19 pandemic raises important questions regarding the treatment of coronaviruses. To the best of our knowledge, no single drug has been demonstrated to be effective in critically ill patients, and more evidence is required [6,7]. Many drugs and treatments (e.g. hydroxychloroquine, lopinavir/ritonavir, darunavir/cobicistat, etc.) have been proposed for the treatment of critically ill COVID-19 patients. One goal of these treatments is to reduce viral spread and replication. Another is to limit hyperinflammation and the triggering of a systemic response during the later phase of an infection which could lead to multiorgan dysfunction [8].
Steroids constitute the cornerstone treatment for COVID-19. The aim of steroid treatment is to modulate the inflammatory response, being recognized as a standard of care in the latest WHO guidelines [9]. Other drugs have also been proposed and tested for their capacity to limit the hyperinflammation that characterizes the later stages of COVID-19. These include inhibitors of the IL-1β and IL-6 receptor, of which anakinra and tocilizumab are the most commonly used. It is worth noting here that IL-6 also promotes viral and bacterial clearance. However, excessive inflammation could increase vascular permeability, inducing acute respiratory distress syndrome (ARDS), cardiac arrhythmia and other negative consequences [10].
From a theoretical perspective, tocilizumab therapy is currently considered the most appropriate. Its overall goal is to prevent multiorgan dysfunction caused by a cytokine storm. However, the associated consequences of immunosuppression must also be taken into account. Warnings about the increased risk of bacterial and fungal infections following immunosuppressant therapy have become more numerous over the last year [11]. Lymphopenia is present in a high percentage of COVID-19 patients. The additional use of steroids and other immunosuppressive drugs thus increases the risk for fungal infections, especially Aspergillus sp. In the case described, HBV-related cirrhosis was an additional risk factor for fungal infection. Indeed, evidence suggests there to be more secondary infections in COVID-19 patients treated with tocilizumab than in those not receiving the drug [12]. Moreover, it is difficult to confirm suspected infections using standard laboratory tests for infection, such as C-reactive protein or procalcitonin. These markers rapidly decrease after tocilizumab administration, with very low values persisting for many days. As a consequence, doctors are unlikely to suspect an infection.
Some authors recommend empirical antibiotic prophylaxis, including antifungal drugs. Indeed, the difficulty and time involved in isolating Aspergillus from bronchoalveolar lavage fluid further support the adoption of an empirical antifungal approach to COVID-19 therapy in critically ill patients [13]. In fact, in the case herein described, following our initial suspicion of CAPA due to the significant increase in β–D glucan levels (on day 23), the first microbiological specimen testing positive for Aspergillus was not obtained until 12 days later.
Diagnosis of invasive pulmonary aspergillosis (IPA) in the ICU remains challenging. For this reason, the European Organization for Research and Treatment of Cancer/Mycoses Study Group (EORTC/MSG) criteria have been supplemented with a specific algorithm in critically ill patients [14]. Although biomarkers of Aspergillus infection, such as serum galactomannan or β–D glucan, are generally deemed to be unsensitive, testing for their presence in serum and bronchoalveolar lavage fluid was recently added to the EORTC/MSG criteria to aid the identification of IPA in influenza patients admitted to ICU. In our case, in addition to the patient's risk factors for IPA, the sudden increase in β–D glucan levels was enough for us to deem therapy with a broad spectrum antifungal necessary. Curiously, although the patient tested positive for β–D glucan, he remained negative for galactomannan.
In the present case, tocilizumab may have favoured CAPA, although this remains to be proven.
Many questions remain unanswered regarding the role of tocilizumab therapy in COVID-19. Physicians generally prescribe it believing that they are damping down the fire … however, in some cases, it might be better likened to adding gasoline and not water!
Declaration of competing interest
The authors have no conflicts of interest to declare.
Acknowledgements
The authors do not wish to make any specific acknowledgements. | CEFTOBIPROLE, DEXAMETHASONE, ENTECAVIR, TOCILIZUMAB | DrugsGivenReaction | CC BY | 33520634 | 18,923,578 | 2021-03 |
Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Off label use'. | Tocilizumab administration in COVID-19 patients: Water on the fire or gasoline?
Tocilizumab is widely being used to treat COVID-19. Although reducing systemic inflammation, it also increases the risk for secondary infections as a result of the immunosuppression produced. We report the case of a 69-year-old patient admitted to the ICU with severe respiratory distress caused by COVID-19 pneumonia who developed pulmonary aspergillosis. On the basis of these findings, we suggest early testing for pulmonary aspergillosis in COVID-19 patients treated with tocilizumab.
1 Introduction
Aspergillus is an opportunistic fungus mainly affecting immunocompromised patients. A high rate of invasive pulmonary aspergillosis has been demonstrated among critically ill patients admitted to the ICU with severe influenza, which may contribute to their high odds of mortality [1]. In the early days of the Sars-CoV-2 pandemic, several case reports emerged from Wuhan of COVID-19-associated pulmonary aspergillosis (CAPA) [2]. Many risk factors for CAPA were recognized among critically ill COVID-19 patients, including lymphopenia, high levels of systemic pro-inflammatory cytokines, and the use of steroids [3].
Tocilizumab is a recombinant humanized monoclonal antibody against the interleukin-6 receptor. Initially, it showed promising results in reducing the severity of COVID-19 infection in critically ill patients. It dramatically reduces the potent inflammatory effects of IL-6 responsible for causing the lung damage and eventual multiorgan failure associated with COVID-19 [4]. A large retrospective study found that tocilizumab reduced the risk of death and the odds of needing mechanical ventilation in severe COVID-19 pneumonia [5]. However, subsequent findings from large randomized controlled trials raised doubts regarding these findings.
Here, we report the case of a critically ill patient who developed CAPA following tocilizumab administration.
2 Case
A 69-year-old man was admitted to the emergency department (ED) with fever and a cough which he had had for two days. His medical history included HBV-related liver cirrhosis, arterial hypertension and mild obesity (Body Mass Index 32). The man was calm and cooperative during his ED visit. His vital signs were: ABP 160/100 mmHg, SpO2 97% while breathing room air (PaO2/FIO2=303 mmHg), HR 75/min, and body temperature 36.7 °C. His white blood cell count was 3849/mm3, platelets were 62,000/mm3 (abnormal), and lymphocytes were 2140/mm3. C-reactive protein was 1.48 mg/L, procalcitonin (PCT) was 0.04 ng/ml, pro-adrenomedullin (pro-ADM) was 0.69 nMol/L, and IL-6 was 27.0 pg/mL (abnormal). A real-time PCR nasal swab tested positive for SARS-COV2.
The patient was then admitted to the infectious diseases ward (day 0) where he was treated with dexamethasone intravenously 6 mg per day. Given his worsening clinical situation, which necessitated increasing levels of oxygen provided by non-invasive ventilation using a full face mask, he was finally admitted to the ICU (day 8). In the ICU, the patient required immediate endotracheal intubation and invasive mechanical ventilation due to worsening dyspnoea associated with a PaO2/FIO2 of 135 mmHg. On his second day in the ICU (day 10), the patient's IL-6 levels reached 223.0 pg/mL (abnormal), thus the decision to administer tocilizumab that same day was taken (the patient was also being treated with entecavir for HBV-related cirrhosis).
Following tocilizumab administration, pre-emptive ceftobiprole treatment was started, 500 mg intravenously every 8 hours according to our internal protocol (day 10 until day 19). On day 15, the patient underwent an early percutaneous tracheostomy, as per our routine practice in COVID-19 patients, in order to facilitate easier weaning from mechanical ventilation.
On day 23, acyclovir (10 mg/kg BW) was administered intravenously every 8 hours to treat Herpes reactivation (HSV1-DNA detected in blood: 5197 copies/mL, abnormal). The same day, liposomal amphotericin B (3 mg/kg BW that was stopped after 30 days of therapy) was also given despite the absence of microbiological findings due to the suspicion of CAPA as suggested by the patient's high serum levels of β–D glucan (86.9 pg/ml, abnormal).
Aspergillus fumigatus was finally isolated from the bronchial aspirate on day 37, 22 days after tocilizumab administration and 12 days after the first positive result for serum β–D glucan.
Galactomannan levels in serum and alveolar fluid were tested on day 17, 20, 26 and 32. In the same days bronchoalveolar lavage fluid was also investigated through standard bacterial and fungal cultures and multiplex PCR filmarray. All these tests resulted negative for Aspergillus.
Repeated CT scans of the thorax showed the development over time of a cavity in the lung parenchyma, supporting our suspicion of pulmonary Aspergillus infection (see Fig. 1, Fig. 2, Fig. 3).Fig. 1 CT scan of the thorax at hospital admission (day 0) demonstrates diffuse subpleural ground-glass opacity.
Fig. 1
Fig. 2 CT scan of the thorax taken on day 14 demonstrates the appearance of consolidation in the upper left pulmonary lobe (blue arrow), extended ground-glass opacity and the crazy-paving pattern associated with posterior lung consolidation. (For interpretation of the references to colour in this figure legend, the reader is referred to the Web version of this article.)
Fig. 2
Fig. 3 CT scan (day 28) demonstrating a large septated cavity in the lung parenchyma suspected to be an Aspergillus lesion (blue arrow). (For interpretation of the references to colour in this figure legend, the reader is referred to the Web version of this article.)
Fig. 3
On day 43, the patient was discharged from the ICU to the Pneumology Unit with spontaneous breathing through the tracheostomy, which was removed on day 58. He went to rehabilitation unit in good condition after 68 days of hospitalization.
3 Discussion
The COVID-19 pandemic raises important questions regarding the treatment of coronaviruses. To the best of our knowledge, no single drug has been demonstrated to be effective in critically ill patients, and more evidence is required [6,7]. Many drugs and treatments (e.g. hydroxychloroquine, lopinavir/ritonavir, darunavir/cobicistat, etc.) have been proposed for the treatment of critically ill COVID-19 patients. One goal of these treatments is to reduce viral spread and replication. Another is to limit hyperinflammation and the triggering of a systemic response during the later phase of an infection which could lead to multiorgan dysfunction [8].
Steroids constitute the cornerstone treatment for COVID-19. The aim of steroid treatment is to modulate the inflammatory response, being recognized as a standard of care in the latest WHO guidelines [9]. Other drugs have also been proposed and tested for their capacity to limit the hyperinflammation that characterizes the later stages of COVID-19. These include inhibitors of the IL-1β and IL-6 receptor, of which anakinra and tocilizumab are the most commonly used. It is worth noting here that IL-6 also promotes viral and bacterial clearance. However, excessive inflammation could increase vascular permeability, inducing acute respiratory distress syndrome (ARDS), cardiac arrhythmia and other negative consequences [10].
From a theoretical perspective, tocilizumab therapy is currently considered the most appropriate. Its overall goal is to prevent multiorgan dysfunction caused by a cytokine storm. However, the associated consequences of immunosuppression must also be taken into account. Warnings about the increased risk of bacterial and fungal infections following immunosuppressant therapy have become more numerous over the last year [11]. Lymphopenia is present in a high percentage of COVID-19 patients. The additional use of steroids and other immunosuppressive drugs thus increases the risk for fungal infections, especially Aspergillus sp. In the case described, HBV-related cirrhosis was an additional risk factor for fungal infection. Indeed, evidence suggests there to be more secondary infections in COVID-19 patients treated with tocilizumab than in those not receiving the drug [12]. Moreover, it is difficult to confirm suspected infections using standard laboratory tests for infection, such as C-reactive protein or procalcitonin. These markers rapidly decrease after tocilizumab administration, with very low values persisting for many days. As a consequence, doctors are unlikely to suspect an infection.
Some authors recommend empirical antibiotic prophylaxis, including antifungal drugs. Indeed, the difficulty and time involved in isolating Aspergillus from bronchoalveolar lavage fluid further support the adoption of an empirical antifungal approach to COVID-19 therapy in critically ill patients [13]. In fact, in the case herein described, following our initial suspicion of CAPA due to the significant increase in β–D glucan levels (on day 23), the first microbiological specimen testing positive for Aspergillus was not obtained until 12 days later.
Diagnosis of invasive pulmonary aspergillosis (IPA) in the ICU remains challenging. For this reason, the European Organization for Research and Treatment of Cancer/Mycoses Study Group (EORTC/MSG) criteria have been supplemented with a specific algorithm in critically ill patients [14]. Although biomarkers of Aspergillus infection, such as serum galactomannan or β–D glucan, are generally deemed to be unsensitive, testing for their presence in serum and bronchoalveolar lavage fluid was recently added to the EORTC/MSG criteria to aid the identification of IPA in influenza patients admitted to ICU. In our case, in addition to the patient's risk factors for IPA, the sudden increase in β–D glucan levels was enough for us to deem therapy with a broad spectrum antifungal necessary. Curiously, although the patient tested positive for β–D glucan, he remained negative for galactomannan.
In the present case, tocilizumab may have favoured CAPA, although this remains to be proven.
Many questions remain unanswered regarding the role of tocilizumab therapy in COVID-19. Physicians generally prescribe it believing that they are damping down the fire … however, in some cases, it might be better likened to adding gasoline and not water!
Declaration of competing interest
The authors have no conflicts of interest to declare.
Acknowledgements
The authors do not wish to make any specific acknowledgements. | CEFTOBIPROLE, DEXAMETHASONE, ENTECAVIR, TOCILIZUMAB | DrugsGivenReaction | CC BY | 33520634 | 18,923,578 | 2021-03 |
Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Product use in unapproved indication'. | Tocilizumab administration in COVID-19 patients: Water on the fire or gasoline?
Tocilizumab is widely being used to treat COVID-19. Although reducing systemic inflammation, it also increases the risk for secondary infections as a result of the immunosuppression produced. We report the case of a 69-year-old patient admitted to the ICU with severe respiratory distress caused by COVID-19 pneumonia who developed pulmonary aspergillosis. On the basis of these findings, we suggest early testing for pulmonary aspergillosis in COVID-19 patients treated with tocilizumab.
1 Introduction
Aspergillus is an opportunistic fungus mainly affecting immunocompromised patients. A high rate of invasive pulmonary aspergillosis has been demonstrated among critically ill patients admitted to the ICU with severe influenza, which may contribute to their high odds of mortality [1]. In the early days of the Sars-CoV-2 pandemic, several case reports emerged from Wuhan of COVID-19-associated pulmonary aspergillosis (CAPA) [2]. Many risk factors for CAPA were recognized among critically ill COVID-19 patients, including lymphopenia, high levels of systemic pro-inflammatory cytokines, and the use of steroids [3].
Tocilizumab is a recombinant humanized monoclonal antibody against the interleukin-6 receptor. Initially, it showed promising results in reducing the severity of COVID-19 infection in critically ill patients. It dramatically reduces the potent inflammatory effects of IL-6 responsible for causing the lung damage and eventual multiorgan failure associated with COVID-19 [4]. A large retrospective study found that tocilizumab reduced the risk of death and the odds of needing mechanical ventilation in severe COVID-19 pneumonia [5]. However, subsequent findings from large randomized controlled trials raised doubts regarding these findings.
Here, we report the case of a critically ill patient who developed CAPA following tocilizumab administration.
2 Case
A 69-year-old man was admitted to the emergency department (ED) with fever and a cough which he had had for two days. His medical history included HBV-related liver cirrhosis, arterial hypertension and mild obesity (Body Mass Index 32). The man was calm and cooperative during his ED visit. His vital signs were: ABP 160/100 mmHg, SpO2 97% while breathing room air (PaO2/FIO2=303 mmHg), HR 75/min, and body temperature 36.7 °C. His white blood cell count was 3849/mm3, platelets were 62,000/mm3 (abnormal), and lymphocytes were 2140/mm3. C-reactive protein was 1.48 mg/L, procalcitonin (PCT) was 0.04 ng/ml, pro-adrenomedullin (pro-ADM) was 0.69 nMol/L, and IL-6 was 27.0 pg/mL (abnormal). A real-time PCR nasal swab tested positive for SARS-COV2.
The patient was then admitted to the infectious diseases ward (day 0) where he was treated with dexamethasone intravenously 6 mg per day. Given his worsening clinical situation, which necessitated increasing levels of oxygen provided by non-invasive ventilation using a full face mask, he was finally admitted to the ICU (day 8). In the ICU, the patient required immediate endotracheal intubation and invasive mechanical ventilation due to worsening dyspnoea associated with a PaO2/FIO2 of 135 mmHg. On his second day in the ICU (day 10), the patient's IL-6 levels reached 223.0 pg/mL (abnormal), thus the decision to administer tocilizumab that same day was taken (the patient was also being treated with entecavir for HBV-related cirrhosis).
Following tocilizumab administration, pre-emptive ceftobiprole treatment was started, 500 mg intravenously every 8 hours according to our internal protocol (day 10 until day 19). On day 15, the patient underwent an early percutaneous tracheostomy, as per our routine practice in COVID-19 patients, in order to facilitate easier weaning from mechanical ventilation.
On day 23, acyclovir (10 mg/kg BW) was administered intravenously every 8 hours to treat Herpes reactivation (HSV1-DNA detected in blood: 5197 copies/mL, abnormal). The same day, liposomal amphotericin B (3 mg/kg BW that was stopped after 30 days of therapy) was also given despite the absence of microbiological findings due to the suspicion of CAPA as suggested by the patient's high serum levels of β–D glucan (86.9 pg/ml, abnormal).
Aspergillus fumigatus was finally isolated from the bronchial aspirate on day 37, 22 days after tocilizumab administration and 12 days after the first positive result for serum β–D glucan.
Galactomannan levels in serum and alveolar fluid were tested on day 17, 20, 26 and 32. In the same days bronchoalveolar lavage fluid was also investigated through standard bacterial and fungal cultures and multiplex PCR filmarray. All these tests resulted negative for Aspergillus.
Repeated CT scans of the thorax showed the development over time of a cavity in the lung parenchyma, supporting our suspicion of pulmonary Aspergillus infection (see Fig. 1, Fig. 2, Fig. 3).Fig. 1 CT scan of the thorax at hospital admission (day 0) demonstrates diffuse subpleural ground-glass opacity.
Fig. 1
Fig. 2 CT scan of the thorax taken on day 14 demonstrates the appearance of consolidation in the upper left pulmonary lobe (blue arrow), extended ground-glass opacity and the crazy-paving pattern associated with posterior lung consolidation. (For interpretation of the references to colour in this figure legend, the reader is referred to the Web version of this article.)
Fig. 2
Fig. 3 CT scan (day 28) demonstrating a large septated cavity in the lung parenchyma suspected to be an Aspergillus lesion (blue arrow). (For interpretation of the references to colour in this figure legend, the reader is referred to the Web version of this article.)
Fig. 3
On day 43, the patient was discharged from the ICU to the Pneumology Unit with spontaneous breathing through the tracheostomy, which was removed on day 58. He went to rehabilitation unit in good condition after 68 days of hospitalization.
3 Discussion
The COVID-19 pandemic raises important questions regarding the treatment of coronaviruses. To the best of our knowledge, no single drug has been demonstrated to be effective in critically ill patients, and more evidence is required [6,7]. Many drugs and treatments (e.g. hydroxychloroquine, lopinavir/ritonavir, darunavir/cobicistat, etc.) have been proposed for the treatment of critically ill COVID-19 patients. One goal of these treatments is to reduce viral spread and replication. Another is to limit hyperinflammation and the triggering of a systemic response during the later phase of an infection which could lead to multiorgan dysfunction [8].
Steroids constitute the cornerstone treatment for COVID-19. The aim of steroid treatment is to modulate the inflammatory response, being recognized as a standard of care in the latest WHO guidelines [9]. Other drugs have also been proposed and tested for their capacity to limit the hyperinflammation that characterizes the later stages of COVID-19. These include inhibitors of the IL-1β and IL-6 receptor, of which anakinra and tocilizumab are the most commonly used. It is worth noting here that IL-6 also promotes viral and bacterial clearance. However, excessive inflammation could increase vascular permeability, inducing acute respiratory distress syndrome (ARDS), cardiac arrhythmia and other negative consequences [10].
From a theoretical perspective, tocilizumab therapy is currently considered the most appropriate. Its overall goal is to prevent multiorgan dysfunction caused by a cytokine storm. However, the associated consequences of immunosuppression must also be taken into account. Warnings about the increased risk of bacterial and fungal infections following immunosuppressant therapy have become more numerous over the last year [11]. Lymphopenia is present in a high percentage of COVID-19 patients. The additional use of steroids and other immunosuppressive drugs thus increases the risk for fungal infections, especially Aspergillus sp. In the case described, HBV-related cirrhosis was an additional risk factor for fungal infection. Indeed, evidence suggests there to be more secondary infections in COVID-19 patients treated with tocilizumab than in those not receiving the drug [12]. Moreover, it is difficult to confirm suspected infections using standard laboratory tests for infection, such as C-reactive protein or procalcitonin. These markers rapidly decrease after tocilizumab administration, with very low values persisting for many days. As a consequence, doctors are unlikely to suspect an infection.
Some authors recommend empirical antibiotic prophylaxis, including antifungal drugs. Indeed, the difficulty and time involved in isolating Aspergillus from bronchoalveolar lavage fluid further support the adoption of an empirical antifungal approach to COVID-19 therapy in critically ill patients [13]. In fact, in the case herein described, following our initial suspicion of CAPA due to the significant increase in β–D glucan levels (on day 23), the first microbiological specimen testing positive for Aspergillus was not obtained until 12 days later.
Diagnosis of invasive pulmonary aspergillosis (IPA) in the ICU remains challenging. For this reason, the European Organization for Research and Treatment of Cancer/Mycoses Study Group (EORTC/MSG) criteria have been supplemented with a specific algorithm in critically ill patients [14]. Although biomarkers of Aspergillus infection, such as serum galactomannan or β–D glucan, are generally deemed to be unsensitive, testing for their presence in serum and bronchoalveolar lavage fluid was recently added to the EORTC/MSG criteria to aid the identification of IPA in influenza patients admitted to ICU. In our case, in addition to the patient's risk factors for IPA, the sudden increase in β–D glucan levels was enough for us to deem therapy with a broad spectrum antifungal necessary. Curiously, although the patient tested positive for β–D glucan, he remained negative for galactomannan.
In the present case, tocilizumab may have favoured CAPA, although this remains to be proven.
Many questions remain unanswered regarding the role of tocilizumab therapy in COVID-19. Physicians generally prescribe it believing that they are damping down the fire … however, in some cases, it might be better likened to adding gasoline and not water!
Declaration of competing interest
The authors have no conflicts of interest to declare.
Acknowledgements
The authors do not wish to make any specific acknowledgements. | CEFTOBIPROLE, DEXAMETHASONE, ENTECAVIR, TOCILIZUMAB | DrugsGivenReaction | CC BY | 33520634 | 19,070,160 | 2021-03 |
What was the administration route of drug 'CEFTOBIPROLE'? | Tocilizumab administration in COVID-19 patients: Water on the fire or gasoline?
Tocilizumab is widely being used to treat COVID-19. Although reducing systemic inflammation, it also increases the risk for secondary infections as a result of the immunosuppression produced. We report the case of a 69-year-old patient admitted to the ICU with severe respiratory distress caused by COVID-19 pneumonia who developed pulmonary aspergillosis. On the basis of these findings, we suggest early testing for pulmonary aspergillosis in COVID-19 patients treated with tocilizumab.
1 Introduction
Aspergillus is an opportunistic fungus mainly affecting immunocompromised patients. A high rate of invasive pulmonary aspergillosis has been demonstrated among critically ill patients admitted to the ICU with severe influenza, which may contribute to their high odds of mortality [1]. In the early days of the Sars-CoV-2 pandemic, several case reports emerged from Wuhan of COVID-19-associated pulmonary aspergillosis (CAPA) [2]. Many risk factors for CAPA were recognized among critically ill COVID-19 patients, including lymphopenia, high levels of systemic pro-inflammatory cytokines, and the use of steroids [3].
Tocilizumab is a recombinant humanized monoclonal antibody against the interleukin-6 receptor. Initially, it showed promising results in reducing the severity of COVID-19 infection in critically ill patients. It dramatically reduces the potent inflammatory effects of IL-6 responsible for causing the lung damage and eventual multiorgan failure associated with COVID-19 [4]. A large retrospective study found that tocilizumab reduced the risk of death and the odds of needing mechanical ventilation in severe COVID-19 pneumonia [5]. However, subsequent findings from large randomized controlled trials raised doubts regarding these findings.
Here, we report the case of a critically ill patient who developed CAPA following tocilizumab administration.
2 Case
A 69-year-old man was admitted to the emergency department (ED) with fever and a cough which he had had for two days. His medical history included HBV-related liver cirrhosis, arterial hypertension and mild obesity (Body Mass Index 32). The man was calm and cooperative during his ED visit. His vital signs were: ABP 160/100 mmHg, SpO2 97% while breathing room air (PaO2/FIO2=303 mmHg), HR 75/min, and body temperature 36.7 °C. His white blood cell count was 3849/mm3, platelets were 62,000/mm3 (abnormal), and lymphocytes were 2140/mm3. C-reactive protein was 1.48 mg/L, procalcitonin (PCT) was 0.04 ng/ml, pro-adrenomedullin (pro-ADM) was 0.69 nMol/L, and IL-6 was 27.0 pg/mL (abnormal). A real-time PCR nasal swab tested positive for SARS-COV2.
The patient was then admitted to the infectious diseases ward (day 0) where he was treated with dexamethasone intravenously 6 mg per day. Given his worsening clinical situation, which necessitated increasing levels of oxygen provided by non-invasive ventilation using a full face mask, he was finally admitted to the ICU (day 8). In the ICU, the patient required immediate endotracheal intubation and invasive mechanical ventilation due to worsening dyspnoea associated with a PaO2/FIO2 of 135 mmHg. On his second day in the ICU (day 10), the patient's IL-6 levels reached 223.0 pg/mL (abnormal), thus the decision to administer tocilizumab that same day was taken (the patient was also being treated with entecavir for HBV-related cirrhosis).
Following tocilizumab administration, pre-emptive ceftobiprole treatment was started, 500 mg intravenously every 8 hours according to our internal protocol (day 10 until day 19). On day 15, the patient underwent an early percutaneous tracheostomy, as per our routine practice in COVID-19 patients, in order to facilitate easier weaning from mechanical ventilation.
On day 23, acyclovir (10 mg/kg BW) was administered intravenously every 8 hours to treat Herpes reactivation (HSV1-DNA detected in blood: 5197 copies/mL, abnormal). The same day, liposomal amphotericin B (3 mg/kg BW that was stopped after 30 days of therapy) was also given despite the absence of microbiological findings due to the suspicion of CAPA as suggested by the patient's high serum levels of β–D glucan (86.9 pg/ml, abnormal).
Aspergillus fumigatus was finally isolated from the bronchial aspirate on day 37, 22 days after tocilizumab administration and 12 days after the first positive result for serum β–D glucan.
Galactomannan levels in serum and alveolar fluid were tested on day 17, 20, 26 and 32. In the same days bronchoalveolar lavage fluid was also investigated through standard bacterial and fungal cultures and multiplex PCR filmarray. All these tests resulted negative for Aspergillus.
Repeated CT scans of the thorax showed the development over time of a cavity in the lung parenchyma, supporting our suspicion of pulmonary Aspergillus infection (see Fig. 1, Fig. 2, Fig. 3).Fig. 1 CT scan of the thorax at hospital admission (day 0) demonstrates diffuse subpleural ground-glass opacity.
Fig. 1
Fig. 2 CT scan of the thorax taken on day 14 demonstrates the appearance of consolidation in the upper left pulmonary lobe (blue arrow), extended ground-glass opacity and the crazy-paving pattern associated with posterior lung consolidation. (For interpretation of the references to colour in this figure legend, the reader is referred to the Web version of this article.)
Fig. 2
Fig. 3 CT scan (day 28) demonstrating a large septated cavity in the lung parenchyma suspected to be an Aspergillus lesion (blue arrow). (For interpretation of the references to colour in this figure legend, the reader is referred to the Web version of this article.)
Fig. 3
On day 43, the patient was discharged from the ICU to the Pneumology Unit with spontaneous breathing through the tracheostomy, which was removed on day 58. He went to rehabilitation unit in good condition after 68 days of hospitalization.
3 Discussion
The COVID-19 pandemic raises important questions regarding the treatment of coronaviruses. To the best of our knowledge, no single drug has been demonstrated to be effective in critically ill patients, and more evidence is required [6,7]. Many drugs and treatments (e.g. hydroxychloroquine, lopinavir/ritonavir, darunavir/cobicistat, etc.) have been proposed for the treatment of critically ill COVID-19 patients. One goal of these treatments is to reduce viral spread and replication. Another is to limit hyperinflammation and the triggering of a systemic response during the later phase of an infection which could lead to multiorgan dysfunction [8].
Steroids constitute the cornerstone treatment for COVID-19. The aim of steroid treatment is to modulate the inflammatory response, being recognized as a standard of care in the latest WHO guidelines [9]. Other drugs have also been proposed and tested for their capacity to limit the hyperinflammation that characterizes the later stages of COVID-19. These include inhibitors of the IL-1β and IL-6 receptor, of which anakinra and tocilizumab are the most commonly used. It is worth noting here that IL-6 also promotes viral and bacterial clearance. However, excessive inflammation could increase vascular permeability, inducing acute respiratory distress syndrome (ARDS), cardiac arrhythmia and other negative consequences [10].
From a theoretical perspective, tocilizumab therapy is currently considered the most appropriate. Its overall goal is to prevent multiorgan dysfunction caused by a cytokine storm. However, the associated consequences of immunosuppression must also be taken into account. Warnings about the increased risk of bacterial and fungal infections following immunosuppressant therapy have become more numerous over the last year [11]. Lymphopenia is present in a high percentage of COVID-19 patients. The additional use of steroids and other immunosuppressive drugs thus increases the risk for fungal infections, especially Aspergillus sp. In the case described, HBV-related cirrhosis was an additional risk factor for fungal infection. Indeed, evidence suggests there to be more secondary infections in COVID-19 patients treated with tocilizumab than in those not receiving the drug [12]. Moreover, it is difficult to confirm suspected infections using standard laboratory tests for infection, such as C-reactive protein or procalcitonin. These markers rapidly decrease after tocilizumab administration, with very low values persisting for many days. As a consequence, doctors are unlikely to suspect an infection.
Some authors recommend empirical antibiotic prophylaxis, including antifungal drugs. Indeed, the difficulty and time involved in isolating Aspergillus from bronchoalveolar lavage fluid further support the adoption of an empirical antifungal approach to COVID-19 therapy in critically ill patients [13]. In fact, in the case herein described, following our initial suspicion of CAPA due to the significant increase in β–D glucan levels (on day 23), the first microbiological specimen testing positive for Aspergillus was not obtained until 12 days later.
Diagnosis of invasive pulmonary aspergillosis (IPA) in the ICU remains challenging. For this reason, the European Organization for Research and Treatment of Cancer/Mycoses Study Group (EORTC/MSG) criteria have been supplemented with a specific algorithm in critically ill patients [14]. Although biomarkers of Aspergillus infection, such as serum galactomannan or β–D glucan, are generally deemed to be unsensitive, testing for their presence in serum and bronchoalveolar lavage fluid was recently added to the EORTC/MSG criteria to aid the identification of IPA in influenza patients admitted to ICU. In our case, in addition to the patient's risk factors for IPA, the sudden increase in β–D glucan levels was enough for us to deem therapy with a broad spectrum antifungal necessary. Curiously, although the patient tested positive for β–D glucan, he remained negative for galactomannan.
In the present case, tocilizumab may have favoured CAPA, although this remains to be proven.
Many questions remain unanswered regarding the role of tocilizumab therapy in COVID-19. Physicians generally prescribe it believing that they are damping down the fire … however, in some cases, it might be better likened to adding gasoline and not water!
Declaration of competing interest
The authors have no conflicts of interest to declare.
Acknowledgements
The authors do not wish to make any specific acknowledgements. | Intravenous (not otherwise specified) | DrugAdministrationRoute | CC BY | 33520634 | 18,923,578 | 2021-03 |
What was the administration route of drug 'DEXAMETHASONE'? | Tocilizumab administration in COVID-19 patients: Water on the fire or gasoline?
Tocilizumab is widely being used to treat COVID-19. Although reducing systemic inflammation, it also increases the risk for secondary infections as a result of the immunosuppression produced. We report the case of a 69-year-old patient admitted to the ICU with severe respiratory distress caused by COVID-19 pneumonia who developed pulmonary aspergillosis. On the basis of these findings, we suggest early testing for pulmonary aspergillosis in COVID-19 patients treated with tocilizumab.
1 Introduction
Aspergillus is an opportunistic fungus mainly affecting immunocompromised patients. A high rate of invasive pulmonary aspergillosis has been demonstrated among critically ill patients admitted to the ICU with severe influenza, which may contribute to their high odds of mortality [1]. In the early days of the Sars-CoV-2 pandemic, several case reports emerged from Wuhan of COVID-19-associated pulmonary aspergillosis (CAPA) [2]. Many risk factors for CAPA were recognized among critically ill COVID-19 patients, including lymphopenia, high levels of systemic pro-inflammatory cytokines, and the use of steroids [3].
Tocilizumab is a recombinant humanized monoclonal antibody against the interleukin-6 receptor. Initially, it showed promising results in reducing the severity of COVID-19 infection in critically ill patients. It dramatically reduces the potent inflammatory effects of IL-6 responsible for causing the lung damage and eventual multiorgan failure associated with COVID-19 [4]. A large retrospective study found that tocilizumab reduced the risk of death and the odds of needing mechanical ventilation in severe COVID-19 pneumonia [5]. However, subsequent findings from large randomized controlled trials raised doubts regarding these findings.
Here, we report the case of a critically ill patient who developed CAPA following tocilizumab administration.
2 Case
A 69-year-old man was admitted to the emergency department (ED) with fever and a cough which he had had for two days. His medical history included HBV-related liver cirrhosis, arterial hypertension and mild obesity (Body Mass Index 32). The man was calm and cooperative during his ED visit. His vital signs were: ABP 160/100 mmHg, SpO2 97% while breathing room air (PaO2/FIO2=303 mmHg), HR 75/min, and body temperature 36.7 °C. His white blood cell count was 3849/mm3, platelets were 62,000/mm3 (abnormal), and lymphocytes were 2140/mm3. C-reactive protein was 1.48 mg/L, procalcitonin (PCT) was 0.04 ng/ml, pro-adrenomedullin (pro-ADM) was 0.69 nMol/L, and IL-6 was 27.0 pg/mL (abnormal). A real-time PCR nasal swab tested positive for SARS-COV2.
The patient was then admitted to the infectious diseases ward (day 0) where he was treated with dexamethasone intravenously 6 mg per day. Given his worsening clinical situation, which necessitated increasing levels of oxygen provided by non-invasive ventilation using a full face mask, he was finally admitted to the ICU (day 8). In the ICU, the patient required immediate endotracheal intubation and invasive mechanical ventilation due to worsening dyspnoea associated with a PaO2/FIO2 of 135 mmHg. On his second day in the ICU (day 10), the patient's IL-6 levels reached 223.0 pg/mL (abnormal), thus the decision to administer tocilizumab that same day was taken (the patient was also being treated with entecavir for HBV-related cirrhosis).
Following tocilizumab administration, pre-emptive ceftobiprole treatment was started, 500 mg intravenously every 8 hours according to our internal protocol (day 10 until day 19). On day 15, the patient underwent an early percutaneous tracheostomy, as per our routine practice in COVID-19 patients, in order to facilitate easier weaning from mechanical ventilation.
On day 23, acyclovir (10 mg/kg BW) was administered intravenously every 8 hours to treat Herpes reactivation (HSV1-DNA detected in blood: 5197 copies/mL, abnormal). The same day, liposomal amphotericin B (3 mg/kg BW that was stopped after 30 days of therapy) was also given despite the absence of microbiological findings due to the suspicion of CAPA as suggested by the patient's high serum levels of β–D glucan (86.9 pg/ml, abnormal).
Aspergillus fumigatus was finally isolated from the bronchial aspirate on day 37, 22 days after tocilizumab administration and 12 days after the first positive result for serum β–D glucan.
Galactomannan levels in serum and alveolar fluid were tested on day 17, 20, 26 and 32. In the same days bronchoalveolar lavage fluid was also investigated through standard bacterial and fungal cultures and multiplex PCR filmarray. All these tests resulted negative for Aspergillus.
Repeated CT scans of the thorax showed the development over time of a cavity in the lung parenchyma, supporting our suspicion of pulmonary Aspergillus infection (see Fig. 1, Fig. 2, Fig. 3).Fig. 1 CT scan of the thorax at hospital admission (day 0) demonstrates diffuse subpleural ground-glass opacity.
Fig. 1
Fig. 2 CT scan of the thorax taken on day 14 demonstrates the appearance of consolidation in the upper left pulmonary lobe (blue arrow), extended ground-glass opacity and the crazy-paving pattern associated with posterior lung consolidation. (For interpretation of the references to colour in this figure legend, the reader is referred to the Web version of this article.)
Fig. 2
Fig. 3 CT scan (day 28) demonstrating a large septated cavity in the lung parenchyma suspected to be an Aspergillus lesion (blue arrow). (For interpretation of the references to colour in this figure legend, the reader is referred to the Web version of this article.)
Fig. 3
On day 43, the patient was discharged from the ICU to the Pneumology Unit with spontaneous breathing through the tracheostomy, which was removed on day 58. He went to rehabilitation unit in good condition after 68 days of hospitalization.
3 Discussion
The COVID-19 pandemic raises important questions regarding the treatment of coronaviruses. To the best of our knowledge, no single drug has been demonstrated to be effective in critically ill patients, and more evidence is required [6,7]. Many drugs and treatments (e.g. hydroxychloroquine, lopinavir/ritonavir, darunavir/cobicistat, etc.) have been proposed for the treatment of critically ill COVID-19 patients. One goal of these treatments is to reduce viral spread and replication. Another is to limit hyperinflammation and the triggering of a systemic response during the later phase of an infection which could lead to multiorgan dysfunction [8].
Steroids constitute the cornerstone treatment for COVID-19. The aim of steroid treatment is to modulate the inflammatory response, being recognized as a standard of care in the latest WHO guidelines [9]. Other drugs have also been proposed and tested for their capacity to limit the hyperinflammation that characterizes the later stages of COVID-19. These include inhibitors of the IL-1β and IL-6 receptor, of which anakinra and tocilizumab are the most commonly used. It is worth noting here that IL-6 also promotes viral and bacterial clearance. However, excessive inflammation could increase vascular permeability, inducing acute respiratory distress syndrome (ARDS), cardiac arrhythmia and other negative consequences [10].
From a theoretical perspective, tocilizumab therapy is currently considered the most appropriate. Its overall goal is to prevent multiorgan dysfunction caused by a cytokine storm. However, the associated consequences of immunosuppression must also be taken into account. Warnings about the increased risk of bacterial and fungal infections following immunosuppressant therapy have become more numerous over the last year [11]. Lymphopenia is present in a high percentage of COVID-19 patients. The additional use of steroids and other immunosuppressive drugs thus increases the risk for fungal infections, especially Aspergillus sp. In the case described, HBV-related cirrhosis was an additional risk factor for fungal infection. Indeed, evidence suggests there to be more secondary infections in COVID-19 patients treated with tocilizumab than in those not receiving the drug [12]. Moreover, it is difficult to confirm suspected infections using standard laboratory tests for infection, such as C-reactive protein or procalcitonin. These markers rapidly decrease after tocilizumab administration, with very low values persisting for many days. As a consequence, doctors are unlikely to suspect an infection.
Some authors recommend empirical antibiotic prophylaxis, including antifungal drugs. Indeed, the difficulty and time involved in isolating Aspergillus from bronchoalveolar lavage fluid further support the adoption of an empirical antifungal approach to COVID-19 therapy in critically ill patients [13]. In fact, in the case herein described, following our initial suspicion of CAPA due to the significant increase in β–D glucan levels (on day 23), the first microbiological specimen testing positive for Aspergillus was not obtained until 12 days later.
Diagnosis of invasive pulmonary aspergillosis (IPA) in the ICU remains challenging. For this reason, the European Organization for Research and Treatment of Cancer/Mycoses Study Group (EORTC/MSG) criteria have been supplemented with a specific algorithm in critically ill patients [14]. Although biomarkers of Aspergillus infection, such as serum galactomannan or β–D glucan, are generally deemed to be unsensitive, testing for their presence in serum and bronchoalveolar lavage fluid was recently added to the EORTC/MSG criteria to aid the identification of IPA in influenza patients admitted to ICU. In our case, in addition to the patient's risk factors for IPA, the sudden increase in β–D glucan levels was enough for us to deem therapy with a broad spectrum antifungal necessary. Curiously, although the patient tested positive for β–D glucan, he remained negative for galactomannan.
In the present case, tocilizumab may have favoured CAPA, although this remains to be proven.
Many questions remain unanswered regarding the role of tocilizumab therapy in COVID-19. Physicians generally prescribe it believing that they are damping down the fire … however, in some cases, it might be better likened to adding gasoline and not water!
Declaration of competing interest
The authors have no conflicts of interest to declare.
Acknowledgements
The authors do not wish to make any specific acknowledgements. | Intravenous (not otherwise specified) | DrugAdministrationRoute | CC BY | 33520634 | 19,070,160 | 2021-03 |
What was the dosage of drug 'CEFTOBIPROLE'? | Tocilizumab administration in COVID-19 patients: Water on the fire or gasoline?
Tocilizumab is widely being used to treat COVID-19. Although reducing systemic inflammation, it also increases the risk for secondary infections as a result of the immunosuppression produced. We report the case of a 69-year-old patient admitted to the ICU with severe respiratory distress caused by COVID-19 pneumonia who developed pulmonary aspergillosis. On the basis of these findings, we suggest early testing for pulmonary aspergillosis in COVID-19 patients treated with tocilizumab.
1 Introduction
Aspergillus is an opportunistic fungus mainly affecting immunocompromised patients. A high rate of invasive pulmonary aspergillosis has been demonstrated among critically ill patients admitted to the ICU with severe influenza, which may contribute to their high odds of mortality [1]. In the early days of the Sars-CoV-2 pandemic, several case reports emerged from Wuhan of COVID-19-associated pulmonary aspergillosis (CAPA) [2]. Many risk factors for CAPA were recognized among critically ill COVID-19 patients, including lymphopenia, high levels of systemic pro-inflammatory cytokines, and the use of steroids [3].
Tocilizumab is a recombinant humanized monoclonal antibody against the interleukin-6 receptor. Initially, it showed promising results in reducing the severity of COVID-19 infection in critically ill patients. It dramatically reduces the potent inflammatory effects of IL-6 responsible for causing the lung damage and eventual multiorgan failure associated with COVID-19 [4]. A large retrospective study found that tocilizumab reduced the risk of death and the odds of needing mechanical ventilation in severe COVID-19 pneumonia [5]. However, subsequent findings from large randomized controlled trials raised doubts regarding these findings.
Here, we report the case of a critically ill patient who developed CAPA following tocilizumab administration.
2 Case
A 69-year-old man was admitted to the emergency department (ED) with fever and a cough which he had had for two days. His medical history included HBV-related liver cirrhosis, arterial hypertension and mild obesity (Body Mass Index 32). The man was calm and cooperative during his ED visit. His vital signs were: ABP 160/100 mmHg, SpO2 97% while breathing room air (PaO2/FIO2=303 mmHg), HR 75/min, and body temperature 36.7 °C. His white blood cell count was 3849/mm3, platelets were 62,000/mm3 (abnormal), and lymphocytes were 2140/mm3. C-reactive protein was 1.48 mg/L, procalcitonin (PCT) was 0.04 ng/ml, pro-adrenomedullin (pro-ADM) was 0.69 nMol/L, and IL-6 was 27.0 pg/mL (abnormal). A real-time PCR nasal swab tested positive for SARS-COV2.
The patient was then admitted to the infectious diseases ward (day 0) where he was treated with dexamethasone intravenously 6 mg per day. Given his worsening clinical situation, which necessitated increasing levels of oxygen provided by non-invasive ventilation using a full face mask, he was finally admitted to the ICU (day 8). In the ICU, the patient required immediate endotracheal intubation and invasive mechanical ventilation due to worsening dyspnoea associated with a PaO2/FIO2 of 135 mmHg. On his second day in the ICU (day 10), the patient's IL-6 levels reached 223.0 pg/mL (abnormal), thus the decision to administer tocilizumab that same day was taken (the patient was also being treated with entecavir for HBV-related cirrhosis).
Following tocilizumab administration, pre-emptive ceftobiprole treatment was started, 500 mg intravenously every 8 hours according to our internal protocol (day 10 until day 19). On day 15, the patient underwent an early percutaneous tracheostomy, as per our routine practice in COVID-19 patients, in order to facilitate easier weaning from mechanical ventilation.
On day 23, acyclovir (10 mg/kg BW) was administered intravenously every 8 hours to treat Herpes reactivation (HSV1-DNA detected in blood: 5197 copies/mL, abnormal). The same day, liposomal amphotericin B (3 mg/kg BW that was stopped after 30 days of therapy) was also given despite the absence of microbiological findings due to the suspicion of CAPA as suggested by the patient's high serum levels of β–D glucan (86.9 pg/ml, abnormal).
Aspergillus fumigatus was finally isolated from the bronchial aspirate on day 37, 22 days after tocilizumab administration and 12 days after the first positive result for serum β–D glucan.
Galactomannan levels in serum and alveolar fluid were tested on day 17, 20, 26 and 32. In the same days bronchoalveolar lavage fluid was also investigated through standard bacterial and fungal cultures and multiplex PCR filmarray. All these tests resulted negative for Aspergillus.
Repeated CT scans of the thorax showed the development over time of a cavity in the lung parenchyma, supporting our suspicion of pulmonary Aspergillus infection (see Fig. 1, Fig. 2, Fig. 3).Fig. 1 CT scan of the thorax at hospital admission (day 0) demonstrates diffuse subpleural ground-glass opacity.
Fig. 1
Fig. 2 CT scan of the thorax taken on day 14 demonstrates the appearance of consolidation in the upper left pulmonary lobe (blue arrow), extended ground-glass opacity and the crazy-paving pattern associated with posterior lung consolidation. (For interpretation of the references to colour in this figure legend, the reader is referred to the Web version of this article.)
Fig. 2
Fig. 3 CT scan (day 28) demonstrating a large septated cavity in the lung parenchyma suspected to be an Aspergillus lesion (blue arrow). (For interpretation of the references to colour in this figure legend, the reader is referred to the Web version of this article.)
Fig. 3
On day 43, the patient was discharged from the ICU to the Pneumology Unit with spontaneous breathing through the tracheostomy, which was removed on day 58. He went to rehabilitation unit in good condition after 68 days of hospitalization.
3 Discussion
The COVID-19 pandemic raises important questions regarding the treatment of coronaviruses. To the best of our knowledge, no single drug has been demonstrated to be effective in critically ill patients, and more evidence is required [6,7]. Many drugs and treatments (e.g. hydroxychloroquine, lopinavir/ritonavir, darunavir/cobicistat, etc.) have been proposed for the treatment of critically ill COVID-19 patients. One goal of these treatments is to reduce viral spread and replication. Another is to limit hyperinflammation and the triggering of a systemic response during the later phase of an infection which could lead to multiorgan dysfunction [8].
Steroids constitute the cornerstone treatment for COVID-19. The aim of steroid treatment is to modulate the inflammatory response, being recognized as a standard of care in the latest WHO guidelines [9]. Other drugs have also been proposed and tested for their capacity to limit the hyperinflammation that characterizes the later stages of COVID-19. These include inhibitors of the IL-1β and IL-6 receptor, of which anakinra and tocilizumab are the most commonly used. It is worth noting here that IL-6 also promotes viral and bacterial clearance. However, excessive inflammation could increase vascular permeability, inducing acute respiratory distress syndrome (ARDS), cardiac arrhythmia and other negative consequences [10].
From a theoretical perspective, tocilizumab therapy is currently considered the most appropriate. Its overall goal is to prevent multiorgan dysfunction caused by a cytokine storm. However, the associated consequences of immunosuppression must also be taken into account. Warnings about the increased risk of bacterial and fungal infections following immunosuppressant therapy have become more numerous over the last year [11]. Lymphopenia is present in a high percentage of COVID-19 patients. The additional use of steroids and other immunosuppressive drugs thus increases the risk for fungal infections, especially Aspergillus sp. In the case described, HBV-related cirrhosis was an additional risk factor for fungal infection. Indeed, evidence suggests there to be more secondary infections in COVID-19 patients treated with tocilizumab than in those not receiving the drug [12]. Moreover, it is difficult to confirm suspected infections using standard laboratory tests for infection, such as C-reactive protein or procalcitonin. These markers rapidly decrease after tocilizumab administration, with very low values persisting for many days. As a consequence, doctors are unlikely to suspect an infection.
Some authors recommend empirical antibiotic prophylaxis, including antifungal drugs. Indeed, the difficulty and time involved in isolating Aspergillus from bronchoalveolar lavage fluid further support the adoption of an empirical antifungal approach to COVID-19 therapy in critically ill patients [13]. In fact, in the case herein described, following our initial suspicion of CAPA due to the significant increase in β–D glucan levels (on day 23), the first microbiological specimen testing positive for Aspergillus was not obtained until 12 days later.
Diagnosis of invasive pulmonary aspergillosis (IPA) in the ICU remains challenging. For this reason, the European Organization for Research and Treatment of Cancer/Mycoses Study Group (EORTC/MSG) criteria have been supplemented with a specific algorithm in critically ill patients [14]. Although biomarkers of Aspergillus infection, such as serum galactomannan or β–D glucan, are generally deemed to be unsensitive, testing for their presence in serum and bronchoalveolar lavage fluid was recently added to the EORTC/MSG criteria to aid the identification of IPA in influenza patients admitted to ICU. In our case, in addition to the patient's risk factors for IPA, the sudden increase in β–D glucan levels was enough for us to deem therapy with a broad spectrum antifungal necessary. Curiously, although the patient tested positive for β–D glucan, he remained negative for galactomannan.
In the present case, tocilizumab may have favoured CAPA, although this remains to be proven.
Many questions remain unanswered regarding the role of tocilizumab therapy in COVID-19. Physicians generally prescribe it believing that they are damping down the fire … however, in some cases, it might be better likened to adding gasoline and not water!
Declaration of competing interest
The authors have no conflicts of interest to declare.
Acknowledgements
The authors do not wish to make any specific acknowledgements. | 500 mg (milligrams). | DrugDosage | CC BY | 33520634 | 18,923,578 | 2021-03 |
What was the dosage of drug 'DEXAMETHASONE'? | Tocilizumab administration in COVID-19 patients: Water on the fire or gasoline?
Tocilizumab is widely being used to treat COVID-19. Although reducing systemic inflammation, it also increases the risk for secondary infections as a result of the immunosuppression produced. We report the case of a 69-year-old patient admitted to the ICU with severe respiratory distress caused by COVID-19 pneumonia who developed pulmonary aspergillosis. On the basis of these findings, we suggest early testing for pulmonary aspergillosis in COVID-19 patients treated with tocilizumab.
1 Introduction
Aspergillus is an opportunistic fungus mainly affecting immunocompromised patients. A high rate of invasive pulmonary aspergillosis has been demonstrated among critically ill patients admitted to the ICU with severe influenza, which may contribute to their high odds of mortality [1]. In the early days of the Sars-CoV-2 pandemic, several case reports emerged from Wuhan of COVID-19-associated pulmonary aspergillosis (CAPA) [2]. Many risk factors for CAPA were recognized among critically ill COVID-19 patients, including lymphopenia, high levels of systemic pro-inflammatory cytokines, and the use of steroids [3].
Tocilizumab is a recombinant humanized monoclonal antibody against the interleukin-6 receptor. Initially, it showed promising results in reducing the severity of COVID-19 infection in critically ill patients. It dramatically reduces the potent inflammatory effects of IL-6 responsible for causing the lung damage and eventual multiorgan failure associated with COVID-19 [4]. A large retrospective study found that tocilizumab reduced the risk of death and the odds of needing mechanical ventilation in severe COVID-19 pneumonia [5]. However, subsequent findings from large randomized controlled trials raised doubts regarding these findings.
Here, we report the case of a critically ill patient who developed CAPA following tocilizumab administration.
2 Case
A 69-year-old man was admitted to the emergency department (ED) with fever and a cough which he had had for two days. His medical history included HBV-related liver cirrhosis, arterial hypertension and mild obesity (Body Mass Index 32). The man was calm and cooperative during his ED visit. His vital signs were: ABP 160/100 mmHg, SpO2 97% while breathing room air (PaO2/FIO2=303 mmHg), HR 75/min, and body temperature 36.7 °C. His white blood cell count was 3849/mm3, platelets were 62,000/mm3 (abnormal), and lymphocytes were 2140/mm3. C-reactive protein was 1.48 mg/L, procalcitonin (PCT) was 0.04 ng/ml, pro-adrenomedullin (pro-ADM) was 0.69 nMol/L, and IL-6 was 27.0 pg/mL (abnormal). A real-time PCR nasal swab tested positive for SARS-COV2.
The patient was then admitted to the infectious diseases ward (day 0) where he was treated with dexamethasone intravenously 6 mg per day. Given his worsening clinical situation, which necessitated increasing levels of oxygen provided by non-invasive ventilation using a full face mask, he was finally admitted to the ICU (day 8). In the ICU, the patient required immediate endotracheal intubation and invasive mechanical ventilation due to worsening dyspnoea associated with a PaO2/FIO2 of 135 mmHg. On his second day in the ICU (day 10), the patient's IL-6 levels reached 223.0 pg/mL (abnormal), thus the decision to administer tocilizumab that same day was taken (the patient was also being treated with entecavir for HBV-related cirrhosis).
Following tocilizumab administration, pre-emptive ceftobiprole treatment was started, 500 mg intravenously every 8 hours according to our internal protocol (day 10 until day 19). On day 15, the patient underwent an early percutaneous tracheostomy, as per our routine practice in COVID-19 patients, in order to facilitate easier weaning from mechanical ventilation.
On day 23, acyclovir (10 mg/kg BW) was administered intravenously every 8 hours to treat Herpes reactivation (HSV1-DNA detected in blood: 5197 copies/mL, abnormal). The same day, liposomal amphotericin B (3 mg/kg BW that was stopped after 30 days of therapy) was also given despite the absence of microbiological findings due to the suspicion of CAPA as suggested by the patient's high serum levels of β–D glucan (86.9 pg/ml, abnormal).
Aspergillus fumigatus was finally isolated from the bronchial aspirate on day 37, 22 days after tocilizumab administration and 12 days after the first positive result for serum β–D glucan.
Galactomannan levels in serum and alveolar fluid were tested on day 17, 20, 26 and 32. In the same days bronchoalveolar lavage fluid was also investigated through standard bacterial and fungal cultures and multiplex PCR filmarray. All these tests resulted negative for Aspergillus.
Repeated CT scans of the thorax showed the development over time of a cavity in the lung parenchyma, supporting our suspicion of pulmonary Aspergillus infection (see Fig. 1, Fig. 2, Fig. 3).Fig. 1 CT scan of the thorax at hospital admission (day 0) demonstrates diffuse subpleural ground-glass opacity.
Fig. 1
Fig. 2 CT scan of the thorax taken on day 14 demonstrates the appearance of consolidation in the upper left pulmonary lobe (blue arrow), extended ground-glass opacity and the crazy-paving pattern associated with posterior lung consolidation. (For interpretation of the references to colour in this figure legend, the reader is referred to the Web version of this article.)
Fig. 2
Fig. 3 CT scan (day 28) demonstrating a large septated cavity in the lung parenchyma suspected to be an Aspergillus lesion (blue arrow). (For interpretation of the references to colour in this figure legend, the reader is referred to the Web version of this article.)
Fig. 3
On day 43, the patient was discharged from the ICU to the Pneumology Unit with spontaneous breathing through the tracheostomy, which was removed on day 58. He went to rehabilitation unit in good condition after 68 days of hospitalization.
3 Discussion
The COVID-19 pandemic raises important questions regarding the treatment of coronaviruses. To the best of our knowledge, no single drug has been demonstrated to be effective in critically ill patients, and more evidence is required [6,7]. Many drugs and treatments (e.g. hydroxychloroquine, lopinavir/ritonavir, darunavir/cobicistat, etc.) have been proposed for the treatment of critically ill COVID-19 patients. One goal of these treatments is to reduce viral spread and replication. Another is to limit hyperinflammation and the triggering of a systemic response during the later phase of an infection which could lead to multiorgan dysfunction [8].
Steroids constitute the cornerstone treatment for COVID-19. The aim of steroid treatment is to modulate the inflammatory response, being recognized as a standard of care in the latest WHO guidelines [9]. Other drugs have also been proposed and tested for their capacity to limit the hyperinflammation that characterizes the later stages of COVID-19. These include inhibitors of the IL-1β and IL-6 receptor, of which anakinra and tocilizumab are the most commonly used. It is worth noting here that IL-6 also promotes viral and bacterial clearance. However, excessive inflammation could increase vascular permeability, inducing acute respiratory distress syndrome (ARDS), cardiac arrhythmia and other negative consequences [10].
From a theoretical perspective, tocilizumab therapy is currently considered the most appropriate. Its overall goal is to prevent multiorgan dysfunction caused by a cytokine storm. However, the associated consequences of immunosuppression must also be taken into account. Warnings about the increased risk of bacterial and fungal infections following immunosuppressant therapy have become more numerous over the last year [11]. Lymphopenia is present in a high percentage of COVID-19 patients. The additional use of steroids and other immunosuppressive drugs thus increases the risk for fungal infections, especially Aspergillus sp. In the case described, HBV-related cirrhosis was an additional risk factor for fungal infection. Indeed, evidence suggests there to be more secondary infections in COVID-19 patients treated with tocilizumab than in those not receiving the drug [12]. Moreover, it is difficult to confirm suspected infections using standard laboratory tests for infection, such as C-reactive protein or procalcitonin. These markers rapidly decrease after tocilizumab administration, with very low values persisting for many days. As a consequence, doctors are unlikely to suspect an infection.
Some authors recommend empirical antibiotic prophylaxis, including antifungal drugs. Indeed, the difficulty and time involved in isolating Aspergillus from bronchoalveolar lavage fluid further support the adoption of an empirical antifungal approach to COVID-19 therapy in critically ill patients [13]. In fact, in the case herein described, following our initial suspicion of CAPA due to the significant increase in β–D glucan levels (on day 23), the first microbiological specimen testing positive for Aspergillus was not obtained until 12 days later.
Diagnosis of invasive pulmonary aspergillosis (IPA) in the ICU remains challenging. For this reason, the European Organization for Research and Treatment of Cancer/Mycoses Study Group (EORTC/MSG) criteria have been supplemented with a specific algorithm in critically ill patients [14]. Although biomarkers of Aspergillus infection, such as serum galactomannan or β–D glucan, are generally deemed to be unsensitive, testing for their presence in serum and bronchoalveolar lavage fluid was recently added to the EORTC/MSG criteria to aid the identification of IPA in influenza patients admitted to ICU. In our case, in addition to the patient's risk factors for IPA, the sudden increase in β–D glucan levels was enough for us to deem therapy with a broad spectrum antifungal necessary. Curiously, although the patient tested positive for β–D glucan, he remained negative for galactomannan.
In the present case, tocilizumab may have favoured CAPA, although this remains to be proven.
Many questions remain unanswered regarding the role of tocilizumab therapy in COVID-19. Physicians generally prescribe it believing that they are damping down the fire … however, in some cases, it might be better likened to adding gasoline and not water!
Declaration of competing interest
The authors have no conflicts of interest to declare.
Acknowledgements
The authors do not wish to make any specific acknowledgements. | 6 mg (milligrams). | DrugDosage | CC BY | 33520634 | 19,154,715 | 2021-03 |
What was the outcome of reaction 'Aspergillus infection'? | Tocilizumab administration in COVID-19 patients: Water on the fire or gasoline?
Tocilizumab is widely being used to treat COVID-19. Although reducing systemic inflammation, it also increases the risk for secondary infections as a result of the immunosuppression produced. We report the case of a 69-year-old patient admitted to the ICU with severe respiratory distress caused by COVID-19 pneumonia who developed pulmonary aspergillosis. On the basis of these findings, we suggest early testing for pulmonary aspergillosis in COVID-19 patients treated with tocilizumab.
1 Introduction
Aspergillus is an opportunistic fungus mainly affecting immunocompromised patients. A high rate of invasive pulmonary aspergillosis has been demonstrated among critically ill patients admitted to the ICU with severe influenza, which may contribute to their high odds of mortality [1]. In the early days of the Sars-CoV-2 pandemic, several case reports emerged from Wuhan of COVID-19-associated pulmonary aspergillosis (CAPA) [2]. Many risk factors for CAPA were recognized among critically ill COVID-19 patients, including lymphopenia, high levels of systemic pro-inflammatory cytokines, and the use of steroids [3].
Tocilizumab is a recombinant humanized monoclonal antibody against the interleukin-6 receptor. Initially, it showed promising results in reducing the severity of COVID-19 infection in critically ill patients. It dramatically reduces the potent inflammatory effects of IL-6 responsible for causing the lung damage and eventual multiorgan failure associated with COVID-19 [4]. A large retrospective study found that tocilizumab reduced the risk of death and the odds of needing mechanical ventilation in severe COVID-19 pneumonia [5]. However, subsequent findings from large randomized controlled trials raised doubts regarding these findings.
Here, we report the case of a critically ill patient who developed CAPA following tocilizumab administration.
2 Case
A 69-year-old man was admitted to the emergency department (ED) with fever and a cough which he had had for two days. His medical history included HBV-related liver cirrhosis, arterial hypertension and mild obesity (Body Mass Index 32). The man was calm and cooperative during his ED visit. His vital signs were: ABP 160/100 mmHg, SpO2 97% while breathing room air (PaO2/FIO2=303 mmHg), HR 75/min, and body temperature 36.7 °C. His white blood cell count was 3849/mm3, platelets were 62,000/mm3 (abnormal), and lymphocytes were 2140/mm3. C-reactive protein was 1.48 mg/L, procalcitonin (PCT) was 0.04 ng/ml, pro-adrenomedullin (pro-ADM) was 0.69 nMol/L, and IL-6 was 27.0 pg/mL (abnormal). A real-time PCR nasal swab tested positive for SARS-COV2.
The patient was then admitted to the infectious diseases ward (day 0) where he was treated with dexamethasone intravenously 6 mg per day. Given his worsening clinical situation, which necessitated increasing levels of oxygen provided by non-invasive ventilation using a full face mask, he was finally admitted to the ICU (day 8). In the ICU, the patient required immediate endotracheal intubation and invasive mechanical ventilation due to worsening dyspnoea associated with a PaO2/FIO2 of 135 mmHg. On his second day in the ICU (day 10), the patient's IL-6 levels reached 223.0 pg/mL (abnormal), thus the decision to administer tocilizumab that same day was taken (the patient was also being treated with entecavir for HBV-related cirrhosis).
Following tocilizumab administration, pre-emptive ceftobiprole treatment was started, 500 mg intravenously every 8 hours according to our internal protocol (day 10 until day 19). On day 15, the patient underwent an early percutaneous tracheostomy, as per our routine practice in COVID-19 patients, in order to facilitate easier weaning from mechanical ventilation.
On day 23, acyclovir (10 mg/kg BW) was administered intravenously every 8 hours to treat Herpes reactivation (HSV1-DNA detected in blood: 5197 copies/mL, abnormal). The same day, liposomal amphotericin B (3 mg/kg BW that was stopped after 30 days of therapy) was also given despite the absence of microbiological findings due to the suspicion of CAPA as suggested by the patient's high serum levels of β–D glucan (86.9 pg/ml, abnormal).
Aspergillus fumigatus was finally isolated from the bronchial aspirate on day 37, 22 days after tocilizumab administration and 12 days after the first positive result for serum β–D glucan.
Galactomannan levels in serum and alveolar fluid were tested on day 17, 20, 26 and 32. In the same days bronchoalveolar lavage fluid was also investigated through standard bacterial and fungal cultures and multiplex PCR filmarray. All these tests resulted negative for Aspergillus.
Repeated CT scans of the thorax showed the development over time of a cavity in the lung parenchyma, supporting our suspicion of pulmonary Aspergillus infection (see Fig. 1, Fig. 2, Fig. 3).Fig. 1 CT scan of the thorax at hospital admission (day 0) demonstrates diffuse subpleural ground-glass opacity.
Fig. 1
Fig. 2 CT scan of the thorax taken on day 14 demonstrates the appearance of consolidation in the upper left pulmonary lobe (blue arrow), extended ground-glass opacity and the crazy-paving pattern associated with posterior lung consolidation. (For interpretation of the references to colour in this figure legend, the reader is referred to the Web version of this article.)
Fig. 2
Fig. 3 CT scan (day 28) demonstrating a large septated cavity in the lung parenchyma suspected to be an Aspergillus lesion (blue arrow). (For interpretation of the references to colour in this figure legend, the reader is referred to the Web version of this article.)
Fig. 3
On day 43, the patient was discharged from the ICU to the Pneumology Unit with spontaneous breathing through the tracheostomy, which was removed on day 58. He went to rehabilitation unit in good condition after 68 days of hospitalization.
3 Discussion
The COVID-19 pandemic raises important questions regarding the treatment of coronaviruses. To the best of our knowledge, no single drug has been demonstrated to be effective in critically ill patients, and more evidence is required [6,7]. Many drugs and treatments (e.g. hydroxychloroquine, lopinavir/ritonavir, darunavir/cobicistat, etc.) have been proposed for the treatment of critically ill COVID-19 patients. One goal of these treatments is to reduce viral spread and replication. Another is to limit hyperinflammation and the triggering of a systemic response during the later phase of an infection which could lead to multiorgan dysfunction [8].
Steroids constitute the cornerstone treatment for COVID-19. The aim of steroid treatment is to modulate the inflammatory response, being recognized as a standard of care in the latest WHO guidelines [9]. Other drugs have also been proposed and tested for their capacity to limit the hyperinflammation that characterizes the later stages of COVID-19. These include inhibitors of the IL-1β and IL-6 receptor, of which anakinra and tocilizumab are the most commonly used. It is worth noting here that IL-6 also promotes viral and bacterial clearance. However, excessive inflammation could increase vascular permeability, inducing acute respiratory distress syndrome (ARDS), cardiac arrhythmia and other negative consequences [10].
From a theoretical perspective, tocilizumab therapy is currently considered the most appropriate. Its overall goal is to prevent multiorgan dysfunction caused by a cytokine storm. However, the associated consequences of immunosuppression must also be taken into account. Warnings about the increased risk of bacterial and fungal infections following immunosuppressant therapy have become more numerous over the last year [11]. Lymphopenia is present in a high percentage of COVID-19 patients. The additional use of steroids and other immunosuppressive drugs thus increases the risk for fungal infections, especially Aspergillus sp. In the case described, HBV-related cirrhosis was an additional risk factor for fungal infection. Indeed, evidence suggests there to be more secondary infections in COVID-19 patients treated with tocilizumab than in those not receiving the drug [12]. Moreover, it is difficult to confirm suspected infections using standard laboratory tests for infection, such as C-reactive protein or procalcitonin. These markers rapidly decrease after tocilizumab administration, with very low values persisting for many days. As a consequence, doctors are unlikely to suspect an infection.
Some authors recommend empirical antibiotic prophylaxis, including antifungal drugs. Indeed, the difficulty and time involved in isolating Aspergillus from bronchoalveolar lavage fluid further support the adoption of an empirical antifungal approach to COVID-19 therapy in critically ill patients [13]. In fact, in the case herein described, following our initial suspicion of CAPA due to the significant increase in β–D glucan levels (on day 23), the first microbiological specimen testing positive for Aspergillus was not obtained until 12 days later.
Diagnosis of invasive pulmonary aspergillosis (IPA) in the ICU remains challenging. For this reason, the European Organization for Research and Treatment of Cancer/Mycoses Study Group (EORTC/MSG) criteria have been supplemented with a specific algorithm in critically ill patients [14]. Although biomarkers of Aspergillus infection, such as serum galactomannan or β–D glucan, are generally deemed to be unsensitive, testing for their presence in serum and bronchoalveolar lavage fluid was recently added to the EORTC/MSG criteria to aid the identification of IPA in influenza patients admitted to ICU. In our case, in addition to the patient's risk factors for IPA, the sudden increase in β–D glucan levels was enough for us to deem therapy with a broad spectrum antifungal necessary. Curiously, although the patient tested positive for β–D glucan, he remained negative for galactomannan.
In the present case, tocilizumab may have favoured CAPA, although this remains to be proven.
Many questions remain unanswered regarding the role of tocilizumab therapy in COVID-19. Physicians generally prescribe it believing that they are damping down the fire … however, in some cases, it might be better likened to adding gasoline and not water!
Declaration of competing interest
The authors have no conflicts of interest to declare.
Acknowledgements
The authors do not wish to make any specific acknowledgements. | Recovered | ReactionOutcome | CC BY | 33520634 | 19,154,715 | 2021-03 |
What was the outcome of reaction 'Herpes simplex reactivation'? | Tocilizumab administration in COVID-19 patients: Water on the fire or gasoline?
Tocilizumab is widely being used to treat COVID-19. Although reducing systemic inflammation, it also increases the risk for secondary infections as a result of the immunosuppression produced. We report the case of a 69-year-old patient admitted to the ICU with severe respiratory distress caused by COVID-19 pneumonia who developed pulmonary aspergillosis. On the basis of these findings, we suggest early testing for pulmonary aspergillosis in COVID-19 patients treated with tocilizumab.
1 Introduction
Aspergillus is an opportunistic fungus mainly affecting immunocompromised patients. A high rate of invasive pulmonary aspergillosis has been demonstrated among critically ill patients admitted to the ICU with severe influenza, which may contribute to their high odds of mortality [1]. In the early days of the Sars-CoV-2 pandemic, several case reports emerged from Wuhan of COVID-19-associated pulmonary aspergillosis (CAPA) [2]. Many risk factors for CAPA were recognized among critically ill COVID-19 patients, including lymphopenia, high levels of systemic pro-inflammatory cytokines, and the use of steroids [3].
Tocilizumab is a recombinant humanized monoclonal antibody against the interleukin-6 receptor. Initially, it showed promising results in reducing the severity of COVID-19 infection in critically ill patients. It dramatically reduces the potent inflammatory effects of IL-6 responsible for causing the lung damage and eventual multiorgan failure associated with COVID-19 [4]. A large retrospective study found that tocilizumab reduced the risk of death and the odds of needing mechanical ventilation in severe COVID-19 pneumonia [5]. However, subsequent findings from large randomized controlled trials raised doubts regarding these findings.
Here, we report the case of a critically ill patient who developed CAPA following tocilizumab administration.
2 Case
A 69-year-old man was admitted to the emergency department (ED) with fever and a cough which he had had for two days. His medical history included HBV-related liver cirrhosis, arterial hypertension and mild obesity (Body Mass Index 32). The man was calm and cooperative during his ED visit. His vital signs were: ABP 160/100 mmHg, SpO2 97% while breathing room air (PaO2/FIO2=303 mmHg), HR 75/min, and body temperature 36.7 °C. His white blood cell count was 3849/mm3, platelets were 62,000/mm3 (abnormal), and lymphocytes were 2140/mm3. C-reactive protein was 1.48 mg/L, procalcitonin (PCT) was 0.04 ng/ml, pro-adrenomedullin (pro-ADM) was 0.69 nMol/L, and IL-6 was 27.0 pg/mL (abnormal). A real-time PCR nasal swab tested positive for SARS-COV2.
The patient was then admitted to the infectious diseases ward (day 0) where he was treated with dexamethasone intravenously 6 mg per day. Given his worsening clinical situation, which necessitated increasing levels of oxygen provided by non-invasive ventilation using a full face mask, he was finally admitted to the ICU (day 8). In the ICU, the patient required immediate endotracheal intubation and invasive mechanical ventilation due to worsening dyspnoea associated with a PaO2/FIO2 of 135 mmHg. On his second day in the ICU (day 10), the patient's IL-6 levels reached 223.0 pg/mL (abnormal), thus the decision to administer tocilizumab that same day was taken (the patient was also being treated with entecavir for HBV-related cirrhosis).
Following tocilizumab administration, pre-emptive ceftobiprole treatment was started, 500 mg intravenously every 8 hours according to our internal protocol (day 10 until day 19). On day 15, the patient underwent an early percutaneous tracheostomy, as per our routine practice in COVID-19 patients, in order to facilitate easier weaning from mechanical ventilation.
On day 23, acyclovir (10 mg/kg BW) was administered intravenously every 8 hours to treat Herpes reactivation (HSV1-DNA detected in blood: 5197 copies/mL, abnormal). The same day, liposomal amphotericin B (3 mg/kg BW that was stopped after 30 days of therapy) was also given despite the absence of microbiological findings due to the suspicion of CAPA as suggested by the patient's high serum levels of β–D glucan (86.9 pg/ml, abnormal).
Aspergillus fumigatus was finally isolated from the bronchial aspirate on day 37, 22 days after tocilizumab administration and 12 days after the first positive result for serum β–D glucan.
Galactomannan levels in serum and alveolar fluid were tested on day 17, 20, 26 and 32. In the same days bronchoalveolar lavage fluid was also investigated through standard bacterial and fungal cultures and multiplex PCR filmarray. All these tests resulted negative for Aspergillus.
Repeated CT scans of the thorax showed the development over time of a cavity in the lung parenchyma, supporting our suspicion of pulmonary Aspergillus infection (see Fig. 1, Fig. 2, Fig. 3).Fig. 1 CT scan of the thorax at hospital admission (day 0) demonstrates diffuse subpleural ground-glass opacity.
Fig. 1
Fig. 2 CT scan of the thorax taken on day 14 demonstrates the appearance of consolidation in the upper left pulmonary lobe (blue arrow), extended ground-glass opacity and the crazy-paving pattern associated with posterior lung consolidation. (For interpretation of the references to colour in this figure legend, the reader is referred to the Web version of this article.)
Fig. 2
Fig. 3 CT scan (day 28) demonstrating a large septated cavity in the lung parenchyma suspected to be an Aspergillus lesion (blue arrow). (For interpretation of the references to colour in this figure legend, the reader is referred to the Web version of this article.)
Fig. 3
On day 43, the patient was discharged from the ICU to the Pneumology Unit with spontaneous breathing through the tracheostomy, which was removed on day 58. He went to rehabilitation unit in good condition after 68 days of hospitalization.
3 Discussion
The COVID-19 pandemic raises important questions regarding the treatment of coronaviruses. To the best of our knowledge, no single drug has been demonstrated to be effective in critically ill patients, and more evidence is required [6,7]. Many drugs and treatments (e.g. hydroxychloroquine, lopinavir/ritonavir, darunavir/cobicistat, etc.) have been proposed for the treatment of critically ill COVID-19 patients. One goal of these treatments is to reduce viral spread and replication. Another is to limit hyperinflammation and the triggering of a systemic response during the later phase of an infection which could lead to multiorgan dysfunction [8].
Steroids constitute the cornerstone treatment for COVID-19. The aim of steroid treatment is to modulate the inflammatory response, being recognized as a standard of care in the latest WHO guidelines [9]. Other drugs have also been proposed and tested for their capacity to limit the hyperinflammation that characterizes the later stages of COVID-19. These include inhibitors of the IL-1β and IL-6 receptor, of which anakinra and tocilizumab are the most commonly used. It is worth noting here that IL-6 also promotes viral and bacterial clearance. However, excessive inflammation could increase vascular permeability, inducing acute respiratory distress syndrome (ARDS), cardiac arrhythmia and other negative consequences [10].
From a theoretical perspective, tocilizumab therapy is currently considered the most appropriate. Its overall goal is to prevent multiorgan dysfunction caused by a cytokine storm. However, the associated consequences of immunosuppression must also be taken into account. Warnings about the increased risk of bacterial and fungal infections following immunosuppressant therapy have become more numerous over the last year [11]. Lymphopenia is present in a high percentage of COVID-19 patients. The additional use of steroids and other immunosuppressive drugs thus increases the risk for fungal infections, especially Aspergillus sp. In the case described, HBV-related cirrhosis was an additional risk factor for fungal infection. Indeed, evidence suggests there to be more secondary infections in COVID-19 patients treated with tocilizumab than in those not receiving the drug [12]. Moreover, it is difficult to confirm suspected infections using standard laboratory tests for infection, such as C-reactive protein or procalcitonin. These markers rapidly decrease after tocilizumab administration, with very low values persisting for many days. As a consequence, doctors are unlikely to suspect an infection.
Some authors recommend empirical antibiotic prophylaxis, including antifungal drugs. Indeed, the difficulty and time involved in isolating Aspergillus from bronchoalveolar lavage fluid further support the adoption of an empirical antifungal approach to COVID-19 therapy in critically ill patients [13]. In fact, in the case herein described, following our initial suspicion of CAPA due to the significant increase in β–D glucan levels (on day 23), the first microbiological specimen testing positive for Aspergillus was not obtained until 12 days later.
Diagnosis of invasive pulmonary aspergillosis (IPA) in the ICU remains challenging. For this reason, the European Organization for Research and Treatment of Cancer/Mycoses Study Group (EORTC/MSG) criteria have been supplemented with a specific algorithm in critically ill patients [14]. Although biomarkers of Aspergillus infection, such as serum galactomannan or β–D glucan, are generally deemed to be unsensitive, testing for their presence in serum and bronchoalveolar lavage fluid was recently added to the EORTC/MSG criteria to aid the identification of IPA in influenza patients admitted to ICU. In our case, in addition to the patient's risk factors for IPA, the sudden increase in β–D glucan levels was enough for us to deem therapy with a broad spectrum antifungal necessary. Curiously, although the patient tested positive for β–D glucan, he remained negative for galactomannan.
In the present case, tocilizumab may have favoured CAPA, although this remains to be proven.
Many questions remain unanswered regarding the role of tocilizumab therapy in COVID-19. Physicians generally prescribe it believing that they are damping down the fire … however, in some cases, it might be better likened to adding gasoline and not water!
Declaration of competing interest
The authors have no conflicts of interest to declare.
Acknowledgements
The authors do not wish to make any specific acknowledgements. | Recovered | ReactionOutcome | CC BY | 33520634 | 19,070,160 | 2021-03 |
Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Drug ineffective'. | Epstein-Barr virus-associated monomorphic post-transplant lymphoproliferative disorder after pediatric kidney transplantation: A case report.
BACKGROUND
Post-transplant lymphoproliferative disease (PTLD) is the most common malignant tumor that occurs after kidney transplantation in children, and is associated with Epstein-Barr virus (EBV).
METHODS
We report a case of PTLD that occurred in a 17-year-old female patient at 5 mo post-transplant. The first symptom was abdominal pain accompanied by fever, nausea, and vomiting. EBV-associated monomorphic PTLD with multiple abdominal nodules was diagnosed by pathology, clinical manifestations, imaging results, and the presence of EB-DNA. After successful treatment with rituximab, the abdominal nodules in the spleen and liver disappeared.
CONCLUSIONS
Early pathological biopsy to confirm the diagnosis is critical to treatment and prognosis. Reducing immunosuppression and rituximab therapy are effective methods for treating PTLD, but need to be initiated as early as possible.
Core Tip: Post-transplant lymphoproliferative disease (PTLD) is related to Epstein-Barr virus infection, but early onset and monomorphic PTLD in childhood kidney transplantation is rare. This case suggests that virological evaluation must be strengthened before and after kidney transplantation in children, and early pathological biopsy to confirm the diagnosis is critical to treatment and prognosis. Rituximab therapy combined with adjusting the immunosuppressive regimen are effective in pediatric kidney transplantation.
INTRODUCTION
Post-transplant lymphoproliferative disease (PTLD) is a rare but serious complication of renal transplantation in children, with an incidence of 1%-2%[1]. The incidence of PTLD is highest during the first year after kidney transplantation[2]. Significant risk factors for PTLD include positive Epstein-Barr virus (EBV) serology before renal transplantation and receiving strong immunosuppressive therapy after renal transplantation. Also, PTLD is more likely to occur in younger transplant recipients[3]. This case report describes a patient who developed PTLD after renal transplantation at our hospital, and reviews the relevant literature to provide a higher awareness of the disease.
CASE PRESENTATION
Chief complaints
A 17-year-old female was hospitalized with complaining of abdominal pain, a fever of 38 °C, nausea, and vomiting for 4 d on June 2019.
History of present illness
Four days before admission, the patient presented with lower abdomen pain accompanied by fever, nausea and vomiting, and went to the emergency room of our hospital. Computed tomography (CT) examination showed splenic mass, diffuse thickening of the small intestine wall in the left abdominal cavity, subcutaneous nodules in the right iliac fossae, and peritoneal effusion.
History of past illness
The recipient was diagnosed with allergic purpura in 2012. The disease progressed to end-stage renal disease and received dialysis in 2017. In January 2019, she underwent kidney transplantation with panel-reactive antibody(-), complement-dependent cytotoxicity(-). Balineximab was used for induction therapy. The kidney donor was a 22-year-old male who suffered from a head injury in a traffic accident. Laboratory results showed that the donor was EB virus antigen IgG-negative, EB virus shell antigen IgG-positive, EB virus shell antigen IgM-negative, cytomegalovirus (CMV) DNA < 400 copies/mL, BK virus DNA < 5000 copies/mL, procalcitonin < 0.05 ng/mL, IgG test < 60 pg/mL, and blood culture negative. A sputum culture was positive for Corynebacterium and a urine culture was positive for Staphylococcus haemolyticus. The graft showed good function during the perioperative period, under the immunosuppression of FK506 + mycophenolate mofetil (MMF) + Pred. However, by 18 d post-operation, the patient’s urine volume had progressively decreased to 150 mL/24 h, and creatinine increased from 91 μmol/L to 288 μmol/L. The patient did not respond to methylprednisolone, and her high flow rate through a renal artery anastomosis was monitored by contrast-enhanced ultrasound. The graft was rescued by successful balloon dilatation of the distal end of the renal artery, after which, the patient’s urine output returned to normal, and her creatinine (Cr) level returned to 108 μmol/L at 25 d post-operation.
Personal and family history
Unremarkable.
Physical examination
A physical examination revealed lower abdominal tenderness, rebound tenderness, and muscle tension.
Laboratory examinations
The patient’s laboratory results were as follows: White blood cells, 10.1 × 109/L; hemoglobin, 83 g/L; Cr, 98 μmol/L; troponin I, 0.01 ng/mL; procalcitonin, 10.2 ng/mL; C-reactive protein, 212 mg/L; neutrophil granulocytes%, 88.7%; LYBL%, 6.3%. A test for EB-DNA was positive at a level of 1.66 × 104 copies/mL.
Imaging examinations
CT scan showed splenomegaly, left abdomen intestinal thickening, and a right iliac subcutaneous nodule. Ultrasound showed multiple low echo groups in the spleen, and magnetic resonance imaging showed multiple spleen occupying nodules, multiple lymph nodes in the right iliac fossa and right inguinal region, and small intestinal wall thickening. Positron emission tomography/computed tomography (PET/CT) scans showed high levels of metabolism in the intestine, liver, spleen, left kidney, T1, L3, S1 vertebral bodies, and the iliac region, suggesting lymphoma (Figure 1).
Figure 1
Positron emission tomography/computed tomography: High metabolism. A: In the intestinal wall; B: In right iliac subcutaneous nodule; C: In the spleen and liver; D: In the S1 vertebral body.
FINAL DIAGNOSIS
Based on pathological biopsy and medical history, the patient was diagnosed as monomorphic PTLD with immunohistochemical positive: EBV-encoded small RNAs(+), cluster of differentiation 38 CD38(+), CD20(+), CD3(+), and Ki67 index of 45% (Figure 2).
Figure 2 Right inguinal lymph node biopsy.
TREATMENT
After confirmation of PTLD, we immediately changed the patient’s immunosup-pressive therapy by stopping MMF and reducing dosage of FK506. Additionally, the patient received 375 mg/m2 rituximab targeted treatment once a week for eight rounds, and EB-DNA level was monitored once a week.
OUTCOME AND FOLLOW-UP
After two rounds of rituximab treatment, EB-DNA turned negative (< 400 copies/mL). After four rounds of rituximab, she had no fever, and PET/CT scan showed that the area of hypermetabolism in the spleen was significantly smaller than before. Furthermore, the hypermetabolic nodules in the liver had disappeared, the numbers of small intestinal lesions were significantly reduced, and signs of S1 vertebral hypermetabolism had disappeared. Subsequently, another four rounds of rituximab treatment were administered until CT showed the spleen’s multi-dimensional position as being unclear. The patient’s kidney function remained stable (creatinine, 56-74 μmol/L) throughout the course of treatment and the concentrations of FK506 was maintained at 5 ng/mL.
DISCUSSION
PTLD is a well-known malignant complication that can occur after pediatric renal transplantation. The cumulative incidence rate of PTLD in the first 10 years after transplantation is 1%-2% in adults and 3% in children; however, new evidence suggests that the incidence rate of PTLD may be decreasing over time[4,5]. Based on the time of occurrence, PTLD can be classified as either early-onset PTLD (occurring < 1 year after transplantation) or late-onset PTLD (occurring ≥ 1 year after transplantation). Here, we report a case of early-onset PTLD with multiple abdominal nodules, and also discuss the clinical characteristics, diagnosis, and treatment of PTLD, as well as the need for virological monitoring and making adjustments in immunosup-pressive therapy. We also review the relevant literature.
It is well known that EBV infection increases the probability of developing PTLD after solid organ transplantation. A univariate analysis using the Cox proportional risk model showed that EBV was a risk factor for early onset PTLD[6]. Furthermore, the EBV positive rate among lymphoma tissue biopsies in the early-onset group was higher than that among biopsies in the late-onset group (88.9% vs 60%, respectively)[6]. A history of anti-rejection treatment was found to be a risk factor for late-onset PTLD, most likely because of decreased immunity of the recipients due to exposure to high doses of immunosuppressants[6]. The patient in this case was 17-years-old, EBV-DNA-positive, and had a history of methylprednisolone pulse therapy, all of which are risk factors for PTLD. Although co-infection with EBV and CMV is also a risk factor for PTLD, the patient described here was CMV negative, as determined by a blood serum test.
The patient displayed signs and symptoms that are typical for PTLD, including fever, sweating, and general discomfort, as well as of nausea and vomiting, because PTLD often involves the gastrointestinal tract, liver, and spleen. A physical examination revealed splenomegaly and right inguinal lymphadenopathy. According to the 2008 World Health Organization classification for lymphoid malignancies, this patient could be diagnosed as early onset (5 mo post-operation), monomorphic PTLD with a lymph node biopsy suggesting diffuse large B-cell lymphoma, which is the most frequent subtype in children. The patient’s good response to treatment with rituximab also suggested this diagnosis.
Currently, EBV virus seropositivity is an established risk factor for early-onset PTLD, and especially in children. The patient described in this report had EBV viremia (EBV-DNA: 1.66 × 104 copies/mL) when her clinical manifestations of PTLD occurred. We believe that being EBV positive might be an important factor in this patient.
Post-transplant monitoring of EBV in transplant recipients by serologic methods appears to be poorly predictive of PTLD and results in a considerable delay in detecting seroconversion. Serum quantitative EBV PCR seems to be required for early detection of primary EBV infection[7], and especially in EBV-seronegative children who receive an organ from an EBV-seropositive donor. Some studies suggest that an organ recipient’s EBV load should be monitored every 2 wk for the first 3 mo after surgery, and then every month for the second 3 mo, followed by every 3 mo for the last 6 mo[8]. However, there is no clear evidence that antiviral therapy helps to reduce a patient’s EBV load or prevent EBV infection[9].
Treatment options for PTLD vary based on the disease subtype, and may include rituximab monotherapy, and rituximab with concurrent or sequential chemoimmuno-therapy, radiation or surgery. A nearly universal initial step is a reduction of immunosuppression. Balancing the mortality risk associated with PTLD with the risk of graft rejection in a setting of reduced immunosuppression is a major challenge for clinicians[10]. Most immunosuppression reduction algorithms include a reduction of the calcineurin inhibitor (CNI) dose (25% to 50% of baseline)[10]. A previous study found that a long-term reduction of immunosuppressive therapy administered post-chemotherapy did not appear to be associated with an increased risk for chronic graft dysfunction[11]. Many patients are switched to immunosup-pressive regimens based on rapamycin inhibitors in a CNI-free regimen that includes prednisolone and/or MMF. However, a study found that a complete withdrawal of CNIs after developing PTLD was associated with poor long-term kidney graft function[10]. In children, there is evidence for a high rate of acute rejection after late CNI withdrawal[12], and CNI withdrawal also increases the risk for developing donor-specific antibodies[13]. In the case, we adopted the immunosup-pressive therapy adjustment strategy of reducing CNI drugs and stopping MMF. The patient’s renal function remained normal throughout the course of treatment, but long-term monitoring was still required.
The treatment options for patients with monomorphic PTLD include rituximab with or without CHOP chemotherapy. Other studies have also demonstrated the effectiveness of RTX therapy. Michonneau et al[14] reported that the 5-year overall survival and disease-free survival rates for patients who received rituximab with or without chemotherapy were 69% and 80%, respectively. We used rituximab without chemotherapy in this patient and obtained a very good response. After two rounds of rituximab, the patient’s EB-DNA level turned negative (< 400 copies/mL), and after eight rounds of rituximab, the foci of the lesions in the spleen, liver, and intestinal wall became unclear, and there were no adverse reactions to the treatment. Although the use of rituximab has significantly improved the prognosis of patients with PTLD, with a treatment response rate of 52%, the long-term survival rate of patients with PTLD remains low, and the 1- and 3-year survival rates are 48% and 30%, respectively[15]. The patient described in this case report still requires long-term monitoring for signs of EB virus infection, as well as assessments of renal function and quality of life.
CONCLUSION
Based on this case and review of the relevant literature, we conclude that children who undergo renal transplantation remain at risk for developing PTLD. Early-onset PTLD is related to EBV infection and EBV-PCR should be performed on a regular basis after a kidney transplantation. Early pathological biopsy to confirm the diagnosis is critical to treatment and prognosis. Reducing immunosuppression and rituximab therapy are effective methods for treating PTLD, but need to be initiated as early as possible. Finally, there remains a need for further follow-up studies to determine PTLD patient survival times, graft function, and detect any adverse reactions to specific treatments.
Informed consent statement: All study participants, or their legal guardian, provided informed written consent prior to study enrollment.
Conflict-of-interest statement: All study participants had no potential conflicts of interest.
CARE Checklist (2016) statement: The authors have read the CARE Checklist (2016), and the manuscript was prepared and revised according to the CARE Checklist (2016).
Manuscript source: Unsolicited manuscript
Peer-review started: August 27, 2020
First decision: November 3, 2020
Article in press: November 29, 2020
Specialty type: Medicine, research and experimental
Country/Territory of origin: China
Peer-review report’s scientific quality classification
Grade A (Excellent): 0
Grade B (Very good): 0
Grade C (Good): C
Grade D (Fair): 0
Grade E (Poor): 0
P-Reviewer: Chiu KW S-Editor: Huang P L-Editor: Filipodia P-Editor: Li JH | METHYLPREDNISOLONE, MYCOPHENOLATE MOFETIL, PREDNISOLONE, TACROLIMUS | DrugsGivenReaction | CC BY-NC | 33521117 | 18,966,854 | 2021-01-16 |
Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Disease recurrence'. | Double-hit lymphoma (rearrangements of MYC, BCL-2) during pregnancy: A case report.
BACKGROUND
Double-hit lymphoma is a highly aggressive B-cell lymphoma that is genetically characterized by rearrangements of MYC and BCL2 and/or BCL6. Lymphoma is often accompanied by atypical systemic symptoms similar to physiological changes during pregnancy and is often ignored. Herein, we describe a gravid patient with high-grade B-cell lymphoma with a MYC and BCL-2 gene rearrangement involving multiple parts of the body.
METHODS
A 32-year-old female, gestational age 22+5 wk, complained of abdominal distension, chest tightness and limb weakness lasting approximately 4 wk, and ovarian tumors were found 14 d ago. Auxiliary examinations and a trimanual gynecologic examination suggested malignant ovarian tumor and frozen pelvis. Coupled with rapid progression, severe compression symptoms of hydrothorax, ascites and moderate anemia, labor was induced. Next, biopsy and imaging examinations showed high-grade B-cell lymphoma with a MYC and BCL-2 gene rearrangement involving multiple parts of the body. She was referred to the Department of Oncology and Hematology for chemotherapy. Because of multiple recurrences after complete remission, chemotherapy plans were continuously adjusted. At present, the patient remains in treatment and follow-up.
CONCLUSIONS
The early detection and accurate diagnosis of lymphoma during pregnancy can help expedite proper multidisciplinary treatment to delay disease progression and decrease the mortality rate.
Core Tip: To our knowledge, this is the first study to describe a patient with double-hit lymphoma during pregnancy. We should be well aware of the gynecological manifestations of lymphoma and consider it in the differential diagnosis of pelvic tumors. To avoid an unnecessary radical operation, biopsy should be considered instead of exploratory laparotomy in young women with suspected malignant tumors as well as acute onset, rapid progression and growing chylous pleural effusion containing abundant lymphocytes. The early detection and accurate diagnosis of lymphoma during pregnancy can help expedite proper multidisciplinary treatment to delay disease progression and decrease the mortality rate.
INTRODUCTION
Double-hit lymphoma (DHL) is a highly aggressive B-cell lymphoma that is genetically characterized by rearrangements of MYC and BCL2 and/or BCL6. This neoplasm (high-grade B-cell lymphoma with rearrangements of MYC and BCL2 and/or BCL6 called DHL/triple-hit lymphoma) was identified as a new subtype in the 2016 revision of the World Health Organization classification of lymphoid neoplasms[1]. The incidence rate of lymphoma is approximately 1/6000, ranking fourth in malignancies during pregnancy[2]. However, DHL is relatively uncommon. Lymphoma is often accompanied by atypical systemic symptoms similar to physiological changes during pregnancy and is often ignored. Due to its invasive nature, high risks of malignancy and recurrence and the lack of accepted treatment, it is necessary to explore effective therapies for DHL. Herein, we describe a gravid patient with high-grade B-cell lymphoma with a MYC and BCL-2 gene rearrangement involving multiple parts of the body.
CASE PRESENTATION
Chief complaints
A 32-year-old female, gestational age 22+5 wk, presented to the department of obstetrics of our hospital complaining of abdominal distension, chest tightness and limb weakness lasting approximately 4 wk. Ovarian tumors were found 14 d ago.
History of present illness
Fifty-five days prior (gestational age: 14+6 wk), her ultrasound showed no mass in the bilateral adnexal area. According to the patient, her abdominal distension, chest tightness, and limb weakness began approximately 4 wk prior (gestational age: approximately 19 wk), but she did not seek treatment. Fourteen days ago, she was diagnosed with bilateral ovarian tumors in another hospital by ultrasound showing a hypoechoic mass measuring 9.2 cm × 6.7 cm on the right side of the uterus, a hypoechoic mass measuring 9.2 cm × 6.9 cm on the left side of the uterus, an anechoic mass measuring 4.3 cm × 3.6 cm beside the uterus and pelvic effusion.
History of past illness
The patient noted a history of gastritis for more than 10 years.
Personal and family history
Her parents had a history of hypertension. She had no family history of malignancies.
Physical examination
Her face showed signs of anemia. Her chest percussion was voiced, and her abdomen was swollen. A trimanual gynecologic examination after induced labor revealed a uterus with poor mobility, irregular masses in the bilateral adnexal area with poor mobility, a rectal fossa filled with lesions and a narrow space between the intestines.
Laboratory examinations
Upon admission, her laboratory results were as follows: hemoglobin 66 g/L, hematocrit 20.4%, reticulocyte 3.28%, serum albumin 35.1 g/L, free triiodothyonine 2.34 pmol/L, and free thyroxine 16.35 pmol/L. Tumor marker levels were as follows: CA125 578.50 U/mL, alpha-fetoprotein 157.84 ng/mL, carcinoembryonic antigen 0.53 ng/mL, CA199 16.13 U/mL, Cyfra21-1 2.60 ng/mL, Fer 749.58 ng/mL, β 2-microglobulin 5.56 μg/mL, neuron-specific enolase 15.84 ng/mL, CA50 7.19 U/mL, CA153 25.70 U/mL and serum lactic dehydrogenase (LDH) 1160 U/L.
Imaging examinations
At admission, ultrasound indicated a hypoechoic mass measuring 10.7 cm × 7.8 cm in the right adnexal area and a hypoechoic mass measuring 11.2 cm × 8.2 in the left adnexa. Then, pelvic magnetic resonance imaging (MRI) showed a soft tissue mass shadow in the pelvic cavity measuring approximately 12.7 cm in the largest diameter and lesions involving the posterior wall of the bladder, adjacent bowel, cervix, upper part of the vagina and bilateral iliac vessels. The patient was diagnosed with a bilateral adnexal malignant tumor, and the pelvic mass was not excluded as metastasis (Figure 1A-D). MRI also revealed pelvic effusion, soft tissue swelling in the pelvic wall and buttock, changes in the pelvic bone and bilateral ureteral dilatation.
Figure 1
Magnetic resonance imaging and computed tomography imaging. A and B: Coronal (A) and axial (B) images showed bilateral adnexal malignant tumors; C and D: Sagittal images showed masses in the left (C) and right (D) adnexal area; E and F: Computed tomography images of the arterial phase (E) and venous phase (F) showed bilateral adnexal malignant tumors.
Ultrasonography and computed tomography (CT) showed massive peritoneal and bilateral pleural effusion. Therefore, we performed ultrasound-guided puncture catheter drainage in the abdominal cavity and right thoracic cavity. Whole-abdomen CT showed bilateral pleural effusion, abdominal and pelvic effusion and malignancies of the bilateral adnexal origin that did not involve the rectum and bladder (Figure 1E and 1F). Whole-abdomen CT also revealed an irregularly shaped uterus and cervix that were not excluded as metastases, multiple soft tissue masses in the abdomen believed to be metastases, a nodular shadow in the left lateral lobe of the liver that was not excluded as metastasis, tumor involvement in the bilateral middle and lower ureters, secondary left kidney atrophy, bilateral hydronephrosis, bilateral upper ureteral dilatation and bilateral inguinal lymph nodes. After receiving the pathological results, positron emission tomography-computed tomography (PET-CT) was performed and revealed multiple enlarged lymph nodes throughout the body with increased metabolism (indicative of lymphoma), some lesions that were unclearly demarcated from the uterus and adnexa, thickening of the bilateral pleural wall, pleura, pericardium, peritoneum, omentum and mesentery with increased metabolism (indicative of lymphoma infiltration), lymphoma in the right breast and increased systemic skeletal metabolism (indicative of lymphoma infiltration).
Histopathological examination
The exfoliative cytology of hydrothorax and hydroperitoneum showed many lymphocytes without cancer cells. The pathological results supported high-grade B-cell lymphoma, and the immunohistochemical staining results were as follows: LCA (+), CD20 (+), CD3 (-), CD5 (-), Cyclin D1 (-), Ki67 (positive rate 90%), CK (AE1/AE3) (-), BCL-6 (+), TdT (-), MPO (-), CgA (-), Syn (-), CD56 (-), PAX-5 (+), CD34 (-), CD10 (+), BCL-2 (+), MUM1 (-), MYC (+), CD21 (-) and CD99 (weakly +). The pathological consultation at the superior hospital resulted in a diagnosis of non-Hodgkin high-grade B-cell lymphoma with rearrangements of the MYC gene and BCL2 gene (DHL). Immunohistochemistry revealed MUM-1+, CD10+, CD38+ and LMO 2- and in situ hybridization revealed EBER-.
FINAL DIAGNOSIS
The final diagnosis was high-grade B-cell lymphoma with rearrangements of MYC and BCL2 (stage IV, International Prognostic Index = 4 points, age-adjusted International Prognostic Index = 3 points) (involving multiple lymph nodes, the bilateral chest wall, pleura, pericardium, peritoneum, omentum, mesentery, right breast and whole body skeleton).
TREATMENT
Considering the patient’s rapidly progressing condition and severe systemic symptoms, we explained the treatment options and possible risks to the patient and her husband, and then informed consent was obtained to perform rivanol-induced labor. The patient also received a blood transfusion and anti-infection, expectorant and other symptomatic treatments. After consultation, we performed ultrasound-guided puncture catheter drainage in the abdominal cavity and right thoracic cavity due to massive abdominal and pleural effusion. A large amount of yellowish chyliform fluid was drained (Figure 2). Because of severe abdominal distension and difficulty associated with enema administration, we carried out ultrasound-guided puncture biopsy of the pelvic masses rather than colonoscopy with biopsy.
Figure 2 Yellowish chyliform fluid drained from the abdomen.
The patient was immediately referred and admitted to the Department of Oncology and Hematology for chemotherapy. First, she received rituximab plus cyclo-phosphamide, doxorubicin, vincristine and prednisone (R-CHOP) chemotherapy. One course later, chemotherapy was adjusted to dose-adjusted R-EPOCH (DA-R-EPOCH) because of grade IV myelosuppression. The patient then achieved complete remission (CR) after four courses. Two months later, the disease relapsed. She received rituximab, dexamethasone, ifosfamide, cisplatin, etoposide + lenalidomide, R-DICE and the treatment of chimeric antigen receptor T-cell therapy and achieved CR again. Two months later, the lymphoma relapsed again, and the patient received rituximab combined with a Btk inhibitor, gemcitabine + oxaliplatin, combined with azacytidine chemotherapy, oral ibrutinib and a combination of methotrexate + rituximab + gemcitabine + oxaliplatin + azacytidine.
OUTCOME AND FOLLOW-UP
The patient achieved CR following treatment but relapsed so rapidly that chemotherapy was continuously adjusted. At present, the patient remains in treatment and close follow-up.
DISCUSSION
The median age of onset for DHL is 51-67 years. DHL is characterized by a high level of LDH, an elevated Ki-67 index, a high-risk International Prognostic Index score and susceptibility to extranodal invasion, especially bone marrow and central nervous system (CNS) involvement[3]. The onset of lymphoma during pregnancy is insidious without typical symptoms. Lymphoma is often accompanied by systemic symptoms, such as fatigue, shortness of breath and night sweats, which is similar to physiological changes during pregnancy and is often ignored. Therefore, patients do not often visit a doctor until severe clinical symptoms appear, which may postpone the diagnosis and optimal treatment. The proportion of reproductive organs involved in non-Hodgkin lymphoma (NHL) is higher during pregnancy than during nonpregnancy and commonly involves invasion of the breast followed by the ovaries and uterus[4]. Because pelvic blood flow and lymphatic drainage are abundant during pregnancy and might enhance the growth and spread of tumor cells, pregnancy may promote the occurrence and development of lymphoma. Our patient developed symptoms at 19 wk of gestation and was found to have ovarian masses reaching the frozen pelvis approximately 4 wk later. However, ultrasound showed no mass in the bilateral adnexal area at 14+6 wk of gestation. DHL progressed rapidly because pregnancy may have accelerated tumor growth and spread.
A pathological examination, including lymph node biopsy and tissue biopsy, which can be performed safely during pregnancy, is the principal means of lymphoma diagnosis. DHL can be diagnosed by fluorescent in situ hybridization[5]. Concerning the immunophenotype, B-cell markers, including CD19, CD20, CD22, CD79a and CD45, are generally positive in these lymphomas, and high CD38 expression is usually observed[5]. For pregnant patients with lymphoma, it is advisable to evaluate the condition by ultrasound, MRI, a chest X-ray examination with an abdomen shield and CT or PET-CT after delivery. Bone marrow biopsy is critical to the diagnosis and staging of lymphoma and is safe during pregnancy[6]. It should be noted that when ovarian tumors are suspected to be malignant, we often perform an exploratory laparotomy. However, for young women with acute onset, rapid progression and increasing chylous pleural effusion containing abundant lymphocytes, biopsy of the lesion should be considered to avoid an unnecessary radical surgery.
As DHL is associated with a poor prognosis during pregnancy, it is necessary to consider many factors, including the stage of pregnancy, pathological type, current feasible treatment methods and patients’ willingness, when making treatment plans. Indolent NHL, with gradual progression can be monitored closely before treatment begins in the second and third trimesters[7]. For most aggressive and highly aggressive NHLs, it is crucial to begin combination chemotherapy immediately and terminate the pregnancy during early pregnancy[7]. For young women who require that their reproductive function be preserved, we should take relevant measures.
These individuals respond poorly to traditional R-CHOP alone and rapidly develop resistance to cytotoxic chemotherapy, which can result in an increased risk of relapse and a poor prognosis[5]. Recently, several centers have used DA-R-EPOCH as DHL’s preferred induction scheme[8]. A retrospective study at the MD Anderson Cancer Center showed that the DA-R-EPOCH regimen could prolong the progression-free survival (PFS) and overall survival (OS) of DHL patients compared with the chemotherapy regimens such as R-CHOP and rituximab, hyperfractionated cyclophosphamide, vincristine, doxorubicin, dexamethasone, alternating with cytarabine + methotrexate[9]. A large multicenter retrospective study showed that high-intensity induction programs such as DA-R-EPOCH, rituximab, hyperfractionated cyclophosphamide, vincristine, doxorubicin, dexamethasone, alternating with cytarabine + methotrexate and cyclophosphamide, vincristine, doxorubicin, high-dose methotrexate/ifosfamide, etoposide, high-dose cytarabine could better prolong PFS in patients than R-CHOP, but there was no difference in OS[10].
Rosenthal et al[11] recommended CNS prevention for all patients with DHL. CNS prophylaxis with intravenous high-dose methotrexate should be given only after delivery[4]. Cellular therapies such as CAR-T-cell therapy can be considered in patients with refractory or repeatedly relapsed disease, preferably in the context of a clinical trial[5]. In addition, targeted agents for MYC, BCL-2 and/or BCL-6 provide new ideas for clinical research and treatment. The patient described herein had a poor response to R-CHOP therapy but was sensitive to the DA-R-EPOCH regimen and CAR-T therapy. The patient achieved CR but relapsed rapidly due to the extremely invasive nature of the tumor.
In summary, DHL is highly aggressive and malignant and responds poorly to standard R-CHOP chemotherapy. In contrast, it is sensitive to high-intensity induction chemotherapy, yet there is a high risk of recurrence after achieving CR. Therefore, it is suggested to closely monitor patients who achieve CR and adjust the chemotherapy plan when conditions change. However, more clinical trials and studies are needed to identify effective therapies.
CONCLUSION
As obstetricians and gynecologists, we should be well aware of the gynecological manifestations of lymphoma and consider it in the differential diagnosis of pelvic tumors. It is necessary to be aware of the occurrence of lymphoma when faced with unexplained abdominal distension and fatigue, a fast-growing pelvic mass, increasing hydrothorax and ascites containing many lymphocytes. Then, biopsy might be a good choice to avoid an unnecessary or excessive radical surgery. The early detection and accurate diagnosis of lymphoma during pregnancy can help expedite proper multidisciplinary treatment to delay progression and decrease the mortality rate.
ACKNOWLEDGEMENTS
We thank the family who participated in this study.
Informed consent statement: Informed written consent was obtained from the patient for publication of this report and any accompanying images.
Conflict-of-interest statement: The authors declare that they have no conflict of interest.
CARE Checklist (2016) statement: The authors have read the CARE Checklist (2016), and the manuscript was prepared and revised according to the CARE Checklist (2016).
Manuscript source: Unsolicited manuscript
Peer-review started: September 11, 2020
First decision: November 14, 2020
Article in press: November 21, 2020
Specialty type: Medicine, research and experimental
Country/Territory of origin: China
Peer-review report’s scientific quality classification
Grade A (Excellent): 0
Grade B (Very good): B
Grade C (Good): 0
Grade D (Fair): 0
Grade E (Poor): 0
P-Reviewer: Ristic-Medic D S-Editor: Huang P L-Editor: Filipodia P-Editor: Ma YJ | AZACITIDINE, CISPLATIN, CYCLOPHOSPHAMIDE, DEXAMETHASONE, DOXORUBICIN, ETOPOSIDE, GEMCITABINE, IBRUTINIB, IFOSFAMIDE, LENALIDOMIDE, METHOTREXATE, OXALIPLATIN, PREDNISONE, RITUXIMAB, VINCRISTINE | DrugsGivenReaction | CC BY-NC | 33521119 | 19,011,051 | 2021-01-16 |
What was the administration route of drug 'IBRUTINIB'? | Double-hit lymphoma (rearrangements of MYC, BCL-2) during pregnancy: A case report.
BACKGROUND
Double-hit lymphoma is a highly aggressive B-cell lymphoma that is genetically characterized by rearrangements of MYC and BCL2 and/or BCL6. Lymphoma is often accompanied by atypical systemic symptoms similar to physiological changes during pregnancy and is often ignored. Herein, we describe a gravid patient with high-grade B-cell lymphoma with a MYC and BCL-2 gene rearrangement involving multiple parts of the body.
METHODS
A 32-year-old female, gestational age 22+5 wk, complained of abdominal distension, chest tightness and limb weakness lasting approximately 4 wk, and ovarian tumors were found 14 d ago. Auxiliary examinations and a trimanual gynecologic examination suggested malignant ovarian tumor and frozen pelvis. Coupled with rapid progression, severe compression symptoms of hydrothorax, ascites and moderate anemia, labor was induced. Next, biopsy and imaging examinations showed high-grade B-cell lymphoma with a MYC and BCL-2 gene rearrangement involving multiple parts of the body. She was referred to the Department of Oncology and Hematology for chemotherapy. Because of multiple recurrences after complete remission, chemotherapy plans were continuously adjusted. At present, the patient remains in treatment and follow-up.
CONCLUSIONS
The early detection and accurate diagnosis of lymphoma during pregnancy can help expedite proper multidisciplinary treatment to delay disease progression and decrease the mortality rate.
Core Tip: To our knowledge, this is the first study to describe a patient with double-hit lymphoma during pregnancy. We should be well aware of the gynecological manifestations of lymphoma and consider it in the differential diagnosis of pelvic tumors. To avoid an unnecessary radical operation, biopsy should be considered instead of exploratory laparotomy in young women with suspected malignant tumors as well as acute onset, rapid progression and growing chylous pleural effusion containing abundant lymphocytes. The early detection and accurate diagnosis of lymphoma during pregnancy can help expedite proper multidisciplinary treatment to delay disease progression and decrease the mortality rate.
INTRODUCTION
Double-hit lymphoma (DHL) is a highly aggressive B-cell lymphoma that is genetically characterized by rearrangements of MYC and BCL2 and/or BCL6. This neoplasm (high-grade B-cell lymphoma with rearrangements of MYC and BCL2 and/or BCL6 called DHL/triple-hit lymphoma) was identified as a new subtype in the 2016 revision of the World Health Organization classification of lymphoid neoplasms[1]. The incidence rate of lymphoma is approximately 1/6000, ranking fourth in malignancies during pregnancy[2]. However, DHL is relatively uncommon. Lymphoma is often accompanied by atypical systemic symptoms similar to physiological changes during pregnancy and is often ignored. Due to its invasive nature, high risks of malignancy and recurrence and the lack of accepted treatment, it is necessary to explore effective therapies for DHL. Herein, we describe a gravid patient with high-grade B-cell lymphoma with a MYC and BCL-2 gene rearrangement involving multiple parts of the body.
CASE PRESENTATION
Chief complaints
A 32-year-old female, gestational age 22+5 wk, presented to the department of obstetrics of our hospital complaining of abdominal distension, chest tightness and limb weakness lasting approximately 4 wk. Ovarian tumors were found 14 d ago.
History of present illness
Fifty-five days prior (gestational age: 14+6 wk), her ultrasound showed no mass in the bilateral adnexal area. According to the patient, her abdominal distension, chest tightness, and limb weakness began approximately 4 wk prior (gestational age: approximately 19 wk), but she did not seek treatment. Fourteen days ago, she was diagnosed with bilateral ovarian tumors in another hospital by ultrasound showing a hypoechoic mass measuring 9.2 cm × 6.7 cm on the right side of the uterus, a hypoechoic mass measuring 9.2 cm × 6.9 cm on the left side of the uterus, an anechoic mass measuring 4.3 cm × 3.6 cm beside the uterus and pelvic effusion.
History of past illness
The patient noted a history of gastritis for more than 10 years.
Personal and family history
Her parents had a history of hypertension. She had no family history of malignancies.
Physical examination
Her face showed signs of anemia. Her chest percussion was voiced, and her abdomen was swollen. A trimanual gynecologic examination after induced labor revealed a uterus with poor mobility, irregular masses in the bilateral adnexal area with poor mobility, a rectal fossa filled with lesions and a narrow space between the intestines.
Laboratory examinations
Upon admission, her laboratory results were as follows: hemoglobin 66 g/L, hematocrit 20.4%, reticulocyte 3.28%, serum albumin 35.1 g/L, free triiodothyonine 2.34 pmol/L, and free thyroxine 16.35 pmol/L. Tumor marker levels were as follows: CA125 578.50 U/mL, alpha-fetoprotein 157.84 ng/mL, carcinoembryonic antigen 0.53 ng/mL, CA199 16.13 U/mL, Cyfra21-1 2.60 ng/mL, Fer 749.58 ng/mL, β 2-microglobulin 5.56 μg/mL, neuron-specific enolase 15.84 ng/mL, CA50 7.19 U/mL, CA153 25.70 U/mL and serum lactic dehydrogenase (LDH) 1160 U/L.
Imaging examinations
At admission, ultrasound indicated a hypoechoic mass measuring 10.7 cm × 7.8 cm in the right adnexal area and a hypoechoic mass measuring 11.2 cm × 8.2 in the left adnexa. Then, pelvic magnetic resonance imaging (MRI) showed a soft tissue mass shadow in the pelvic cavity measuring approximately 12.7 cm in the largest diameter and lesions involving the posterior wall of the bladder, adjacent bowel, cervix, upper part of the vagina and bilateral iliac vessels. The patient was diagnosed with a bilateral adnexal malignant tumor, and the pelvic mass was not excluded as metastasis (Figure 1A-D). MRI also revealed pelvic effusion, soft tissue swelling in the pelvic wall and buttock, changes in the pelvic bone and bilateral ureteral dilatation.
Figure 1
Magnetic resonance imaging and computed tomography imaging. A and B: Coronal (A) and axial (B) images showed bilateral adnexal malignant tumors; C and D: Sagittal images showed masses in the left (C) and right (D) adnexal area; E and F: Computed tomography images of the arterial phase (E) and venous phase (F) showed bilateral adnexal malignant tumors.
Ultrasonography and computed tomography (CT) showed massive peritoneal and bilateral pleural effusion. Therefore, we performed ultrasound-guided puncture catheter drainage in the abdominal cavity and right thoracic cavity. Whole-abdomen CT showed bilateral pleural effusion, abdominal and pelvic effusion and malignancies of the bilateral adnexal origin that did not involve the rectum and bladder (Figure 1E and 1F). Whole-abdomen CT also revealed an irregularly shaped uterus and cervix that were not excluded as metastases, multiple soft tissue masses in the abdomen believed to be metastases, a nodular shadow in the left lateral lobe of the liver that was not excluded as metastasis, tumor involvement in the bilateral middle and lower ureters, secondary left kidney atrophy, bilateral hydronephrosis, bilateral upper ureteral dilatation and bilateral inguinal lymph nodes. After receiving the pathological results, positron emission tomography-computed tomography (PET-CT) was performed and revealed multiple enlarged lymph nodes throughout the body with increased metabolism (indicative of lymphoma), some lesions that were unclearly demarcated from the uterus and adnexa, thickening of the bilateral pleural wall, pleura, pericardium, peritoneum, omentum and mesentery with increased metabolism (indicative of lymphoma infiltration), lymphoma in the right breast and increased systemic skeletal metabolism (indicative of lymphoma infiltration).
Histopathological examination
The exfoliative cytology of hydrothorax and hydroperitoneum showed many lymphocytes without cancer cells. The pathological results supported high-grade B-cell lymphoma, and the immunohistochemical staining results were as follows: LCA (+), CD20 (+), CD3 (-), CD5 (-), Cyclin D1 (-), Ki67 (positive rate 90%), CK (AE1/AE3) (-), BCL-6 (+), TdT (-), MPO (-), CgA (-), Syn (-), CD56 (-), PAX-5 (+), CD34 (-), CD10 (+), BCL-2 (+), MUM1 (-), MYC (+), CD21 (-) and CD99 (weakly +). The pathological consultation at the superior hospital resulted in a diagnosis of non-Hodgkin high-grade B-cell lymphoma with rearrangements of the MYC gene and BCL2 gene (DHL). Immunohistochemistry revealed MUM-1+, CD10+, CD38+ and LMO 2- and in situ hybridization revealed EBER-.
FINAL DIAGNOSIS
The final diagnosis was high-grade B-cell lymphoma with rearrangements of MYC and BCL2 (stage IV, International Prognostic Index = 4 points, age-adjusted International Prognostic Index = 3 points) (involving multiple lymph nodes, the bilateral chest wall, pleura, pericardium, peritoneum, omentum, mesentery, right breast and whole body skeleton).
TREATMENT
Considering the patient’s rapidly progressing condition and severe systemic symptoms, we explained the treatment options and possible risks to the patient and her husband, and then informed consent was obtained to perform rivanol-induced labor. The patient also received a blood transfusion and anti-infection, expectorant and other symptomatic treatments. After consultation, we performed ultrasound-guided puncture catheter drainage in the abdominal cavity and right thoracic cavity due to massive abdominal and pleural effusion. A large amount of yellowish chyliform fluid was drained (Figure 2). Because of severe abdominal distension and difficulty associated with enema administration, we carried out ultrasound-guided puncture biopsy of the pelvic masses rather than colonoscopy with biopsy.
Figure 2 Yellowish chyliform fluid drained from the abdomen.
The patient was immediately referred and admitted to the Department of Oncology and Hematology for chemotherapy. First, she received rituximab plus cyclo-phosphamide, doxorubicin, vincristine and prednisone (R-CHOP) chemotherapy. One course later, chemotherapy was adjusted to dose-adjusted R-EPOCH (DA-R-EPOCH) because of grade IV myelosuppression. The patient then achieved complete remission (CR) after four courses. Two months later, the disease relapsed. She received rituximab, dexamethasone, ifosfamide, cisplatin, etoposide + lenalidomide, R-DICE and the treatment of chimeric antigen receptor T-cell therapy and achieved CR again. Two months later, the lymphoma relapsed again, and the patient received rituximab combined with a Btk inhibitor, gemcitabine + oxaliplatin, combined with azacytidine chemotherapy, oral ibrutinib and a combination of methotrexate + rituximab + gemcitabine + oxaliplatin + azacytidine.
OUTCOME AND FOLLOW-UP
The patient achieved CR following treatment but relapsed so rapidly that chemotherapy was continuously adjusted. At present, the patient remains in treatment and close follow-up.
DISCUSSION
The median age of onset for DHL is 51-67 years. DHL is characterized by a high level of LDH, an elevated Ki-67 index, a high-risk International Prognostic Index score and susceptibility to extranodal invasion, especially bone marrow and central nervous system (CNS) involvement[3]. The onset of lymphoma during pregnancy is insidious without typical symptoms. Lymphoma is often accompanied by systemic symptoms, such as fatigue, shortness of breath and night sweats, which is similar to physiological changes during pregnancy and is often ignored. Therefore, patients do not often visit a doctor until severe clinical symptoms appear, which may postpone the diagnosis and optimal treatment. The proportion of reproductive organs involved in non-Hodgkin lymphoma (NHL) is higher during pregnancy than during nonpregnancy and commonly involves invasion of the breast followed by the ovaries and uterus[4]. Because pelvic blood flow and lymphatic drainage are abundant during pregnancy and might enhance the growth and spread of tumor cells, pregnancy may promote the occurrence and development of lymphoma. Our patient developed symptoms at 19 wk of gestation and was found to have ovarian masses reaching the frozen pelvis approximately 4 wk later. However, ultrasound showed no mass in the bilateral adnexal area at 14+6 wk of gestation. DHL progressed rapidly because pregnancy may have accelerated tumor growth and spread.
A pathological examination, including lymph node biopsy and tissue biopsy, which can be performed safely during pregnancy, is the principal means of lymphoma diagnosis. DHL can be diagnosed by fluorescent in situ hybridization[5]. Concerning the immunophenotype, B-cell markers, including CD19, CD20, CD22, CD79a and CD45, are generally positive in these lymphomas, and high CD38 expression is usually observed[5]. For pregnant patients with lymphoma, it is advisable to evaluate the condition by ultrasound, MRI, a chest X-ray examination with an abdomen shield and CT or PET-CT after delivery. Bone marrow biopsy is critical to the diagnosis and staging of lymphoma and is safe during pregnancy[6]. It should be noted that when ovarian tumors are suspected to be malignant, we often perform an exploratory laparotomy. However, for young women with acute onset, rapid progression and increasing chylous pleural effusion containing abundant lymphocytes, biopsy of the lesion should be considered to avoid an unnecessary radical surgery.
As DHL is associated with a poor prognosis during pregnancy, it is necessary to consider many factors, including the stage of pregnancy, pathological type, current feasible treatment methods and patients’ willingness, when making treatment plans. Indolent NHL, with gradual progression can be monitored closely before treatment begins in the second and third trimesters[7]. For most aggressive and highly aggressive NHLs, it is crucial to begin combination chemotherapy immediately and terminate the pregnancy during early pregnancy[7]. For young women who require that their reproductive function be preserved, we should take relevant measures.
These individuals respond poorly to traditional R-CHOP alone and rapidly develop resistance to cytotoxic chemotherapy, which can result in an increased risk of relapse and a poor prognosis[5]. Recently, several centers have used DA-R-EPOCH as DHL’s preferred induction scheme[8]. A retrospective study at the MD Anderson Cancer Center showed that the DA-R-EPOCH regimen could prolong the progression-free survival (PFS) and overall survival (OS) of DHL patients compared with the chemotherapy regimens such as R-CHOP and rituximab, hyperfractionated cyclophosphamide, vincristine, doxorubicin, dexamethasone, alternating with cytarabine + methotrexate[9]. A large multicenter retrospective study showed that high-intensity induction programs such as DA-R-EPOCH, rituximab, hyperfractionated cyclophosphamide, vincristine, doxorubicin, dexamethasone, alternating with cytarabine + methotrexate and cyclophosphamide, vincristine, doxorubicin, high-dose methotrexate/ifosfamide, etoposide, high-dose cytarabine could better prolong PFS in patients than R-CHOP, but there was no difference in OS[10].
Rosenthal et al[11] recommended CNS prevention for all patients with DHL. CNS prophylaxis with intravenous high-dose methotrexate should be given only after delivery[4]. Cellular therapies such as CAR-T-cell therapy can be considered in patients with refractory or repeatedly relapsed disease, preferably in the context of a clinical trial[5]. In addition, targeted agents for MYC, BCL-2 and/or BCL-6 provide new ideas for clinical research and treatment. The patient described herein had a poor response to R-CHOP therapy but was sensitive to the DA-R-EPOCH regimen and CAR-T therapy. The patient achieved CR but relapsed rapidly due to the extremely invasive nature of the tumor.
In summary, DHL is highly aggressive and malignant and responds poorly to standard R-CHOP chemotherapy. In contrast, it is sensitive to high-intensity induction chemotherapy, yet there is a high risk of recurrence after achieving CR. Therefore, it is suggested to closely monitor patients who achieve CR and adjust the chemotherapy plan when conditions change. However, more clinical trials and studies are needed to identify effective therapies.
CONCLUSION
As obstetricians and gynecologists, we should be well aware of the gynecological manifestations of lymphoma and consider it in the differential diagnosis of pelvic tumors. It is necessary to be aware of the occurrence of lymphoma when faced with unexplained abdominal distension and fatigue, a fast-growing pelvic mass, increasing hydrothorax and ascites containing many lymphocytes. Then, biopsy might be a good choice to avoid an unnecessary or excessive radical surgery. The early detection and accurate diagnosis of lymphoma during pregnancy can help expedite proper multidisciplinary treatment to delay progression and decrease the mortality rate.
ACKNOWLEDGEMENTS
We thank the family who participated in this study.
Informed consent statement: Informed written consent was obtained from the patient for publication of this report and any accompanying images.
Conflict-of-interest statement: The authors declare that they have no conflict of interest.
CARE Checklist (2016) statement: The authors have read the CARE Checklist (2016), and the manuscript was prepared and revised according to the CARE Checklist (2016).
Manuscript source: Unsolicited manuscript
Peer-review started: September 11, 2020
First decision: November 14, 2020
Article in press: November 21, 2020
Specialty type: Medicine, research and experimental
Country/Territory of origin: China
Peer-review report’s scientific quality classification
Grade A (Excellent): 0
Grade B (Very good): B
Grade C (Good): 0
Grade D (Fair): 0
Grade E (Poor): 0
P-Reviewer: Ristic-Medic D S-Editor: Huang P L-Editor: Filipodia P-Editor: Ma YJ | Oral | DrugAdministrationRoute | CC BY-NC | 33521119 | 19,011,051 | 2021-01-16 |
What was the dosage of drug 'CYCLOPHOSPHAMIDE'? | Double-hit lymphoma (rearrangements of MYC, BCL-2) during pregnancy: A case report.
BACKGROUND
Double-hit lymphoma is a highly aggressive B-cell lymphoma that is genetically characterized by rearrangements of MYC and BCL2 and/or BCL6. Lymphoma is often accompanied by atypical systemic symptoms similar to physiological changes during pregnancy and is often ignored. Herein, we describe a gravid patient with high-grade B-cell lymphoma with a MYC and BCL-2 gene rearrangement involving multiple parts of the body.
METHODS
A 32-year-old female, gestational age 22+5 wk, complained of abdominal distension, chest tightness and limb weakness lasting approximately 4 wk, and ovarian tumors were found 14 d ago. Auxiliary examinations and a trimanual gynecologic examination suggested malignant ovarian tumor and frozen pelvis. Coupled with rapid progression, severe compression symptoms of hydrothorax, ascites and moderate anemia, labor was induced. Next, biopsy and imaging examinations showed high-grade B-cell lymphoma with a MYC and BCL-2 gene rearrangement involving multiple parts of the body. She was referred to the Department of Oncology and Hematology for chemotherapy. Because of multiple recurrences after complete remission, chemotherapy plans were continuously adjusted. At present, the patient remains in treatment and follow-up.
CONCLUSIONS
The early detection and accurate diagnosis of lymphoma during pregnancy can help expedite proper multidisciplinary treatment to delay disease progression and decrease the mortality rate.
Core Tip: To our knowledge, this is the first study to describe a patient with double-hit lymphoma during pregnancy. We should be well aware of the gynecological manifestations of lymphoma and consider it in the differential diagnosis of pelvic tumors. To avoid an unnecessary radical operation, biopsy should be considered instead of exploratory laparotomy in young women with suspected malignant tumors as well as acute onset, rapid progression and growing chylous pleural effusion containing abundant lymphocytes. The early detection and accurate diagnosis of lymphoma during pregnancy can help expedite proper multidisciplinary treatment to delay disease progression and decrease the mortality rate.
INTRODUCTION
Double-hit lymphoma (DHL) is a highly aggressive B-cell lymphoma that is genetically characterized by rearrangements of MYC and BCL2 and/or BCL6. This neoplasm (high-grade B-cell lymphoma with rearrangements of MYC and BCL2 and/or BCL6 called DHL/triple-hit lymphoma) was identified as a new subtype in the 2016 revision of the World Health Organization classification of lymphoid neoplasms[1]. The incidence rate of lymphoma is approximately 1/6000, ranking fourth in malignancies during pregnancy[2]. However, DHL is relatively uncommon. Lymphoma is often accompanied by atypical systemic symptoms similar to physiological changes during pregnancy and is often ignored. Due to its invasive nature, high risks of malignancy and recurrence and the lack of accepted treatment, it is necessary to explore effective therapies for DHL. Herein, we describe a gravid patient with high-grade B-cell lymphoma with a MYC and BCL-2 gene rearrangement involving multiple parts of the body.
CASE PRESENTATION
Chief complaints
A 32-year-old female, gestational age 22+5 wk, presented to the department of obstetrics of our hospital complaining of abdominal distension, chest tightness and limb weakness lasting approximately 4 wk. Ovarian tumors were found 14 d ago.
History of present illness
Fifty-five days prior (gestational age: 14+6 wk), her ultrasound showed no mass in the bilateral adnexal area. According to the patient, her abdominal distension, chest tightness, and limb weakness began approximately 4 wk prior (gestational age: approximately 19 wk), but she did not seek treatment. Fourteen days ago, she was diagnosed with bilateral ovarian tumors in another hospital by ultrasound showing a hypoechoic mass measuring 9.2 cm × 6.7 cm on the right side of the uterus, a hypoechoic mass measuring 9.2 cm × 6.9 cm on the left side of the uterus, an anechoic mass measuring 4.3 cm × 3.6 cm beside the uterus and pelvic effusion.
History of past illness
The patient noted a history of gastritis for more than 10 years.
Personal and family history
Her parents had a history of hypertension. She had no family history of malignancies.
Physical examination
Her face showed signs of anemia. Her chest percussion was voiced, and her abdomen was swollen. A trimanual gynecologic examination after induced labor revealed a uterus with poor mobility, irregular masses in the bilateral adnexal area with poor mobility, a rectal fossa filled with lesions and a narrow space between the intestines.
Laboratory examinations
Upon admission, her laboratory results were as follows: hemoglobin 66 g/L, hematocrit 20.4%, reticulocyte 3.28%, serum albumin 35.1 g/L, free triiodothyonine 2.34 pmol/L, and free thyroxine 16.35 pmol/L. Tumor marker levels were as follows: CA125 578.50 U/mL, alpha-fetoprotein 157.84 ng/mL, carcinoembryonic antigen 0.53 ng/mL, CA199 16.13 U/mL, Cyfra21-1 2.60 ng/mL, Fer 749.58 ng/mL, β 2-microglobulin 5.56 μg/mL, neuron-specific enolase 15.84 ng/mL, CA50 7.19 U/mL, CA153 25.70 U/mL and serum lactic dehydrogenase (LDH) 1160 U/L.
Imaging examinations
At admission, ultrasound indicated a hypoechoic mass measuring 10.7 cm × 7.8 cm in the right adnexal area and a hypoechoic mass measuring 11.2 cm × 8.2 in the left adnexa. Then, pelvic magnetic resonance imaging (MRI) showed a soft tissue mass shadow in the pelvic cavity measuring approximately 12.7 cm in the largest diameter and lesions involving the posterior wall of the bladder, adjacent bowel, cervix, upper part of the vagina and bilateral iliac vessels. The patient was diagnosed with a bilateral adnexal malignant tumor, and the pelvic mass was not excluded as metastasis (Figure 1A-D). MRI also revealed pelvic effusion, soft tissue swelling in the pelvic wall and buttock, changes in the pelvic bone and bilateral ureteral dilatation.
Figure 1
Magnetic resonance imaging and computed tomography imaging. A and B: Coronal (A) and axial (B) images showed bilateral adnexal malignant tumors; C and D: Sagittal images showed masses in the left (C) and right (D) adnexal area; E and F: Computed tomography images of the arterial phase (E) and venous phase (F) showed bilateral adnexal malignant tumors.
Ultrasonography and computed tomography (CT) showed massive peritoneal and bilateral pleural effusion. Therefore, we performed ultrasound-guided puncture catheter drainage in the abdominal cavity and right thoracic cavity. Whole-abdomen CT showed bilateral pleural effusion, abdominal and pelvic effusion and malignancies of the bilateral adnexal origin that did not involve the rectum and bladder (Figure 1E and 1F). Whole-abdomen CT also revealed an irregularly shaped uterus and cervix that were not excluded as metastases, multiple soft tissue masses in the abdomen believed to be metastases, a nodular shadow in the left lateral lobe of the liver that was not excluded as metastasis, tumor involvement in the bilateral middle and lower ureters, secondary left kidney atrophy, bilateral hydronephrosis, bilateral upper ureteral dilatation and bilateral inguinal lymph nodes. After receiving the pathological results, positron emission tomography-computed tomography (PET-CT) was performed and revealed multiple enlarged lymph nodes throughout the body with increased metabolism (indicative of lymphoma), some lesions that were unclearly demarcated from the uterus and adnexa, thickening of the bilateral pleural wall, pleura, pericardium, peritoneum, omentum and mesentery with increased metabolism (indicative of lymphoma infiltration), lymphoma in the right breast and increased systemic skeletal metabolism (indicative of lymphoma infiltration).
Histopathological examination
The exfoliative cytology of hydrothorax and hydroperitoneum showed many lymphocytes without cancer cells. The pathological results supported high-grade B-cell lymphoma, and the immunohistochemical staining results were as follows: LCA (+), CD20 (+), CD3 (-), CD5 (-), Cyclin D1 (-), Ki67 (positive rate 90%), CK (AE1/AE3) (-), BCL-6 (+), TdT (-), MPO (-), CgA (-), Syn (-), CD56 (-), PAX-5 (+), CD34 (-), CD10 (+), BCL-2 (+), MUM1 (-), MYC (+), CD21 (-) and CD99 (weakly +). The pathological consultation at the superior hospital resulted in a diagnosis of non-Hodgkin high-grade B-cell lymphoma with rearrangements of the MYC gene and BCL2 gene (DHL). Immunohistochemistry revealed MUM-1+, CD10+, CD38+ and LMO 2- and in situ hybridization revealed EBER-.
FINAL DIAGNOSIS
The final diagnosis was high-grade B-cell lymphoma with rearrangements of MYC and BCL2 (stage IV, International Prognostic Index = 4 points, age-adjusted International Prognostic Index = 3 points) (involving multiple lymph nodes, the bilateral chest wall, pleura, pericardium, peritoneum, omentum, mesentery, right breast and whole body skeleton).
TREATMENT
Considering the patient’s rapidly progressing condition and severe systemic symptoms, we explained the treatment options and possible risks to the patient and her husband, and then informed consent was obtained to perform rivanol-induced labor. The patient also received a blood transfusion and anti-infection, expectorant and other symptomatic treatments. After consultation, we performed ultrasound-guided puncture catheter drainage in the abdominal cavity and right thoracic cavity due to massive abdominal and pleural effusion. A large amount of yellowish chyliform fluid was drained (Figure 2). Because of severe abdominal distension and difficulty associated with enema administration, we carried out ultrasound-guided puncture biopsy of the pelvic masses rather than colonoscopy with biopsy.
Figure 2 Yellowish chyliform fluid drained from the abdomen.
The patient was immediately referred and admitted to the Department of Oncology and Hematology for chemotherapy. First, she received rituximab plus cyclo-phosphamide, doxorubicin, vincristine and prednisone (R-CHOP) chemotherapy. One course later, chemotherapy was adjusted to dose-adjusted R-EPOCH (DA-R-EPOCH) because of grade IV myelosuppression. The patient then achieved complete remission (CR) after four courses. Two months later, the disease relapsed. She received rituximab, dexamethasone, ifosfamide, cisplatin, etoposide + lenalidomide, R-DICE and the treatment of chimeric antigen receptor T-cell therapy and achieved CR again. Two months later, the lymphoma relapsed again, and the patient received rituximab combined with a Btk inhibitor, gemcitabine + oxaliplatin, combined with azacytidine chemotherapy, oral ibrutinib and a combination of methotrexate + rituximab + gemcitabine + oxaliplatin + azacytidine.
OUTCOME AND FOLLOW-UP
The patient achieved CR following treatment but relapsed so rapidly that chemotherapy was continuously adjusted. At present, the patient remains in treatment and close follow-up.
DISCUSSION
The median age of onset for DHL is 51-67 years. DHL is characterized by a high level of LDH, an elevated Ki-67 index, a high-risk International Prognostic Index score and susceptibility to extranodal invasion, especially bone marrow and central nervous system (CNS) involvement[3]. The onset of lymphoma during pregnancy is insidious without typical symptoms. Lymphoma is often accompanied by systemic symptoms, such as fatigue, shortness of breath and night sweats, which is similar to physiological changes during pregnancy and is often ignored. Therefore, patients do not often visit a doctor until severe clinical symptoms appear, which may postpone the diagnosis and optimal treatment. The proportion of reproductive organs involved in non-Hodgkin lymphoma (NHL) is higher during pregnancy than during nonpregnancy and commonly involves invasion of the breast followed by the ovaries and uterus[4]. Because pelvic blood flow and lymphatic drainage are abundant during pregnancy and might enhance the growth and spread of tumor cells, pregnancy may promote the occurrence and development of lymphoma. Our patient developed symptoms at 19 wk of gestation and was found to have ovarian masses reaching the frozen pelvis approximately 4 wk later. However, ultrasound showed no mass in the bilateral adnexal area at 14+6 wk of gestation. DHL progressed rapidly because pregnancy may have accelerated tumor growth and spread.
A pathological examination, including lymph node biopsy and tissue biopsy, which can be performed safely during pregnancy, is the principal means of lymphoma diagnosis. DHL can be diagnosed by fluorescent in situ hybridization[5]. Concerning the immunophenotype, B-cell markers, including CD19, CD20, CD22, CD79a and CD45, are generally positive in these lymphomas, and high CD38 expression is usually observed[5]. For pregnant patients with lymphoma, it is advisable to evaluate the condition by ultrasound, MRI, a chest X-ray examination with an abdomen shield and CT or PET-CT after delivery. Bone marrow biopsy is critical to the diagnosis and staging of lymphoma and is safe during pregnancy[6]. It should be noted that when ovarian tumors are suspected to be malignant, we often perform an exploratory laparotomy. However, for young women with acute onset, rapid progression and increasing chylous pleural effusion containing abundant lymphocytes, biopsy of the lesion should be considered to avoid an unnecessary radical surgery.
As DHL is associated with a poor prognosis during pregnancy, it is necessary to consider many factors, including the stage of pregnancy, pathological type, current feasible treatment methods and patients’ willingness, when making treatment plans. Indolent NHL, with gradual progression can be monitored closely before treatment begins in the second and third trimesters[7]. For most aggressive and highly aggressive NHLs, it is crucial to begin combination chemotherapy immediately and terminate the pregnancy during early pregnancy[7]. For young women who require that their reproductive function be preserved, we should take relevant measures.
These individuals respond poorly to traditional R-CHOP alone and rapidly develop resistance to cytotoxic chemotherapy, which can result in an increased risk of relapse and a poor prognosis[5]. Recently, several centers have used DA-R-EPOCH as DHL’s preferred induction scheme[8]. A retrospective study at the MD Anderson Cancer Center showed that the DA-R-EPOCH regimen could prolong the progression-free survival (PFS) and overall survival (OS) of DHL patients compared with the chemotherapy regimens such as R-CHOP and rituximab, hyperfractionated cyclophosphamide, vincristine, doxorubicin, dexamethasone, alternating with cytarabine + methotrexate[9]. A large multicenter retrospective study showed that high-intensity induction programs such as DA-R-EPOCH, rituximab, hyperfractionated cyclophosphamide, vincristine, doxorubicin, dexamethasone, alternating with cytarabine + methotrexate and cyclophosphamide, vincristine, doxorubicin, high-dose methotrexate/ifosfamide, etoposide, high-dose cytarabine could better prolong PFS in patients than R-CHOP, but there was no difference in OS[10].
Rosenthal et al[11] recommended CNS prevention for all patients with DHL. CNS prophylaxis with intravenous high-dose methotrexate should be given only after delivery[4]. Cellular therapies such as CAR-T-cell therapy can be considered in patients with refractory or repeatedly relapsed disease, preferably in the context of a clinical trial[5]. In addition, targeted agents for MYC, BCL-2 and/or BCL-6 provide new ideas for clinical research and treatment. The patient described herein had a poor response to R-CHOP therapy but was sensitive to the DA-R-EPOCH regimen and CAR-T therapy. The patient achieved CR but relapsed rapidly due to the extremely invasive nature of the tumor.
In summary, DHL is highly aggressive and malignant and responds poorly to standard R-CHOP chemotherapy. In contrast, it is sensitive to high-intensity induction chemotherapy, yet there is a high risk of recurrence after achieving CR. Therefore, it is suggested to closely monitor patients who achieve CR and adjust the chemotherapy plan when conditions change. However, more clinical trials and studies are needed to identify effective therapies.
CONCLUSION
As obstetricians and gynecologists, we should be well aware of the gynecological manifestations of lymphoma and consider it in the differential diagnosis of pelvic tumors. It is necessary to be aware of the occurrence of lymphoma when faced with unexplained abdominal distension and fatigue, a fast-growing pelvic mass, increasing hydrothorax and ascites containing many lymphocytes. Then, biopsy might be a good choice to avoid an unnecessary or excessive radical surgery. The early detection and accurate diagnosis of lymphoma during pregnancy can help expedite proper multidisciplinary treatment to delay progression and decrease the mortality rate.
ACKNOWLEDGEMENTS
We thank the family who participated in this study.
Informed consent statement: Informed written consent was obtained from the patient for publication of this report and any accompanying images.
Conflict-of-interest statement: The authors declare that they have no conflict of interest.
CARE Checklist (2016) statement: The authors have read the CARE Checklist (2016), and the manuscript was prepared and revised according to the CARE Checklist (2016).
Manuscript source: Unsolicited manuscript
Peer-review started: September 11, 2020
First decision: November 14, 2020
Article in press: November 21, 2020
Specialty type: Medicine, research and experimental
Country/Territory of origin: China
Peer-review report’s scientific quality classification
Grade A (Excellent): 0
Grade B (Very good): B
Grade C (Good): 0
Grade D (Fair): 0
Grade E (Poor): 0
P-Reviewer: Ristic-Medic D S-Editor: Huang P L-Editor: Filipodia P-Editor: Ma YJ | CYCLICAL | DrugDosageText | CC BY-NC | 33521119 | 18,990,639 | 2021-01-16 |
What was the dosage of drug 'DOXORUBICIN HYDROCHLORIDE'? | Double-hit lymphoma (rearrangements of MYC, BCL-2) during pregnancy: A case report.
BACKGROUND
Double-hit lymphoma is a highly aggressive B-cell lymphoma that is genetically characterized by rearrangements of MYC and BCL2 and/or BCL6. Lymphoma is often accompanied by atypical systemic symptoms similar to physiological changes during pregnancy and is often ignored. Herein, we describe a gravid patient with high-grade B-cell lymphoma with a MYC and BCL-2 gene rearrangement involving multiple parts of the body.
METHODS
A 32-year-old female, gestational age 22+5 wk, complained of abdominal distension, chest tightness and limb weakness lasting approximately 4 wk, and ovarian tumors were found 14 d ago. Auxiliary examinations and a trimanual gynecologic examination suggested malignant ovarian tumor and frozen pelvis. Coupled with rapid progression, severe compression symptoms of hydrothorax, ascites and moderate anemia, labor was induced. Next, biopsy and imaging examinations showed high-grade B-cell lymphoma with a MYC and BCL-2 gene rearrangement involving multiple parts of the body. She was referred to the Department of Oncology and Hematology for chemotherapy. Because of multiple recurrences after complete remission, chemotherapy plans were continuously adjusted. At present, the patient remains in treatment and follow-up.
CONCLUSIONS
The early detection and accurate diagnosis of lymphoma during pregnancy can help expedite proper multidisciplinary treatment to delay disease progression and decrease the mortality rate.
Core Tip: To our knowledge, this is the first study to describe a patient with double-hit lymphoma during pregnancy. We should be well aware of the gynecological manifestations of lymphoma and consider it in the differential diagnosis of pelvic tumors. To avoid an unnecessary radical operation, biopsy should be considered instead of exploratory laparotomy in young women with suspected malignant tumors as well as acute onset, rapid progression and growing chylous pleural effusion containing abundant lymphocytes. The early detection and accurate diagnosis of lymphoma during pregnancy can help expedite proper multidisciplinary treatment to delay disease progression and decrease the mortality rate.
INTRODUCTION
Double-hit lymphoma (DHL) is a highly aggressive B-cell lymphoma that is genetically characterized by rearrangements of MYC and BCL2 and/or BCL6. This neoplasm (high-grade B-cell lymphoma with rearrangements of MYC and BCL2 and/or BCL6 called DHL/triple-hit lymphoma) was identified as a new subtype in the 2016 revision of the World Health Organization classification of lymphoid neoplasms[1]. The incidence rate of lymphoma is approximately 1/6000, ranking fourth in malignancies during pregnancy[2]. However, DHL is relatively uncommon. Lymphoma is often accompanied by atypical systemic symptoms similar to physiological changes during pregnancy and is often ignored. Due to its invasive nature, high risks of malignancy and recurrence and the lack of accepted treatment, it is necessary to explore effective therapies for DHL. Herein, we describe a gravid patient with high-grade B-cell lymphoma with a MYC and BCL-2 gene rearrangement involving multiple parts of the body.
CASE PRESENTATION
Chief complaints
A 32-year-old female, gestational age 22+5 wk, presented to the department of obstetrics of our hospital complaining of abdominal distension, chest tightness and limb weakness lasting approximately 4 wk. Ovarian tumors were found 14 d ago.
History of present illness
Fifty-five days prior (gestational age: 14+6 wk), her ultrasound showed no mass in the bilateral adnexal area. According to the patient, her abdominal distension, chest tightness, and limb weakness began approximately 4 wk prior (gestational age: approximately 19 wk), but she did not seek treatment. Fourteen days ago, she was diagnosed with bilateral ovarian tumors in another hospital by ultrasound showing a hypoechoic mass measuring 9.2 cm × 6.7 cm on the right side of the uterus, a hypoechoic mass measuring 9.2 cm × 6.9 cm on the left side of the uterus, an anechoic mass measuring 4.3 cm × 3.6 cm beside the uterus and pelvic effusion.
History of past illness
The patient noted a history of gastritis for more than 10 years.
Personal and family history
Her parents had a history of hypertension. She had no family history of malignancies.
Physical examination
Her face showed signs of anemia. Her chest percussion was voiced, and her abdomen was swollen. A trimanual gynecologic examination after induced labor revealed a uterus with poor mobility, irregular masses in the bilateral adnexal area with poor mobility, a rectal fossa filled with lesions and a narrow space between the intestines.
Laboratory examinations
Upon admission, her laboratory results were as follows: hemoglobin 66 g/L, hematocrit 20.4%, reticulocyte 3.28%, serum albumin 35.1 g/L, free triiodothyonine 2.34 pmol/L, and free thyroxine 16.35 pmol/L. Tumor marker levels were as follows: CA125 578.50 U/mL, alpha-fetoprotein 157.84 ng/mL, carcinoembryonic antigen 0.53 ng/mL, CA199 16.13 U/mL, Cyfra21-1 2.60 ng/mL, Fer 749.58 ng/mL, β 2-microglobulin 5.56 μg/mL, neuron-specific enolase 15.84 ng/mL, CA50 7.19 U/mL, CA153 25.70 U/mL and serum lactic dehydrogenase (LDH) 1160 U/L.
Imaging examinations
At admission, ultrasound indicated a hypoechoic mass measuring 10.7 cm × 7.8 cm in the right adnexal area and a hypoechoic mass measuring 11.2 cm × 8.2 in the left adnexa. Then, pelvic magnetic resonance imaging (MRI) showed a soft tissue mass shadow in the pelvic cavity measuring approximately 12.7 cm in the largest diameter and lesions involving the posterior wall of the bladder, adjacent bowel, cervix, upper part of the vagina and bilateral iliac vessels. The patient was diagnosed with a bilateral adnexal malignant tumor, and the pelvic mass was not excluded as metastasis (Figure 1A-D). MRI also revealed pelvic effusion, soft tissue swelling in the pelvic wall and buttock, changes in the pelvic bone and bilateral ureteral dilatation.
Figure 1
Magnetic resonance imaging and computed tomography imaging. A and B: Coronal (A) and axial (B) images showed bilateral adnexal malignant tumors; C and D: Sagittal images showed masses in the left (C) and right (D) adnexal area; E and F: Computed tomography images of the arterial phase (E) and venous phase (F) showed bilateral adnexal malignant tumors.
Ultrasonography and computed tomography (CT) showed massive peritoneal and bilateral pleural effusion. Therefore, we performed ultrasound-guided puncture catheter drainage in the abdominal cavity and right thoracic cavity. Whole-abdomen CT showed bilateral pleural effusion, abdominal and pelvic effusion and malignancies of the bilateral adnexal origin that did not involve the rectum and bladder (Figure 1E and 1F). Whole-abdomen CT also revealed an irregularly shaped uterus and cervix that were not excluded as metastases, multiple soft tissue masses in the abdomen believed to be metastases, a nodular shadow in the left lateral lobe of the liver that was not excluded as metastasis, tumor involvement in the bilateral middle and lower ureters, secondary left kidney atrophy, bilateral hydronephrosis, bilateral upper ureteral dilatation and bilateral inguinal lymph nodes. After receiving the pathological results, positron emission tomography-computed tomography (PET-CT) was performed and revealed multiple enlarged lymph nodes throughout the body with increased metabolism (indicative of lymphoma), some lesions that were unclearly demarcated from the uterus and adnexa, thickening of the bilateral pleural wall, pleura, pericardium, peritoneum, omentum and mesentery with increased metabolism (indicative of lymphoma infiltration), lymphoma in the right breast and increased systemic skeletal metabolism (indicative of lymphoma infiltration).
Histopathological examination
The exfoliative cytology of hydrothorax and hydroperitoneum showed many lymphocytes without cancer cells. The pathological results supported high-grade B-cell lymphoma, and the immunohistochemical staining results were as follows: LCA (+), CD20 (+), CD3 (-), CD5 (-), Cyclin D1 (-), Ki67 (positive rate 90%), CK (AE1/AE3) (-), BCL-6 (+), TdT (-), MPO (-), CgA (-), Syn (-), CD56 (-), PAX-5 (+), CD34 (-), CD10 (+), BCL-2 (+), MUM1 (-), MYC (+), CD21 (-) and CD99 (weakly +). The pathological consultation at the superior hospital resulted in a diagnosis of non-Hodgkin high-grade B-cell lymphoma with rearrangements of the MYC gene and BCL2 gene (DHL). Immunohistochemistry revealed MUM-1+, CD10+, CD38+ and LMO 2- and in situ hybridization revealed EBER-.
FINAL DIAGNOSIS
The final diagnosis was high-grade B-cell lymphoma with rearrangements of MYC and BCL2 (stage IV, International Prognostic Index = 4 points, age-adjusted International Prognostic Index = 3 points) (involving multiple lymph nodes, the bilateral chest wall, pleura, pericardium, peritoneum, omentum, mesentery, right breast and whole body skeleton).
TREATMENT
Considering the patient’s rapidly progressing condition and severe systemic symptoms, we explained the treatment options and possible risks to the patient and her husband, and then informed consent was obtained to perform rivanol-induced labor. The patient also received a blood transfusion and anti-infection, expectorant and other symptomatic treatments. After consultation, we performed ultrasound-guided puncture catheter drainage in the abdominal cavity and right thoracic cavity due to massive abdominal and pleural effusion. A large amount of yellowish chyliform fluid was drained (Figure 2). Because of severe abdominal distension and difficulty associated with enema administration, we carried out ultrasound-guided puncture biopsy of the pelvic masses rather than colonoscopy with biopsy.
Figure 2 Yellowish chyliform fluid drained from the abdomen.
The patient was immediately referred and admitted to the Department of Oncology and Hematology for chemotherapy. First, she received rituximab plus cyclo-phosphamide, doxorubicin, vincristine and prednisone (R-CHOP) chemotherapy. One course later, chemotherapy was adjusted to dose-adjusted R-EPOCH (DA-R-EPOCH) because of grade IV myelosuppression. The patient then achieved complete remission (CR) after four courses. Two months later, the disease relapsed. She received rituximab, dexamethasone, ifosfamide, cisplatin, etoposide + lenalidomide, R-DICE and the treatment of chimeric antigen receptor T-cell therapy and achieved CR again. Two months later, the lymphoma relapsed again, and the patient received rituximab combined with a Btk inhibitor, gemcitabine + oxaliplatin, combined with azacytidine chemotherapy, oral ibrutinib and a combination of methotrexate + rituximab + gemcitabine + oxaliplatin + azacytidine.
OUTCOME AND FOLLOW-UP
The patient achieved CR following treatment but relapsed so rapidly that chemotherapy was continuously adjusted. At present, the patient remains in treatment and close follow-up.
DISCUSSION
The median age of onset for DHL is 51-67 years. DHL is characterized by a high level of LDH, an elevated Ki-67 index, a high-risk International Prognostic Index score and susceptibility to extranodal invasion, especially bone marrow and central nervous system (CNS) involvement[3]. The onset of lymphoma during pregnancy is insidious without typical symptoms. Lymphoma is often accompanied by systemic symptoms, such as fatigue, shortness of breath and night sweats, which is similar to physiological changes during pregnancy and is often ignored. Therefore, patients do not often visit a doctor until severe clinical symptoms appear, which may postpone the diagnosis and optimal treatment. The proportion of reproductive organs involved in non-Hodgkin lymphoma (NHL) is higher during pregnancy than during nonpregnancy and commonly involves invasion of the breast followed by the ovaries and uterus[4]. Because pelvic blood flow and lymphatic drainage are abundant during pregnancy and might enhance the growth and spread of tumor cells, pregnancy may promote the occurrence and development of lymphoma. Our patient developed symptoms at 19 wk of gestation and was found to have ovarian masses reaching the frozen pelvis approximately 4 wk later. However, ultrasound showed no mass in the bilateral adnexal area at 14+6 wk of gestation. DHL progressed rapidly because pregnancy may have accelerated tumor growth and spread.
A pathological examination, including lymph node biopsy and tissue biopsy, which can be performed safely during pregnancy, is the principal means of lymphoma diagnosis. DHL can be diagnosed by fluorescent in situ hybridization[5]. Concerning the immunophenotype, B-cell markers, including CD19, CD20, CD22, CD79a and CD45, are generally positive in these lymphomas, and high CD38 expression is usually observed[5]. For pregnant patients with lymphoma, it is advisable to evaluate the condition by ultrasound, MRI, a chest X-ray examination with an abdomen shield and CT or PET-CT after delivery. Bone marrow biopsy is critical to the diagnosis and staging of lymphoma and is safe during pregnancy[6]. It should be noted that when ovarian tumors are suspected to be malignant, we often perform an exploratory laparotomy. However, for young women with acute onset, rapid progression and increasing chylous pleural effusion containing abundant lymphocytes, biopsy of the lesion should be considered to avoid an unnecessary radical surgery.
As DHL is associated with a poor prognosis during pregnancy, it is necessary to consider many factors, including the stage of pregnancy, pathological type, current feasible treatment methods and patients’ willingness, when making treatment plans. Indolent NHL, with gradual progression can be monitored closely before treatment begins in the second and third trimesters[7]. For most aggressive and highly aggressive NHLs, it is crucial to begin combination chemotherapy immediately and terminate the pregnancy during early pregnancy[7]. For young women who require that their reproductive function be preserved, we should take relevant measures.
These individuals respond poorly to traditional R-CHOP alone and rapidly develop resistance to cytotoxic chemotherapy, which can result in an increased risk of relapse and a poor prognosis[5]. Recently, several centers have used DA-R-EPOCH as DHL’s preferred induction scheme[8]. A retrospective study at the MD Anderson Cancer Center showed that the DA-R-EPOCH regimen could prolong the progression-free survival (PFS) and overall survival (OS) of DHL patients compared with the chemotherapy regimens such as R-CHOP and rituximab, hyperfractionated cyclophosphamide, vincristine, doxorubicin, dexamethasone, alternating with cytarabine + methotrexate[9]. A large multicenter retrospective study showed that high-intensity induction programs such as DA-R-EPOCH, rituximab, hyperfractionated cyclophosphamide, vincristine, doxorubicin, dexamethasone, alternating with cytarabine + methotrexate and cyclophosphamide, vincristine, doxorubicin, high-dose methotrexate/ifosfamide, etoposide, high-dose cytarabine could better prolong PFS in patients than R-CHOP, but there was no difference in OS[10].
Rosenthal et al[11] recommended CNS prevention for all patients with DHL. CNS prophylaxis with intravenous high-dose methotrexate should be given only after delivery[4]. Cellular therapies such as CAR-T-cell therapy can be considered in patients with refractory or repeatedly relapsed disease, preferably in the context of a clinical trial[5]. In addition, targeted agents for MYC, BCL-2 and/or BCL-6 provide new ideas for clinical research and treatment. The patient described herein had a poor response to R-CHOP therapy but was sensitive to the DA-R-EPOCH regimen and CAR-T therapy. The patient achieved CR but relapsed rapidly due to the extremely invasive nature of the tumor.
In summary, DHL is highly aggressive and malignant and responds poorly to standard R-CHOP chemotherapy. In contrast, it is sensitive to high-intensity induction chemotherapy, yet there is a high risk of recurrence after achieving CR. Therefore, it is suggested to closely monitor patients who achieve CR and adjust the chemotherapy plan when conditions change. However, more clinical trials and studies are needed to identify effective therapies.
CONCLUSION
As obstetricians and gynecologists, we should be well aware of the gynecological manifestations of lymphoma and consider it in the differential diagnosis of pelvic tumors. It is necessary to be aware of the occurrence of lymphoma when faced with unexplained abdominal distension and fatigue, a fast-growing pelvic mass, increasing hydrothorax and ascites containing many lymphocytes. Then, biopsy might be a good choice to avoid an unnecessary or excessive radical surgery. The early detection and accurate diagnosis of lymphoma during pregnancy can help expedite proper multidisciplinary treatment to delay progression and decrease the mortality rate.
ACKNOWLEDGEMENTS
We thank the family who participated in this study.
Informed consent statement: Informed written consent was obtained from the patient for publication of this report and any accompanying images.
Conflict-of-interest statement: The authors declare that they have no conflict of interest.
CARE Checklist (2016) statement: The authors have read the CARE Checklist (2016), and the manuscript was prepared and revised according to the CARE Checklist (2016).
Manuscript source: Unsolicited manuscript
Peer-review started: September 11, 2020
First decision: November 14, 2020
Article in press: November 21, 2020
Specialty type: Medicine, research and experimental
Country/Territory of origin: China
Peer-review report’s scientific quality classification
Grade A (Excellent): 0
Grade B (Very good): B
Grade C (Good): 0
Grade D (Fair): 0
Grade E (Poor): 0
P-Reviewer: Ristic-Medic D S-Editor: Huang P L-Editor: Filipodia P-Editor: Ma YJ | CYCLICAL | DrugDosageText | CC BY-NC | 33521119 | 18,990,639 | 2021-01-16 |
What was the dosage of drug 'PREDNISONE'? | Double-hit lymphoma (rearrangements of MYC, BCL-2) during pregnancy: A case report.
BACKGROUND
Double-hit lymphoma is a highly aggressive B-cell lymphoma that is genetically characterized by rearrangements of MYC and BCL2 and/or BCL6. Lymphoma is often accompanied by atypical systemic symptoms similar to physiological changes during pregnancy and is often ignored. Herein, we describe a gravid patient with high-grade B-cell lymphoma with a MYC and BCL-2 gene rearrangement involving multiple parts of the body.
METHODS
A 32-year-old female, gestational age 22+5 wk, complained of abdominal distension, chest tightness and limb weakness lasting approximately 4 wk, and ovarian tumors were found 14 d ago. Auxiliary examinations and a trimanual gynecologic examination suggested malignant ovarian tumor and frozen pelvis. Coupled with rapid progression, severe compression symptoms of hydrothorax, ascites and moderate anemia, labor was induced. Next, biopsy and imaging examinations showed high-grade B-cell lymphoma with a MYC and BCL-2 gene rearrangement involving multiple parts of the body. She was referred to the Department of Oncology and Hematology for chemotherapy. Because of multiple recurrences after complete remission, chemotherapy plans were continuously adjusted. At present, the patient remains in treatment and follow-up.
CONCLUSIONS
The early detection and accurate diagnosis of lymphoma during pregnancy can help expedite proper multidisciplinary treatment to delay disease progression and decrease the mortality rate.
Core Tip: To our knowledge, this is the first study to describe a patient with double-hit lymphoma during pregnancy. We should be well aware of the gynecological manifestations of lymphoma and consider it in the differential diagnosis of pelvic tumors. To avoid an unnecessary radical operation, biopsy should be considered instead of exploratory laparotomy in young women with suspected malignant tumors as well as acute onset, rapid progression and growing chylous pleural effusion containing abundant lymphocytes. The early detection and accurate diagnosis of lymphoma during pregnancy can help expedite proper multidisciplinary treatment to delay disease progression and decrease the mortality rate.
INTRODUCTION
Double-hit lymphoma (DHL) is a highly aggressive B-cell lymphoma that is genetically characterized by rearrangements of MYC and BCL2 and/or BCL6. This neoplasm (high-grade B-cell lymphoma with rearrangements of MYC and BCL2 and/or BCL6 called DHL/triple-hit lymphoma) was identified as a new subtype in the 2016 revision of the World Health Organization classification of lymphoid neoplasms[1]. The incidence rate of lymphoma is approximately 1/6000, ranking fourth in malignancies during pregnancy[2]. However, DHL is relatively uncommon. Lymphoma is often accompanied by atypical systemic symptoms similar to physiological changes during pregnancy and is often ignored. Due to its invasive nature, high risks of malignancy and recurrence and the lack of accepted treatment, it is necessary to explore effective therapies for DHL. Herein, we describe a gravid patient with high-grade B-cell lymphoma with a MYC and BCL-2 gene rearrangement involving multiple parts of the body.
CASE PRESENTATION
Chief complaints
A 32-year-old female, gestational age 22+5 wk, presented to the department of obstetrics of our hospital complaining of abdominal distension, chest tightness and limb weakness lasting approximately 4 wk. Ovarian tumors were found 14 d ago.
History of present illness
Fifty-five days prior (gestational age: 14+6 wk), her ultrasound showed no mass in the bilateral adnexal area. According to the patient, her abdominal distension, chest tightness, and limb weakness began approximately 4 wk prior (gestational age: approximately 19 wk), but she did not seek treatment. Fourteen days ago, she was diagnosed with bilateral ovarian tumors in another hospital by ultrasound showing a hypoechoic mass measuring 9.2 cm × 6.7 cm on the right side of the uterus, a hypoechoic mass measuring 9.2 cm × 6.9 cm on the left side of the uterus, an anechoic mass measuring 4.3 cm × 3.6 cm beside the uterus and pelvic effusion.
History of past illness
The patient noted a history of gastritis for more than 10 years.
Personal and family history
Her parents had a history of hypertension. She had no family history of malignancies.
Physical examination
Her face showed signs of anemia. Her chest percussion was voiced, and her abdomen was swollen. A trimanual gynecologic examination after induced labor revealed a uterus with poor mobility, irregular masses in the bilateral adnexal area with poor mobility, a rectal fossa filled with lesions and a narrow space between the intestines.
Laboratory examinations
Upon admission, her laboratory results were as follows: hemoglobin 66 g/L, hematocrit 20.4%, reticulocyte 3.28%, serum albumin 35.1 g/L, free triiodothyonine 2.34 pmol/L, and free thyroxine 16.35 pmol/L. Tumor marker levels were as follows: CA125 578.50 U/mL, alpha-fetoprotein 157.84 ng/mL, carcinoembryonic antigen 0.53 ng/mL, CA199 16.13 U/mL, Cyfra21-1 2.60 ng/mL, Fer 749.58 ng/mL, β 2-microglobulin 5.56 μg/mL, neuron-specific enolase 15.84 ng/mL, CA50 7.19 U/mL, CA153 25.70 U/mL and serum lactic dehydrogenase (LDH) 1160 U/L.
Imaging examinations
At admission, ultrasound indicated a hypoechoic mass measuring 10.7 cm × 7.8 cm in the right adnexal area and a hypoechoic mass measuring 11.2 cm × 8.2 in the left adnexa. Then, pelvic magnetic resonance imaging (MRI) showed a soft tissue mass shadow in the pelvic cavity measuring approximately 12.7 cm in the largest diameter and lesions involving the posterior wall of the bladder, adjacent bowel, cervix, upper part of the vagina and bilateral iliac vessels. The patient was diagnosed with a bilateral adnexal malignant tumor, and the pelvic mass was not excluded as metastasis (Figure 1A-D). MRI also revealed pelvic effusion, soft tissue swelling in the pelvic wall and buttock, changes in the pelvic bone and bilateral ureteral dilatation.
Figure 1
Magnetic resonance imaging and computed tomography imaging. A and B: Coronal (A) and axial (B) images showed bilateral adnexal malignant tumors; C and D: Sagittal images showed masses in the left (C) and right (D) adnexal area; E and F: Computed tomography images of the arterial phase (E) and venous phase (F) showed bilateral adnexal malignant tumors.
Ultrasonography and computed tomography (CT) showed massive peritoneal and bilateral pleural effusion. Therefore, we performed ultrasound-guided puncture catheter drainage in the abdominal cavity and right thoracic cavity. Whole-abdomen CT showed bilateral pleural effusion, abdominal and pelvic effusion and malignancies of the bilateral adnexal origin that did not involve the rectum and bladder (Figure 1E and 1F). Whole-abdomen CT also revealed an irregularly shaped uterus and cervix that were not excluded as metastases, multiple soft tissue masses in the abdomen believed to be metastases, a nodular shadow in the left lateral lobe of the liver that was not excluded as metastasis, tumor involvement in the bilateral middle and lower ureters, secondary left kidney atrophy, bilateral hydronephrosis, bilateral upper ureteral dilatation and bilateral inguinal lymph nodes. After receiving the pathological results, positron emission tomography-computed tomography (PET-CT) was performed and revealed multiple enlarged lymph nodes throughout the body with increased metabolism (indicative of lymphoma), some lesions that were unclearly demarcated from the uterus and adnexa, thickening of the bilateral pleural wall, pleura, pericardium, peritoneum, omentum and mesentery with increased metabolism (indicative of lymphoma infiltration), lymphoma in the right breast and increased systemic skeletal metabolism (indicative of lymphoma infiltration).
Histopathological examination
The exfoliative cytology of hydrothorax and hydroperitoneum showed many lymphocytes without cancer cells. The pathological results supported high-grade B-cell lymphoma, and the immunohistochemical staining results were as follows: LCA (+), CD20 (+), CD3 (-), CD5 (-), Cyclin D1 (-), Ki67 (positive rate 90%), CK (AE1/AE3) (-), BCL-6 (+), TdT (-), MPO (-), CgA (-), Syn (-), CD56 (-), PAX-5 (+), CD34 (-), CD10 (+), BCL-2 (+), MUM1 (-), MYC (+), CD21 (-) and CD99 (weakly +). The pathological consultation at the superior hospital resulted in a diagnosis of non-Hodgkin high-grade B-cell lymphoma with rearrangements of the MYC gene and BCL2 gene (DHL). Immunohistochemistry revealed MUM-1+, CD10+, CD38+ and LMO 2- and in situ hybridization revealed EBER-.
FINAL DIAGNOSIS
The final diagnosis was high-grade B-cell lymphoma with rearrangements of MYC and BCL2 (stage IV, International Prognostic Index = 4 points, age-adjusted International Prognostic Index = 3 points) (involving multiple lymph nodes, the bilateral chest wall, pleura, pericardium, peritoneum, omentum, mesentery, right breast and whole body skeleton).
TREATMENT
Considering the patient’s rapidly progressing condition and severe systemic symptoms, we explained the treatment options and possible risks to the patient and her husband, and then informed consent was obtained to perform rivanol-induced labor. The patient also received a blood transfusion and anti-infection, expectorant and other symptomatic treatments. After consultation, we performed ultrasound-guided puncture catheter drainage in the abdominal cavity and right thoracic cavity due to massive abdominal and pleural effusion. A large amount of yellowish chyliform fluid was drained (Figure 2). Because of severe abdominal distension and difficulty associated with enema administration, we carried out ultrasound-guided puncture biopsy of the pelvic masses rather than colonoscopy with biopsy.
Figure 2 Yellowish chyliform fluid drained from the abdomen.
The patient was immediately referred and admitted to the Department of Oncology and Hematology for chemotherapy. First, she received rituximab plus cyclo-phosphamide, doxorubicin, vincristine and prednisone (R-CHOP) chemotherapy. One course later, chemotherapy was adjusted to dose-adjusted R-EPOCH (DA-R-EPOCH) because of grade IV myelosuppression. The patient then achieved complete remission (CR) after four courses. Two months later, the disease relapsed. She received rituximab, dexamethasone, ifosfamide, cisplatin, etoposide + lenalidomide, R-DICE and the treatment of chimeric antigen receptor T-cell therapy and achieved CR again. Two months later, the lymphoma relapsed again, and the patient received rituximab combined with a Btk inhibitor, gemcitabine + oxaliplatin, combined with azacytidine chemotherapy, oral ibrutinib and a combination of methotrexate + rituximab + gemcitabine + oxaliplatin + azacytidine.
OUTCOME AND FOLLOW-UP
The patient achieved CR following treatment but relapsed so rapidly that chemotherapy was continuously adjusted. At present, the patient remains in treatment and close follow-up.
DISCUSSION
The median age of onset for DHL is 51-67 years. DHL is characterized by a high level of LDH, an elevated Ki-67 index, a high-risk International Prognostic Index score and susceptibility to extranodal invasion, especially bone marrow and central nervous system (CNS) involvement[3]. The onset of lymphoma during pregnancy is insidious without typical symptoms. Lymphoma is often accompanied by systemic symptoms, such as fatigue, shortness of breath and night sweats, which is similar to physiological changes during pregnancy and is often ignored. Therefore, patients do not often visit a doctor until severe clinical symptoms appear, which may postpone the diagnosis and optimal treatment. The proportion of reproductive organs involved in non-Hodgkin lymphoma (NHL) is higher during pregnancy than during nonpregnancy and commonly involves invasion of the breast followed by the ovaries and uterus[4]. Because pelvic blood flow and lymphatic drainage are abundant during pregnancy and might enhance the growth and spread of tumor cells, pregnancy may promote the occurrence and development of lymphoma. Our patient developed symptoms at 19 wk of gestation and was found to have ovarian masses reaching the frozen pelvis approximately 4 wk later. However, ultrasound showed no mass in the bilateral adnexal area at 14+6 wk of gestation. DHL progressed rapidly because pregnancy may have accelerated tumor growth and spread.
A pathological examination, including lymph node biopsy and tissue biopsy, which can be performed safely during pregnancy, is the principal means of lymphoma diagnosis. DHL can be diagnosed by fluorescent in situ hybridization[5]. Concerning the immunophenotype, B-cell markers, including CD19, CD20, CD22, CD79a and CD45, are generally positive in these lymphomas, and high CD38 expression is usually observed[5]. For pregnant patients with lymphoma, it is advisable to evaluate the condition by ultrasound, MRI, a chest X-ray examination with an abdomen shield and CT or PET-CT after delivery. Bone marrow biopsy is critical to the diagnosis and staging of lymphoma and is safe during pregnancy[6]. It should be noted that when ovarian tumors are suspected to be malignant, we often perform an exploratory laparotomy. However, for young women with acute onset, rapid progression and increasing chylous pleural effusion containing abundant lymphocytes, biopsy of the lesion should be considered to avoid an unnecessary radical surgery.
As DHL is associated with a poor prognosis during pregnancy, it is necessary to consider many factors, including the stage of pregnancy, pathological type, current feasible treatment methods and patients’ willingness, when making treatment plans. Indolent NHL, with gradual progression can be monitored closely before treatment begins in the second and third trimesters[7]. For most aggressive and highly aggressive NHLs, it is crucial to begin combination chemotherapy immediately and terminate the pregnancy during early pregnancy[7]. For young women who require that their reproductive function be preserved, we should take relevant measures.
These individuals respond poorly to traditional R-CHOP alone and rapidly develop resistance to cytotoxic chemotherapy, which can result in an increased risk of relapse and a poor prognosis[5]. Recently, several centers have used DA-R-EPOCH as DHL’s preferred induction scheme[8]. A retrospective study at the MD Anderson Cancer Center showed that the DA-R-EPOCH regimen could prolong the progression-free survival (PFS) and overall survival (OS) of DHL patients compared with the chemotherapy regimens such as R-CHOP and rituximab, hyperfractionated cyclophosphamide, vincristine, doxorubicin, dexamethasone, alternating with cytarabine + methotrexate[9]. A large multicenter retrospective study showed that high-intensity induction programs such as DA-R-EPOCH, rituximab, hyperfractionated cyclophosphamide, vincristine, doxorubicin, dexamethasone, alternating with cytarabine + methotrexate and cyclophosphamide, vincristine, doxorubicin, high-dose methotrexate/ifosfamide, etoposide, high-dose cytarabine could better prolong PFS in patients than R-CHOP, but there was no difference in OS[10].
Rosenthal et al[11] recommended CNS prevention for all patients with DHL. CNS prophylaxis with intravenous high-dose methotrexate should be given only after delivery[4]. Cellular therapies such as CAR-T-cell therapy can be considered in patients with refractory or repeatedly relapsed disease, preferably in the context of a clinical trial[5]. In addition, targeted agents for MYC, BCL-2 and/or BCL-6 provide new ideas for clinical research and treatment. The patient described herein had a poor response to R-CHOP therapy but was sensitive to the DA-R-EPOCH regimen and CAR-T therapy. The patient achieved CR but relapsed rapidly due to the extremely invasive nature of the tumor.
In summary, DHL is highly aggressive and malignant and responds poorly to standard R-CHOP chemotherapy. In contrast, it is sensitive to high-intensity induction chemotherapy, yet there is a high risk of recurrence after achieving CR. Therefore, it is suggested to closely monitor patients who achieve CR and adjust the chemotherapy plan when conditions change. However, more clinical trials and studies are needed to identify effective therapies.
CONCLUSION
As obstetricians and gynecologists, we should be well aware of the gynecological manifestations of lymphoma and consider it in the differential diagnosis of pelvic tumors. It is necessary to be aware of the occurrence of lymphoma when faced with unexplained abdominal distension and fatigue, a fast-growing pelvic mass, increasing hydrothorax and ascites containing many lymphocytes. Then, biopsy might be a good choice to avoid an unnecessary or excessive radical surgery. The early detection and accurate diagnosis of lymphoma during pregnancy can help expedite proper multidisciplinary treatment to delay progression and decrease the mortality rate.
ACKNOWLEDGEMENTS
We thank the family who participated in this study.
Informed consent statement: Informed written consent was obtained from the patient for publication of this report and any accompanying images.
Conflict-of-interest statement: The authors declare that they have no conflict of interest.
CARE Checklist (2016) statement: The authors have read the CARE Checklist (2016), and the manuscript was prepared and revised according to the CARE Checklist (2016).
Manuscript source: Unsolicited manuscript
Peer-review started: September 11, 2020
First decision: November 14, 2020
Article in press: November 21, 2020
Specialty type: Medicine, research and experimental
Country/Territory of origin: China
Peer-review report’s scientific quality classification
Grade A (Excellent): 0
Grade B (Very good): B
Grade C (Good): 0
Grade D (Fair): 0
Grade E (Poor): 0
P-Reviewer: Ristic-Medic D S-Editor: Huang P L-Editor: Filipodia P-Editor: Ma YJ | CYCLICAL | DrugDosageText | CC BY-NC | 33521119 | 18,990,639 | 2021-01-16 |
What was the dosage of drug 'RITUXIMAB'? | Double-hit lymphoma (rearrangements of MYC, BCL-2) during pregnancy: A case report.
BACKGROUND
Double-hit lymphoma is a highly aggressive B-cell lymphoma that is genetically characterized by rearrangements of MYC and BCL2 and/or BCL6. Lymphoma is often accompanied by atypical systemic symptoms similar to physiological changes during pregnancy and is often ignored. Herein, we describe a gravid patient with high-grade B-cell lymphoma with a MYC and BCL-2 gene rearrangement involving multiple parts of the body.
METHODS
A 32-year-old female, gestational age 22+5 wk, complained of abdominal distension, chest tightness and limb weakness lasting approximately 4 wk, and ovarian tumors were found 14 d ago. Auxiliary examinations and a trimanual gynecologic examination suggested malignant ovarian tumor and frozen pelvis. Coupled with rapid progression, severe compression symptoms of hydrothorax, ascites and moderate anemia, labor was induced. Next, biopsy and imaging examinations showed high-grade B-cell lymphoma with a MYC and BCL-2 gene rearrangement involving multiple parts of the body. She was referred to the Department of Oncology and Hematology for chemotherapy. Because of multiple recurrences after complete remission, chemotherapy plans were continuously adjusted. At present, the patient remains in treatment and follow-up.
CONCLUSIONS
The early detection and accurate diagnosis of lymphoma during pregnancy can help expedite proper multidisciplinary treatment to delay disease progression and decrease the mortality rate.
Core Tip: To our knowledge, this is the first study to describe a patient with double-hit lymphoma during pregnancy. We should be well aware of the gynecological manifestations of lymphoma and consider it in the differential diagnosis of pelvic tumors. To avoid an unnecessary radical operation, biopsy should be considered instead of exploratory laparotomy in young women with suspected malignant tumors as well as acute onset, rapid progression and growing chylous pleural effusion containing abundant lymphocytes. The early detection and accurate diagnosis of lymphoma during pregnancy can help expedite proper multidisciplinary treatment to delay disease progression and decrease the mortality rate.
INTRODUCTION
Double-hit lymphoma (DHL) is a highly aggressive B-cell lymphoma that is genetically characterized by rearrangements of MYC and BCL2 and/or BCL6. This neoplasm (high-grade B-cell lymphoma with rearrangements of MYC and BCL2 and/or BCL6 called DHL/triple-hit lymphoma) was identified as a new subtype in the 2016 revision of the World Health Organization classification of lymphoid neoplasms[1]. The incidence rate of lymphoma is approximately 1/6000, ranking fourth in malignancies during pregnancy[2]. However, DHL is relatively uncommon. Lymphoma is often accompanied by atypical systemic symptoms similar to physiological changes during pregnancy and is often ignored. Due to its invasive nature, high risks of malignancy and recurrence and the lack of accepted treatment, it is necessary to explore effective therapies for DHL. Herein, we describe a gravid patient with high-grade B-cell lymphoma with a MYC and BCL-2 gene rearrangement involving multiple parts of the body.
CASE PRESENTATION
Chief complaints
A 32-year-old female, gestational age 22+5 wk, presented to the department of obstetrics of our hospital complaining of abdominal distension, chest tightness and limb weakness lasting approximately 4 wk. Ovarian tumors were found 14 d ago.
History of present illness
Fifty-five days prior (gestational age: 14+6 wk), her ultrasound showed no mass in the bilateral adnexal area. According to the patient, her abdominal distension, chest tightness, and limb weakness began approximately 4 wk prior (gestational age: approximately 19 wk), but she did not seek treatment. Fourteen days ago, she was diagnosed with bilateral ovarian tumors in another hospital by ultrasound showing a hypoechoic mass measuring 9.2 cm × 6.7 cm on the right side of the uterus, a hypoechoic mass measuring 9.2 cm × 6.9 cm on the left side of the uterus, an anechoic mass measuring 4.3 cm × 3.6 cm beside the uterus and pelvic effusion.
History of past illness
The patient noted a history of gastritis for more than 10 years.
Personal and family history
Her parents had a history of hypertension. She had no family history of malignancies.
Physical examination
Her face showed signs of anemia. Her chest percussion was voiced, and her abdomen was swollen. A trimanual gynecologic examination after induced labor revealed a uterus with poor mobility, irregular masses in the bilateral adnexal area with poor mobility, a rectal fossa filled with lesions and a narrow space between the intestines.
Laboratory examinations
Upon admission, her laboratory results were as follows: hemoglobin 66 g/L, hematocrit 20.4%, reticulocyte 3.28%, serum albumin 35.1 g/L, free triiodothyonine 2.34 pmol/L, and free thyroxine 16.35 pmol/L. Tumor marker levels were as follows: CA125 578.50 U/mL, alpha-fetoprotein 157.84 ng/mL, carcinoembryonic antigen 0.53 ng/mL, CA199 16.13 U/mL, Cyfra21-1 2.60 ng/mL, Fer 749.58 ng/mL, β 2-microglobulin 5.56 μg/mL, neuron-specific enolase 15.84 ng/mL, CA50 7.19 U/mL, CA153 25.70 U/mL and serum lactic dehydrogenase (LDH) 1160 U/L.
Imaging examinations
At admission, ultrasound indicated a hypoechoic mass measuring 10.7 cm × 7.8 cm in the right adnexal area and a hypoechoic mass measuring 11.2 cm × 8.2 in the left adnexa. Then, pelvic magnetic resonance imaging (MRI) showed a soft tissue mass shadow in the pelvic cavity measuring approximately 12.7 cm in the largest diameter and lesions involving the posterior wall of the bladder, adjacent bowel, cervix, upper part of the vagina and bilateral iliac vessels. The patient was diagnosed with a bilateral adnexal malignant tumor, and the pelvic mass was not excluded as metastasis (Figure 1A-D). MRI also revealed pelvic effusion, soft tissue swelling in the pelvic wall and buttock, changes in the pelvic bone and bilateral ureteral dilatation.
Figure 1
Magnetic resonance imaging and computed tomography imaging. A and B: Coronal (A) and axial (B) images showed bilateral adnexal malignant tumors; C and D: Sagittal images showed masses in the left (C) and right (D) adnexal area; E and F: Computed tomography images of the arterial phase (E) and venous phase (F) showed bilateral adnexal malignant tumors.
Ultrasonography and computed tomography (CT) showed massive peritoneal and bilateral pleural effusion. Therefore, we performed ultrasound-guided puncture catheter drainage in the abdominal cavity and right thoracic cavity. Whole-abdomen CT showed bilateral pleural effusion, abdominal and pelvic effusion and malignancies of the bilateral adnexal origin that did not involve the rectum and bladder (Figure 1E and 1F). Whole-abdomen CT also revealed an irregularly shaped uterus and cervix that were not excluded as metastases, multiple soft tissue masses in the abdomen believed to be metastases, a nodular shadow in the left lateral lobe of the liver that was not excluded as metastasis, tumor involvement in the bilateral middle and lower ureters, secondary left kidney atrophy, bilateral hydronephrosis, bilateral upper ureteral dilatation and bilateral inguinal lymph nodes. After receiving the pathological results, positron emission tomography-computed tomography (PET-CT) was performed and revealed multiple enlarged lymph nodes throughout the body with increased metabolism (indicative of lymphoma), some lesions that were unclearly demarcated from the uterus and adnexa, thickening of the bilateral pleural wall, pleura, pericardium, peritoneum, omentum and mesentery with increased metabolism (indicative of lymphoma infiltration), lymphoma in the right breast and increased systemic skeletal metabolism (indicative of lymphoma infiltration).
Histopathological examination
The exfoliative cytology of hydrothorax and hydroperitoneum showed many lymphocytes without cancer cells. The pathological results supported high-grade B-cell lymphoma, and the immunohistochemical staining results were as follows: LCA (+), CD20 (+), CD3 (-), CD5 (-), Cyclin D1 (-), Ki67 (positive rate 90%), CK (AE1/AE3) (-), BCL-6 (+), TdT (-), MPO (-), CgA (-), Syn (-), CD56 (-), PAX-5 (+), CD34 (-), CD10 (+), BCL-2 (+), MUM1 (-), MYC (+), CD21 (-) and CD99 (weakly +). The pathological consultation at the superior hospital resulted in a diagnosis of non-Hodgkin high-grade B-cell lymphoma with rearrangements of the MYC gene and BCL2 gene (DHL). Immunohistochemistry revealed MUM-1+, CD10+, CD38+ and LMO 2- and in situ hybridization revealed EBER-.
FINAL DIAGNOSIS
The final diagnosis was high-grade B-cell lymphoma with rearrangements of MYC and BCL2 (stage IV, International Prognostic Index = 4 points, age-adjusted International Prognostic Index = 3 points) (involving multiple lymph nodes, the bilateral chest wall, pleura, pericardium, peritoneum, omentum, mesentery, right breast and whole body skeleton).
TREATMENT
Considering the patient’s rapidly progressing condition and severe systemic symptoms, we explained the treatment options and possible risks to the patient and her husband, and then informed consent was obtained to perform rivanol-induced labor. The patient also received a blood transfusion and anti-infection, expectorant and other symptomatic treatments. After consultation, we performed ultrasound-guided puncture catheter drainage in the abdominal cavity and right thoracic cavity due to massive abdominal and pleural effusion. A large amount of yellowish chyliform fluid was drained (Figure 2). Because of severe abdominal distension and difficulty associated with enema administration, we carried out ultrasound-guided puncture biopsy of the pelvic masses rather than colonoscopy with biopsy.
Figure 2 Yellowish chyliform fluid drained from the abdomen.
The patient was immediately referred and admitted to the Department of Oncology and Hematology for chemotherapy. First, she received rituximab plus cyclo-phosphamide, doxorubicin, vincristine and prednisone (R-CHOP) chemotherapy. One course later, chemotherapy was adjusted to dose-adjusted R-EPOCH (DA-R-EPOCH) because of grade IV myelosuppression. The patient then achieved complete remission (CR) after four courses. Two months later, the disease relapsed. She received rituximab, dexamethasone, ifosfamide, cisplatin, etoposide + lenalidomide, R-DICE and the treatment of chimeric antigen receptor T-cell therapy and achieved CR again. Two months later, the lymphoma relapsed again, and the patient received rituximab combined with a Btk inhibitor, gemcitabine + oxaliplatin, combined with azacytidine chemotherapy, oral ibrutinib and a combination of methotrexate + rituximab + gemcitabine + oxaliplatin + azacytidine.
OUTCOME AND FOLLOW-UP
The patient achieved CR following treatment but relapsed so rapidly that chemotherapy was continuously adjusted. At present, the patient remains in treatment and close follow-up.
DISCUSSION
The median age of onset for DHL is 51-67 years. DHL is characterized by a high level of LDH, an elevated Ki-67 index, a high-risk International Prognostic Index score and susceptibility to extranodal invasion, especially bone marrow and central nervous system (CNS) involvement[3]. The onset of lymphoma during pregnancy is insidious without typical symptoms. Lymphoma is often accompanied by systemic symptoms, such as fatigue, shortness of breath and night sweats, which is similar to physiological changes during pregnancy and is often ignored. Therefore, patients do not often visit a doctor until severe clinical symptoms appear, which may postpone the diagnosis and optimal treatment. The proportion of reproductive organs involved in non-Hodgkin lymphoma (NHL) is higher during pregnancy than during nonpregnancy and commonly involves invasion of the breast followed by the ovaries and uterus[4]. Because pelvic blood flow and lymphatic drainage are abundant during pregnancy and might enhance the growth and spread of tumor cells, pregnancy may promote the occurrence and development of lymphoma. Our patient developed symptoms at 19 wk of gestation and was found to have ovarian masses reaching the frozen pelvis approximately 4 wk later. However, ultrasound showed no mass in the bilateral adnexal area at 14+6 wk of gestation. DHL progressed rapidly because pregnancy may have accelerated tumor growth and spread.
A pathological examination, including lymph node biopsy and tissue biopsy, which can be performed safely during pregnancy, is the principal means of lymphoma diagnosis. DHL can be diagnosed by fluorescent in situ hybridization[5]. Concerning the immunophenotype, B-cell markers, including CD19, CD20, CD22, CD79a and CD45, are generally positive in these lymphomas, and high CD38 expression is usually observed[5]. For pregnant patients with lymphoma, it is advisable to evaluate the condition by ultrasound, MRI, a chest X-ray examination with an abdomen shield and CT or PET-CT after delivery. Bone marrow biopsy is critical to the diagnosis and staging of lymphoma and is safe during pregnancy[6]. It should be noted that when ovarian tumors are suspected to be malignant, we often perform an exploratory laparotomy. However, for young women with acute onset, rapid progression and increasing chylous pleural effusion containing abundant lymphocytes, biopsy of the lesion should be considered to avoid an unnecessary radical surgery.
As DHL is associated with a poor prognosis during pregnancy, it is necessary to consider many factors, including the stage of pregnancy, pathological type, current feasible treatment methods and patients’ willingness, when making treatment plans. Indolent NHL, with gradual progression can be monitored closely before treatment begins in the second and third trimesters[7]. For most aggressive and highly aggressive NHLs, it is crucial to begin combination chemotherapy immediately and terminate the pregnancy during early pregnancy[7]. For young women who require that their reproductive function be preserved, we should take relevant measures.
These individuals respond poorly to traditional R-CHOP alone and rapidly develop resistance to cytotoxic chemotherapy, which can result in an increased risk of relapse and a poor prognosis[5]. Recently, several centers have used DA-R-EPOCH as DHL’s preferred induction scheme[8]. A retrospective study at the MD Anderson Cancer Center showed that the DA-R-EPOCH regimen could prolong the progression-free survival (PFS) and overall survival (OS) of DHL patients compared with the chemotherapy regimens such as R-CHOP and rituximab, hyperfractionated cyclophosphamide, vincristine, doxorubicin, dexamethasone, alternating with cytarabine + methotrexate[9]. A large multicenter retrospective study showed that high-intensity induction programs such as DA-R-EPOCH, rituximab, hyperfractionated cyclophosphamide, vincristine, doxorubicin, dexamethasone, alternating with cytarabine + methotrexate and cyclophosphamide, vincristine, doxorubicin, high-dose methotrexate/ifosfamide, etoposide, high-dose cytarabine could better prolong PFS in patients than R-CHOP, but there was no difference in OS[10].
Rosenthal et al[11] recommended CNS prevention for all patients with DHL. CNS prophylaxis with intravenous high-dose methotrexate should be given only after delivery[4]. Cellular therapies such as CAR-T-cell therapy can be considered in patients with refractory or repeatedly relapsed disease, preferably in the context of a clinical trial[5]. In addition, targeted agents for MYC, BCL-2 and/or BCL-6 provide new ideas for clinical research and treatment. The patient described herein had a poor response to R-CHOP therapy but was sensitive to the DA-R-EPOCH regimen and CAR-T therapy. The patient achieved CR but relapsed rapidly due to the extremely invasive nature of the tumor.
In summary, DHL is highly aggressive and malignant and responds poorly to standard R-CHOP chemotherapy. In contrast, it is sensitive to high-intensity induction chemotherapy, yet there is a high risk of recurrence after achieving CR. Therefore, it is suggested to closely monitor patients who achieve CR and adjust the chemotherapy plan when conditions change. However, more clinical trials and studies are needed to identify effective therapies.
CONCLUSION
As obstetricians and gynecologists, we should be well aware of the gynecological manifestations of lymphoma and consider it in the differential diagnosis of pelvic tumors. It is necessary to be aware of the occurrence of lymphoma when faced with unexplained abdominal distension and fatigue, a fast-growing pelvic mass, increasing hydrothorax and ascites containing many lymphocytes. Then, biopsy might be a good choice to avoid an unnecessary or excessive radical surgery. The early detection and accurate diagnosis of lymphoma during pregnancy can help expedite proper multidisciplinary treatment to delay progression and decrease the mortality rate.
ACKNOWLEDGEMENTS
We thank the family who participated in this study.
Informed consent statement: Informed written consent was obtained from the patient for publication of this report and any accompanying images.
Conflict-of-interest statement: The authors declare that they have no conflict of interest.
CARE Checklist (2016) statement: The authors have read the CARE Checklist (2016), and the manuscript was prepared and revised according to the CARE Checklist (2016).
Manuscript source: Unsolicited manuscript
Peer-review started: September 11, 2020
First decision: November 14, 2020
Article in press: November 21, 2020
Specialty type: Medicine, research and experimental
Country/Territory of origin: China
Peer-review report’s scientific quality classification
Grade A (Excellent): 0
Grade B (Very good): B
Grade C (Good): 0
Grade D (Fair): 0
Grade E (Poor): 0
P-Reviewer: Ristic-Medic D S-Editor: Huang P L-Editor: Filipodia P-Editor: Ma YJ | CYCLICAL | DrugDosageText | CC BY-NC | 33521119 | 18,990,639 | 2021-01-16 |
What was the dosage of drug 'VINCRISTINE'? | Double-hit lymphoma (rearrangements of MYC, BCL-2) during pregnancy: A case report.
BACKGROUND
Double-hit lymphoma is a highly aggressive B-cell lymphoma that is genetically characterized by rearrangements of MYC and BCL2 and/or BCL6. Lymphoma is often accompanied by atypical systemic symptoms similar to physiological changes during pregnancy and is often ignored. Herein, we describe a gravid patient with high-grade B-cell lymphoma with a MYC and BCL-2 gene rearrangement involving multiple parts of the body.
METHODS
A 32-year-old female, gestational age 22+5 wk, complained of abdominal distension, chest tightness and limb weakness lasting approximately 4 wk, and ovarian tumors were found 14 d ago. Auxiliary examinations and a trimanual gynecologic examination suggested malignant ovarian tumor and frozen pelvis. Coupled with rapid progression, severe compression symptoms of hydrothorax, ascites and moderate anemia, labor was induced. Next, biopsy and imaging examinations showed high-grade B-cell lymphoma with a MYC and BCL-2 gene rearrangement involving multiple parts of the body. She was referred to the Department of Oncology and Hematology for chemotherapy. Because of multiple recurrences after complete remission, chemotherapy plans were continuously adjusted. At present, the patient remains in treatment and follow-up.
CONCLUSIONS
The early detection and accurate diagnosis of lymphoma during pregnancy can help expedite proper multidisciplinary treatment to delay disease progression and decrease the mortality rate.
Core Tip: To our knowledge, this is the first study to describe a patient with double-hit lymphoma during pregnancy. We should be well aware of the gynecological manifestations of lymphoma and consider it in the differential diagnosis of pelvic tumors. To avoid an unnecessary radical operation, biopsy should be considered instead of exploratory laparotomy in young women with suspected malignant tumors as well as acute onset, rapid progression and growing chylous pleural effusion containing abundant lymphocytes. The early detection and accurate diagnosis of lymphoma during pregnancy can help expedite proper multidisciplinary treatment to delay disease progression and decrease the mortality rate.
INTRODUCTION
Double-hit lymphoma (DHL) is a highly aggressive B-cell lymphoma that is genetically characterized by rearrangements of MYC and BCL2 and/or BCL6. This neoplasm (high-grade B-cell lymphoma with rearrangements of MYC and BCL2 and/or BCL6 called DHL/triple-hit lymphoma) was identified as a new subtype in the 2016 revision of the World Health Organization classification of lymphoid neoplasms[1]. The incidence rate of lymphoma is approximately 1/6000, ranking fourth in malignancies during pregnancy[2]. However, DHL is relatively uncommon. Lymphoma is often accompanied by atypical systemic symptoms similar to physiological changes during pregnancy and is often ignored. Due to its invasive nature, high risks of malignancy and recurrence and the lack of accepted treatment, it is necessary to explore effective therapies for DHL. Herein, we describe a gravid patient with high-grade B-cell lymphoma with a MYC and BCL-2 gene rearrangement involving multiple parts of the body.
CASE PRESENTATION
Chief complaints
A 32-year-old female, gestational age 22+5 wk, presented to the department of obstetrics of our hospital complaining of abdominal distension, chest tightness and limb weakness lasting approximately 4 wk. Ovarian tumors were found 14 d ago.
History of present illness
Fifty-five days prior (gestational age: 14+6 wk), her ultrasound showed no mass in the bilateral adnexal area. According to the patient, her abdominal distension, chest tightness, and limb weakness began approximately 4 wk prior (gestational age: approximately 19 wk), but she did not seek treatment. Fourteen days ago, she was diagnosed with bilateral ovarian tumors in another hospital by ultrasound showing a hypoechoic mass measuring 9.2 cm × 6.7 cm on the right side of the uterus, a hypoechoic mass measuring 9.2 cm × 6.9 cm on the left side of the uterus, an anechoic mass measuring 4.3 cm × 3.6 cm beside the uterus and pelvic effusion.
History of past illness
The patient noted a history of gastritis for more than 10 years.
Personal and family history
Her parents had a history of hypertension. She had no family history of malignancies.
Physical examination
Her face showed signs of anemia. Her chest percussion was voiced, and her abdomen was swollen. A trimanual gynecologic examination after induced labor revealed a uterus with poor mobility, irregular masses in the bilateral adnexal area with poor mobility, a rectal fossa filled with lesions and a narrow space between the intestines.
Laboratory examinations
Upon admission, her laboratory results were as follows: hemoglobin 66 g/L, hematocrit 20.4%, reticulocyte 3.28%, serum albumin 35.1 g/L, free triiodothyonine 2.34 pmol/L, and free thyroxine 16.35 pmol/L. Tumor marker levels were as follows: CA125 578.50 U/mL, alpha-fetoprotein 157.84 ng/mL, carcinoembryonic antigen 0.53 ng/mL, CA199 16.13 U/mL, Cyfra21-1 2.60 ng/mL, Fer 749.58 ng/mL, β 2-microglobulin 5.56 μg/mL, neuron-specific enolase 15.84 ng/mL, CA50 7.19 U/mL, CA153 25.70 U/mL and serum lactic dehydrogenase (LDH) 1160 U/L.
Imaging examinations
At admission, ultrasound indicated a hypoechoic mass measuring 10.7 cm × 7.8 cm in the right adnexal area and a hypoechoic mass measuring 11.2 cm × 8.2 in the left adnexa. Then, pelvic magnetic resonance imaging (MRI) showed a soft tissue mass shadow in the pelvic cavity measuring approximately 12.7 cm in the largest diameter and lesions involving the posterior wall of the bladder, adjacent bowel, cervix, upper part of the vagina and bilateral iliac vessels. The patient was diagnosed with a bilateral adnexal malignant tumor, and the pelvic mass was not excluded as metastasis (Figure 1A-D). MRI also revealed pelvic effusion, soft tissue swelling in the pelvic wall and buttock, changes in the pelvic bone and bilateral ureteral dilatation.
Figure 1
Magnetic resonance imaging and computed tomography imaging. A and B: Coronal (A) and axial (B) images showed bilateral adnexal malignant tumors; C and D: Sagittal images showed masses in the left (C) and right (D) adnexal area; E and F: Computed tomography images of the arterial phase (E) and venous phase (F) showed bilateral adnexal malignant tumors.
Ultrasonography and computed tomography (CT) showed massive peritoneal and bilateral pleural effusion. Therefore, we performed ultrasound-guided puncture catheter drainage in the abdominal cavity and right thoracic cavity. Whole-abdomen CT showed bilateral pleural effusion, abdominal and pelvic effusion and malignancies of the bilateral adnexal origin that did not involve the rectum and bladder (Figure 1E and 1F). Whole-abdomen CT also revealed an irregularly shaped uterus and cervix that were not excluded as metastases, multiple soft tissue masses in the abdomen believed to be metastases, a nodular shadow in the left lateral lobe of the liver that was not excluded as metastasis, tumor involvement in the bilateral middle and lower ureters, secondary left kidney atrophy, bilateral hydronephrosis, bilateral upper ureteral dilatation and bilateral inguinal lymph nodes. After receiving the pathological results, positron emission tomography-computed tomography (PET-CT) was performed and revealed multiple enlarged lymph nodes throughout the body with increased metabolism (indicative of lymphoma), some lesions that were unclearly demarcated from the uterus and adnexa, thickening of the bilateral pleural wall, pleura, pericardium, peritoneum, omentum and mesentery with increased metabolism (indicative of lymphoma infiltration), lymphoma in the right breast and increased systemic skeletal metabolism (indicative of lymphoma infiltration).
Histopathological examination
The exfoliative cytology of hydrothorax and hydroperitoneum showed many lymphocytes without cancer cells. The pathological results supported high-grade B-cell lymphoma, and the immunohistochemical staining results were as follows: LCA (+), CD20 (+), CD3 (-), CD5 (-), Cyclin D1 (-), Ki67 (positive rate 90%), CK (AE1/AE3) (-), BCL-6 (+), TdT (-), MPO (-), CgA (-), Syn (-), CD56 (-), PAX-5 (+), CD34 (-), CD10 (+), BCL-2 (+), MUM1 (-), MYC (+), CD21 (-) and CD99 (weakly +). The pathological consultation at the superior hospital resulted in a diagnosis of non-Hodgkin high-grade B-cell lymphoma with rearrangements of the MYC gene and BCL2 gene (DHL). Immunohistochemistry revealed MUM-1+, CD10+, CD38+ and LMO 2- and in situ hybridization revealed EBER-.
FINAL DIAGNOSIS
The final diagnosis was high-grade B-cell lymphoma with rearrangements of MYC and BCL2 (stage IV, International Prognostic Index = 4 points, age-adjusted International Prognostic Index = 3 points) (involving multiple lymph nodes, the bilateral chest wall, pleura, pericardium, peritoneum, omentum, mesentery, right breast and whole body skeleton).
TREATMENT
Considering the patient’s rapidly progressing condition and severe systemic symptoms, we explained the treatment options and possible risks to the patient and her husband, and then informed consent was obtained to perform rivanol-induced labor. The patient also received a blood transfusion and anti-infection, expectorant and other symptomatic treatments. After consultation, we performed ultrasound-guided puncture catheter drainage in the abdominal cavity and right thoracic cavity due to massive abdominal and pleural effusion. A large amount of yellowish chyliform fluid was drained (Figure 2). Because of severe abdominal distension and difficulty associated with enema administration, we carried out ultrasound-guided puncture biopsy of the pelvic masses rather than colonoscopy with biopsy.
Figure 2 Yellowish chyliform fluid drained from the abdomen.
The patient was immediately referred and admitted to the Department of Oncology and Hematology for chemotherapy. First, she received rituximab plus cyclo-phosphamide, doxorubicin, vincristine and prednisone (R-CHOP) chemotherapy. One course later, chemotherapy was adjusted to dose-adjusted R-EPOCH (DA-R-EPOCH) because of grade IV myelosuppression. The patient then achieved complete remission (CR) after four courses. Two months later, the disease relapsed. She received rituximab, dexamethasone, ifosfamide, cisplatin, etoposide + lenalidomide, R-DICE and the treatment of chimeric antigen receptor T-cell therapy and achieved CR again. Two months later, the lymphoma relapsed again, and the patient received rituximab combined with a Btk inhibitor, gemcitabine + oxaliplatin, combined with azacytidine chemotherapy, oral ibrutinib and a combination of methotrexate + rituximab + gemcitabine + oxaliplatin + azacytidine.
OUTCOME AND FOLLOW-UP
The patient achieved CR following treatment but relapsed so rapidly that chemotherapy was continuously adjusted. At present, the patient remains in treatment and close follow-up.
DISCUSSION
The median age of onset for DHL is 51-67 years. DHL is characterized by a high level of LDH, an elevated Ki-67 index, a high-risk International Prognostic Index score and susceptibility to extranodal invasion, especially bone marrow and central nervous system (CNS) involvement[3]. The onset of lymphoma during pregnancy is insidious without typical symptoms. Lymphoma is often accompanied by systemic symptoms, such as fatigue, shortness of breath and night sweats, which is similar to physiological changes during pregnancy and is often ignored. Therefore, patients do not often visit a doctor until severe clinical symptoms appear, which may postpone the diagnosis and optimal treatment. The proportion of reproductive organs involved in non-Hodgkin lymphoma (NHL) is higher during pregnancy than during nonpregnancy and commonly involves invasion of the breast followed by the ovaries and uterus[4]. Because pelvic blood flow and lymphatic drainage are abundant during pregnancy and might enhance the growth and spread of tumor cells, pregnancy may promote the occurrence and development of lymphoma. Our patient developed symptoms at 19 wk of gestation and was found to have ovarian masses reaching the frozen pelvis approximately 4 wk later. However, ultrasound showed no mass in the bilateral adnexal area at 14+6 wk of gestation. DHL progressed rapidly because pregnancy may have accelerated tumor growth and spread.
A pathological examination, including lymph node biopsy and tissue biopsy, which can be performed safely during pregnancy, is the principal means of lymphoma diagnosis. DHL can be diagnosed by fluorescent in situ hybridization[5]. Concerning the immunophenotype, B-cell markers, including CD19, CD20, CD22, CD79a and CD45, are generally positive in these lymphomas, and high CD38 expression is usually observed[5]. For pregnant patients with lymphoma, it is advisable to evaluate the condition by ultrasound, MRI, a chest X-ray examination with an abdomen shield and CT or PET-CT after delivery. Bone marrow biopsy is critical to the diagnosis and staging of lymphoma and is safe during pregnancy[6]. It should be noted that when ovarian tumors are suspected to be malignant, we often perform an exploratory laparotomy. However, for young women with acute onset, rapid progression and increasing chylous pleural effusion containing abundant lymphocytes, biopsy of the lesion should be considered to avoid an unnecessary radical surgery.
As DHL is associated with a poor prognosis during pregnancy, it is necessary to consider many factors, including the stage of pregnancy, pathological type, current feasible treatment methods and patients’ willingness, when making treatment plans. Indolent NHL, with gradual progression can be monitored closely before treatment begins in the second and third trimesters[7]. For most aggressive and highly aggressive NHLs, it is crucial to begin combination chemotherapy immediately and terminate the pregnancy during early pregnancy[7]. For young women who require that their reproductive function be preserved, we should take relevant measures.
These individuals respond poorly to traditional R-CHOP alone and rapidly develop resistance to cytotoxic chemotherapy, which can result in an increased risk of relapse and a poor prognosis[5]. Recently, several centers have used DA-R-EPOCH as DHL’s preferred induction scheme[8]. A retrospective study at the MD Anderson Cancer Center showed that the DA-R-EPOCH regimen could prolong the progression-free survival (PFS) and overall survival (OS) of DHL patients compared with the chemotherapy regimens such as R-CHOP and rituximab, hyperfractionated cyclophosphamide, vincristine, doxorubicin, dexamethasone, alternating with cytarabine + methotrexate[9]. A large multicenter retrospective study showed that high-intensity induction programs such as DA-R-EPOCH, rituximab, hyperfractionated cyclophosphamide, vincristine, doxorubicin, dexamethasone, alternating with cytarabine + methotrexate and cyclophosphamide, vincristine, doxorubicin, high-dose methotrexate/ifosfamide, etoposide, high-dose cytarabine could better prolong PFS in patients than R-CHOP, but there was no difference in OS[10].
Rosenthal et al[11] recommended CNS prevention for all patients with DHL. CNS prophylaxis with intravenous high-dose methotrexate should be given only after delivery[4]. Cellular therapies such as CAR-T-cell therapy can be considered in patients with refractory or repeatedly relapsed disease, preferably in the context of a clinical trial[5]. In addition, targeted agents for MYC, BCL-2 and/or BCL-6 provide new ideas for clinical research and treatment. The patient described herein had a poor response to R-CHOP therapy but was sensitive to the DA-R-EPOCH regimen and CAR-T therapy. The patient achieved CR but relapsed rapidly due to the extremely invasive nature of the tumor.
In summary, DHL is highly aggressive and malignant and responds poorly to standard R-CHOP chemotherapy. In contrast, it is sensitive to high-intensity induction chemotherapy, yet there is a high risk of recurrence after achieving CR. Therefore, it is suggested to closely monitor patients who achieve CR and adjust the chemotherapy plan when conditions change. However, more clinical trials and studies are needed to identify effective therapies.
CONCLUSION
As obstetricians and gynecologists, we should be well aware of the gynecological manifestations of lymphoma and consider it in the differential diagnosis of pelvic tumors. It is necessary to be aware of the occurrence of lymphoma when faced with unexplained abdominal distension and fatigue, a fast-growing pelvic mass, increasing hydrothorax and ascites containing many lymphocytes. Then, biopsy might be a good choice to avoid an unnecessary or excessive radical surgery. The early detection and accurate diagnosis of lymphoma during pregnancy can help expedite proper multidisciplinary treatment to delay progression and decrease the mortality rate.
ACKNOWLEDGEMENTS
We thank the family who participated in this study.
Informed consent statement: Informed written consent was obtained from the patient for publication of this report and any accompanying images.
Conflict-of-interest statement: The authors declare that they have no conflict of interest.
CARE Checklist (2016) statement: The authors have read the CARE Checklist (2016), and the manuscript was prepared and revised according to the CARE Checklist (2016).
Manuscript source: Unsolicited manuscript
Peer-review started: September 11, 2020
First decision: November 14, 2020
Article in press: November 21, 2020
Specialty type: Medicine, research and experimental
Country/Territory of origin: China
Peer-review report’s scientific quality classification
Grade A (Excellent): 0
Grade B (Very good): B
Grade C (Good): 0
Grade D (Fair): 0
Grade E (Poor): 0
P-Reviewer: Ristic-Medic D S-Editor: Huang P L-Editor: Filipodia P-Editor: Ma YJ | CYCLICAL | DrugDosageText | CC BY-NC | 33521119 | 18,990,639 | 2021-01-16 |
What was the outcome of reaction 'Disease recurrence'? | Double-hit lymphoma (rearrangements of MYC, BCL-2) during pregnancy: A case report.
BACKGROUND
Double-hit lymphoma is a highly aggressive B-cell lymphoma that is genetically characterized by rearrangements of MYC and BCL2 and/or BCL6. Lymphoma is often accompanied by atypical systemic symptoms similar to physiological changes during pregnancy and is often ignored. Herein, we describe a gravid patient with high-grade B-cell lymphoma with a MYC and BCL-2 gene rearrangement involving multiple parts of the body.
METHODS
A 32-year-old female, gestational age 22+5 wk, complained of abdominal distension, chest tightness and limb weakness lasting approximately 4 wk, and ovarian tumors were found 14 d ago. Auxiliary examinations and a trimanual gynecologic examination suggested malignant ovarian tumor and frozen pelvis. Coupled with rapid progression, severe compression symptoms of hydrothorax, ascites and moderate anemia, labor was induced. Next, biopsy and imaging examinations showed high-grade B-cell lymphoma with a MYC and BCL-2 gene rearrangement involving multiple parts of the body. She was referred to the Department of Oncology and Hematology for chemotherapy. Because of multiple recurrences after complete remission, chemotherapy plans were continuously adjusted. At present, the patient remains in treatment and follow-up.
CONCLUSIONS
The early detection and accurate diagnosis of lymphoma during pregnancy can help expedite proper multidisciplinary treatment to delay disease progression and decrease the mortality rate.
Core Tip: To our knowledge, this is the first study to describe a patient with double-hit lymphoma during pregnancy. We should be well aware of the gynecological manifestations of lymphoma and consider it in the differential diagnosis of pelvic tumors. To avoid an unnecessary radical operation, biopsy should be considered instead of exploratory laparotomy in young women with suspected malignant tumors as well as acute onset, rapid progression and growing chylous pleural effusion containing abundant lymphocytes. The early detection and accurate diagnosis of lymphoma during pregnancy can help expedite proper multidisciplinary treatment to delay disease progression and decrease the mortality rate.
INTRODUCTION
Double-hit lymphoma (DHL) is a highly aggressive B-cell lymphoma that is genetically characterized by rearrangements of MYC and BCL2 and/or BCL6. This neoplasm (high-grade B-cell lymphoma with rearrangements of MYC and BCL2 and/or BCL6 called DHL/triple-hit lymphoma) was identified as a new subtype in the 2016 revision of the World Health Organization classification of lymphoid neoplasms[1]. The incidence rate of lymphoma is approximately 1/6000, ranking fourth in malignancies during pregnancy[2]. However, DHL is relatively uncommon. Lymphoma is often accompanied by atypical systemic symptoms similar to physiological changes during pregnancy and is often ignored. Due to its invasive nature, high risks of malignancy and recurrence and the lack of accepted treatment, it is necessary to explore effective therapies for DHL. Herein, we describe a gravid patient with high-grade B-cell lymphoma with a MYC and BCL-2 gene rearrangement involving multiple parts of the body.
CASE PRESENTATION
Chief complaints
A 32-year-old female, gestational age 22+5 wk, presented to the department of obstetrics of our hospital complaining of abdominal distension, chest tightness and limb weakness lasting approximately 4 wk. Ovarian tumors were found 14 d ago.
History of present illness
Fifty-five days prior (gestational age: 14+6 wk), her ultrasound showed no mass in the bilateral adnexal area. According to the patient, her abdominal distension, chest tightness, and limb weakness began approximately 4 wk prior (gestational age: approximately 19 wk), but she did not seek treatment. Fourteen days ago, she was diagnosed with bilateral ovarian tumors in another hospital by ultrasound showing a hypoechoic mass measuring 9.2 cm × 6.7 cm on the right side of the uterus, a hypoechoic mass measuring 9.2 cm × 6.9 cm on the left side of the uterus, an anechoic mass measuring 4.3 cm × 3.6 cm beside the uterus and pelvic effusion.
History of past illness
The patient noted a history of gastritis for more than 10 years.
Personal and family history
Her parents had a history of hypertension. She had no family history of malignancies.
Physical examination
Her face showed signs of anemia. Her chest percussion was voiced, and her abdomen was swollen. A trimanual gynecologic examination after induced labor revealed a uterus with poor mobility, irregular masses in the bilateral adnexal area with poor mobility, a rectal fossa filled with lesions and a narrow space between the intestines.
Laboratory examinations
Upon admission, her laboratory results were as follows: hemoglobin 66 g/L, hematocrit 20.4%, reticulocyte 3.28%, serum albumin 35.1 g/L, free triiodothyonine 2.34 pmol/L, and free thyroxine 16.35 pmol/L. Tumor marker levels were as follows: CA125 578.50 U/mL, alpha-fetoprotein 157.84 ng/mL, carcinoembryonic antigen 0.53 ng/mL, CA199 16.13 U/mL, Cyfra21-1 2.60 ng/mL, Fer 749.58 ng/mL, β 2-microglobulin 5.56 μg/mL, neuron-specific enolase 15.84 ng/mL, CA50 7.19 U/mL, CA153 25.70 U/mL and serum lactic dehydrogenase (LDH) 1160 U/L.
Imaging examinations
At admission, ultrasound indicated a hypoechoic mass measuring 10.7 cm × 7.8 cm in the right adnexal area and a hypoechoic mass measuring 11.2 cm × 8.2 in the left adnexa. Then, pelvic magnetic resonance imaging (MRI) showed a soft tissue mass shadow in the pelvic cavity measuring approximately 12.7 cm in the largest diameter and lesions involving the posterior wall of the bladder, adjacent bowel, cervix, upper part of the vagina and bilateral iliac vessels. The patient was diagnosed with a bilateral adnexal malignant tumor, and the pelvic mass was not excluded as metastasis (Figure 1A-D). MRI also revealed pelvic effusion, soft tissue swelling in the pelvic wall and buttock, changes in the pelvic bone and bilateral ureteral dilatation.
Figure 1
Magnetic resonance imaging and computed tomography imaging. A and B: Coronal (A) and axial (B) images showed bilateral adnexal malignant tumors; C and D: Sagittal images showed masses in the left (C) and right (D) adnexal area; E and F: Computed tomography images of the arterial phase (E) and venous phase (F) showed bilateral adnexal malignant tumors.
Ultrasonography and computed tomography (CT) showed massive peritoneal and bilateral pleural effusion. Therefore, we performed ultrasound-guided puncture catheter drainage in the abdominal cavity and right thoracic cavity. Whole-abdomen CT showed bilateral pleural effusion, abdominal and pelvic effusion and malignancies of the bilateral adnexal origin that did not involve the rectum and bladder (Figure 1E and 1F). Whole-abdomen CT also revealed an irregularly shaped uterus and cervix that were not excluded as metastases, multiple soft tissue masses in the abdomen believed to be metastases, a nodular shadow in the left lateral lobe of the liver that was not excluded as metastasis, tumor involvement in the bilateral middle and lower ureters, secondary left kidney atrophy, bilateral hydronephrosis, bilateral upper ureteral dilatation and bilateral inguinal lymph nodes. After receiving the pathological results, positron emission tomography-computed tomography (PET-CT) was performed and revealed multiple enlarged lymph nodes throughout the body with increased metabolism (indicative of lymphoma), some lesions that were unclearly demarcated from the uterus and adnexa, thickening of the bilateral pleural wall, pleura, pericardium, peritoneum, omentum and mesentery with increased metabolism (indicative of lymphoma infiltration), lymphoma in the right breast and increased systemic skeletal metabolism (indicative of lymphoma infiltration).
Histopathological examination
The exfoliative cytology of hydrothorax and hydroperitoneum showed many lymphocytes without cancer cells. The pathological results supported high-grade B-cell lymphoma, and the immunohistochemical staining results were as follows: LCA (+), CD20 (+), CD3 (-), CD5 (-), Cyclin D1 (-), Ki67 (positive rate 90%), CK (AE1/AE3) (-), BCL-6 (+), TdT (-), MPO (-), CgA (-), Syn (-), CD56 (-), PAX-5 (+), CD34 (-), CD10 (+), BCL-2 (+), MUM1 (-), MYC (+), CD21 (-) and CD99 (weakly +). The pathological consultation at the superior hospital resulted in a diagnosis of non-Hodgkin high-grade B-cell lymphoma with rearrangements of the MYC gene and BCL2 gene (DHL). Immunohistochemistry revealed MUM-1+, CD10+, CD38+ and LMO 2- and in situ hybridization revealed EBER-.
FINAL DIAGNOSIS
The final diagnosis was high-grade B-cell lymphoma with rearrangements of MYC and BCL2 (stage IV, International Prognostic Index = 4 points, age-adjusted International Prognostic Index = 3 points) (involving multiple lymph nodes, the bilateral chest wall, pleura, pericardium, peritoneum, omentum, mesentery, right breast and whole body skeleton).
TREATMENT
Considering the patient’s rapidly progressing condition and severe systemic symptoms, we explained the treatment options and possible risks to the patient and her husband, and then informed consent was obtained to perform rivanol-induced labor. The patient also received a blood transfusion and anti-infection, expectorant and other symptomatic treatments. After consultation, we performed ultrasound-guided puncture catheter drainage in the abdominal cavity and right thoracic cavity due to massive abdominal and pleural effusion. A large amount of yellowish chyliform fluid was drained (Figure 2). Because of severe abdominal distension and difficulty associated with enema administration, we carried out ultrasound-guided puncture biopsy of the pelvic masses rather than colonoscopy with biopsy.
Figure 2 Yellowish chyliform fluid drained from the abdomen.
The patient was immediately referred and admitted to the Department of Oncology and Hematology for chemotherapy. First, she received rituximab plus cyclo-phosphamide, doxorubicin, vincristine and prednisone (R-CHOP) chemotherapy. One course later, chemotherapy was adjusted to dose-adjusted R-EPOCH (DA-R-EPOCH) because of grade IV myelosuppression. The patient then achieved complete remission (CR) after four courses. Two months later, the disease relapsed. She received rituximab, dexamethasone, ifosfamide, cisplatin, etoposide + lenalidomide, R-DICE and the treatment of chimeric antigen receptor T-cell therapy and achieved CR again. Two months later, the lymphoma relapsed again, and the patient received rituximab combined with a Btk inhibitor, gemcitabine + oxaliplatin, combined with azacytidine chemotherapy, oral ibrutinib and a combination of methotrexate + rituximab + gemcitabine + oxaliplatin + azacytidine.
OUTCOME AND FOLLOW-UP
The patient achieved CR following treatment but relapsed so rapidly that chemotherapy was continuously adjusted. At present, the patient remains in treatment and close follow-up.
DISCUSSION
The median age of onset for DHL is 51-67 years. DHL is characterized by a high level of LDH, an elevated Ki-67 index, a high-risk International Prognostic Index score and susceptibility to extranodal invasion, especially bone marrow and central nervous system (CNS) involvement[3]. The onset of lymphoma during pregnancy is insidious without typical symptoms. Lymphoma is often accompanied by systemic symptoms, such as fatigue, shortness of breath and night sweats, which is similar to physiological changes during pregnancy and is often ignored. Therefore, patients do not often visit a doctor until severe clinical symptoms appear, which may postpone the diagnosis and optimal treatment. The proportion of reproductive organs involved in non-Hodgkin lymphoma (NHL) is higher during pregnancy than during nonpregnancy and commonly involves invasion of the breast followed by the ovaries and uterus[4]. Because pelvic blood flow and lymphatic drainage are abundant during pregnancy and might enhance the growth and spread of tumor cells, pregnancy may promote the occurrence and development of lymphoma. Our patient developed symptoms at 19 wk of gestation and was found to have ovarian masses reaching the frozen pelvis approximately 4 wk later. However, ultrasound showed no mass in the bilateral adnexal area at 14+6 wk of gestation. DHL progressed rapidly because pregnancy may have accelerated tumor growth and spread.
A pathological examination, including lymph node biopsy and tissue biopsy, which can be performed safely during pregnancy, is the principal means of lymphoma diagnosis. DHL can be diagnosed by fluorescent in situ hybridization[5]. Concerning the immunophenotype, B-cell markers, including CD19, CD20, CD22, CD79a and CD45, are generally positive in these lymphomas, and high CD38 expression is usually observed[5]. For pregnant patients with lymphoma, it is advisable to evaluate the condition by ultrasound, MRI, a chest X-ray examination with an abdomen shield and CT or PET-CT after delivery. Bone marrow biopsy is critical to the diagnosis and staging of lymphoma and is safe during pregnancy[6]. It should be noted that when ovarian tumors are suspected to be malignant, we often perform an exploratory laparotomy. However, for young women with acute onset, rapid progression and increasing chylous pleural effusion containing abundant lymphocytes, biopsy of the lesion should be considered to avoid an unnecessary radical surgery.
As DHL is associated with a poor prognosis during pregnancy, it is necessary to consider many factors, including the stage of pregnancy, pathological type, current feasible treatment methods and patients’ willingness, when making treatment plans. Indolent NHL, with gradual progression can be monitored closely before treatment begins in the second and third trimesters[7]. For most aggressive and highly aggressive NHLs, it is crucial to begin combination chemotherapy immediately and terminate the pregnancy during early pregnancy[7]. For young women who require that their reproductive function be preserved, we should take relevant measures.
These individuals respond poorly to traditional R-CHOP alone and rapidly develop resistance to cytotoxic chemotherapy, which can result in an increased risk of relapse and a poor prognosis[5]. Recently, several centers have used DA-R-EPOCH as DHL’s preferred induction scheme[8]. A retrospective study at the MD Anderson Cancer Center showed that the DA-R-EPOCH regimen could prolong the progression-free survival (PFS) and overall survival (OS) of DHL patients compared with the chemotherapy regimens such as R-CHOP and rituximab, hyperfractionated cyclophosphamide, vincristine, doxorubicin, dexamethasone, alternating with cytarabine + methotrexate[9]. A large multicenter retrospective study showed that high-intensity induction programs such as DA-R-EPOCH, rituximab, hyperfractionated cyclophosphamide, vincristine, doxorubicin, dexamethasone, alternating with cytarabine + methotrexate and cyclophosphamide, vincristine, doxorubicin, high-dose methotrexate/ifosfamide, etoposide, high-dose cytarabine could better prolong PFS in patients than R-CHOP, but there was no difference in OS[10].
Rosenthal et al[11] recommended CNS prevention for all patients with DHL. CNS prophylaxis with intravenous high-dose methotrexate should be given only after delivery[4]. Cellular therapies such as CAR-T-cell therapy can be considered in patients with refractory or repeatedly relapsed disease, preferably in the context of a clinical trial[5]. In addition, targeted agents for MYC, BCL-2 and/or BCL-6 provide new ideas for clinical research and treatment. The patient described herein had a poor response to R-CHOP therapy but was sensitive to the DA-R-EPOCH regimen and CAR-T therapy. The patient achieved CR but relapsed rapidly due to the extremely invasive nature of the tumor.
In summary, DHL is highly aggressive and malignant and responds poorly to standard R-CHOP chemotherapy. In contrast, it is sensitive to high-intensity induction chemotherapy, yet there is a high risk of recurrence after achieving CR. Therefore, it is suggested to closely monitor patients who achieve CR and adjust the chemotherapy plan when conditions change. However, more clinical trials and studies are needed to identify effective therapies.
CONCLUSION
As obstetricians and gynecologists, we should be well aware of the gynecological manifestations of lymphoma and consider it in the differential diagnosis of pelvic tumors. It is necessary to be aware of the occurrence of lymphoma when faced with unexplained abdominal distension and fatigue, a fast-growing pelvic mass, increasing hydrothorax and ascites containing many lymphocytes. Then, biopsy might be a good choice to avoid an unnecessary or excessive radical surgery. The early detection and accurate diagnosis of lymphoma during pregnancy can help expedite proper multidisciplinary treatment to delay progression and decrease the mortality rate.
ACKNOWLEDGEMENTS
We thank the family who participated in this study.
Informed consent statement: Informed written consent was obtained from the patient for publication of this report and any accompanying images.
Conflict-of-interest statement: The authors declare that they have no conflict of interest.
CARE Checklist (2016) statement: The authors have read the CARE Checklist (2016), and the manuscript was prepared and revised according to the CARE Checklist (2016).
Manuscript source: Unsolicited manuscript
Peer-review started: September 11, 2020
First decision: November 14, 2020
Article in press: November 21, 2020
Specialty type: Medicine, research and experimental
Country/Territory of origin: China
Peer-review report’s scientific quality classification
Grade A (Excellent): 0
Grade B (Very good): B
Grade C (Good): 0
Grade D (Fair): 0
Grade E (Poor): 0
P-Reviewer: Ristic-Medic D S-Editor: Huang P L-Editor: Filipodia P-Editor: Ma YJ | Not recovered | ReactionOutcome | CC BY-NC | 33521119 | 19,011,051 | 2021-01-16 |
What was the outcome of reaction 'Exposure during pregnancy'? | Double-hit lymphoma (rearrangements of MYC, BCL-2) during pregnancy: A case report.
BACKGROUND
Double-hit lymphoma is a highly aggressive B-cell lymphoma that is genetically characterized by rearrangements of MYC and BCL2 and/or BCL6. Lymphoma is often accompanied by atypical systemic symptoms similar to physiological changes during pregnancy and is often ignored. Herein, we describe a gravid patient with high-grade B-cell lymphoma with a MYC and BCL-2 gene rearrangement involving multiple parts of the body.
METHODS
A 32-year-old female, gestational age 22+5 wk, complained of abdominal distension, chest tightness and limb weakness lasting approximately 4 wk, and ovarian tumors were found 14 d ago. Auxiliary examinations and a trimanual gynecologic examination suggested malignant ovarian tumor and frozen pelvis. Coupled with rapid progression, severe compression symptoms of hydrothorax, ascites and moderate anemia, labor was induced. Next, biopsy and imaging examinations showed high-grade B-cell lymphoma with a MYC and BCL-2 gene rearrangement involving multiple parts of the body. She was referred to the Department of Oncology and Hematology for chemotherapy. Because of multiple recurrences after complete remission, chemotherapy plans were continuously adjusted. At present, the patient remains in treatment and follow-up.
CONCLUSIONS
The early detection and accurate diagnosis of lymphoma during pregnancy can help expedite proper multidisciplinary treatment to delay disease progression and decrease the mortality rate.
Core Tip: To our knowledge, this is the first study to describe a patient with double-hit lymphoma during pregnancy. We should be well aware of the gynecological manifestations of lymphoma and consider it in the differential diagnosis of pelvic tumors. To avoid an unnecessary radical operation, biopsy should be considered instead of exploratory laparotomy in young women with suspected malignant tumors as well as acute onset, rapid progression and growing chylous pleural effusion containing abundant lymphocytes. The early detection and accurate diagnosis of lymphoma during pregnancy can help expedite proper multidisciplinary treatment to delay disease progression and decrease the mortality rate.
INTRODUCTION
Double-hit lymphoma (DHL) is a highly aggressive B-cell lymphoma that is genetically characterized by rearrangements of MYC and BCL2 and/or BCL6. This neoplasm (high-grade B-cell lymphoma with rearrangements of MYC and BCL2 and/or BCL6 called DHL/triple-hit lymphoma) was identified as a new subtype in the 2016 revision of the World Health Organization classification of lymphoid neoplasms[1]. The incidence rate of lymphoma is approximately 1/6000, ranking fourth in malignancies during pregnancy[2]. However, DHL is relatively uncommon. Lymphoma is often accompanied by atypical systemic symptoms similar to physiological changes during pregnancy and is often ignored. Due to its invasive nature, high risks of malignancy and recurrence and the lack of accepted treatment, it is necessary to explore effective therapies for DHL. Herein, we describe a gravid patient with high-grade B-cell lymphoma with a MYC and BCL-2 gene rearrangement involving multiple parts of the body.
CASE PRESENTATION
Chief complaints
A 32-year-old female, gestational age 22+5 wk, presented to the department of obstetrics of our hospital complaining of abdominal distension, chest tightness and limb weakness lasting approximately 4 wk. Ovarian tumors were found 14 d ago.
History of present illness
Fifty-five days prior (gestational age: 14+6 wk), her ultrasound showed no mass in the bilateral adnexal area. According to the patient, her abdominal distension, chest tightness, and limb weakness began approximately 4 wk prior (gestational age: approximately 19 wk), but she did not seek treatment. Fourteen days ago, she was diagnosed with bilateral ovarian tumors in another hospital by ultrasound showing a hypoechoic mass measuring 9.2 cm × 6.7 cm on the right side of the uterus, a hypoechoic mass measuring 9.2 cm × 6.9 cm on the left side of the uterus, an anechoic mass measuring 4.3 cm × 3.6 cm beside the uterus and pelvic effusion.
History of past illness
The patient noted a history of gastritis for more than 10 years.
Personal and family history
Her parents had a history of hypertension. She had no family history of malignancies.
Physical examination
Her face showed signs of anemia. Her chest percussion was voiced, and her abdomen was swollen. A trimanual gynecologic examination after induced labor revealed a uterus with poor mobility, irregular masses in the bilateral adnexal area with poor mobility, a rectal fossa filled with lesions and a narrow space between the intestines.
Laboratory examinations
Upon admission, her laboratory results were as follows: hemoglobin 66 g/L, hematocrit 20.4%, reticulocyte 3.28%, serum albumin 35.1 g/L, free triiodothyonine 2.34 pmol/L, and free thyroxine 16.35 pmol/L. Tumor marker levels were as follows: CA125 578.50 U/mL, alpha-fetoprotein 157.84 ng/mL, carcinoembryonic antigen 0.53 ng/mL, CA199 16.13 U/mL, Cyfra21-1 2.60 ng/mL, Fer 749.58 ng/mL, β 2-microglobulin 5.56 μg/mL, neuron-specific enolase 15.84 ng/mL, CA50 7.19 U/mL, CA153 25.70 U/mL and serum lactic dehydrogenase (LDH) 1160 U/L.
Imaging examinations
At admission, ultrasound indicated a hypoechoic mass measuring 10.7 cm × 7.8 cm in the right adnexal area and a hypoechoic mass measuring 11.2 cm × 8.2 in the left adnexa. Then, pelvic magnetic resonance imaging (MRI) showed a soft tissue mass shadow in the pelvic cavity measuring approximately 12.7 cm in the largest diameter and lesions involving the posterior wall of the bladder, adjacent bowel, cervix, upper part of the vagina and bilateral iliac vessels. The patient was diagnosed with a bilateral adnexal malignant tumor, and the pelvic mass was not excluded as metastasis (Figure 1A-D). MRI also revealed pelvic effusion, soft tissue swelling in the pelvic wall and buttock, changes in the pelvic bone and bilateral ureteral dilatation.
Figure 1
Magnetic resonance imaging and computed tomography imaging. A and B: Coronal (A) and axial (B) images showed bilateral adnexal malignant tumors; C and D: Sagittal images showed masses in the left (C) and right (D) adnexal area; E and F: Computed tomography images of the arterial phase (E) and venous phase (F) showed bilateral adnexal malignant tumors.
Ultrasonography and computed tomography (CT) showed massive peritoneal and bilateral pleural effusion. Therefore, we performed ultrasound-guided puncture catheter drainage in the abdominal cavity and right thoracic cavity. Whole-abdomen CT showed bilateral pleural effusion, abdominal and pelvic effusion and malignancies of the bilateral adnexal origin that did not involve the rectum and bladder (Figure 1E and 1F). Whole-abdomen CT also revealed an irregularly shaped uterus and cervix that were not excluded as metastases, multiple soft tissue masses in the abdomen believed to be metastases, a nodular shadow in the left lateral lobe of the liver that was not excluded as metastasis, tumor involvement in the bilateral middle and lower ureters, secondary left kidney atrophy, bilateral hydronephrosis, bilateral upper ureteral dilatation and bilateral inguinal lymph nodes. After receiving the pathological results, positron emission tomography-computed tomography (PET-CT) was performed and revealed multiple enlarged lymph nodes throughout the body with increased metabolism (indicative of lymphoma), some lesions that were unclearly demarcated from the uterus and adnexa, thickening of the bilateral pleural wall, pleura, pericardium, peritoneum, omentum and mesentery with increased metabolism (indicative of lymphoma infiltration), lymphoma in the right breast and increased systemic skeletal metabolism (indicative of lymphoma infiltration).
Histopathological examination
The exfoliative cytology of hydrothorax and hydroperitoneum showed many lymphocytes without cancer cells. The pathological results supported high-grade B-cell lymphoma, and the immunohistochemical staining results were as follows: LCA (+), CD20 (+), CD3 (-), CD5 (-), Cyclin D1 (-), Ki67 (positive rate 90%), CK (AE1/AE3) (-), BCL-6 (+), TdT (-), MPO (-), CgA (-), Syn (-), CD56 (-), PAX-5 (+), CD34 (-), CD10 (+), BCL-2 (+), MUM1 (-), MYC (+), CD21 (-) and CD99 (weakly +). The pathological consultation at the superior hospital resulted in a diagnosis of non-Hodgkin high-grade B-cell lymphoma with rearrangements of the MYC gene and BCL2 gene (DHL). Immunohistochemistry revealed MUM-1+, CD10+, CD38+ and LMO 2- and in situ hybridization revealed EBER-.
FINAL DIAGNOSIS
The final diagnosis was high-grade B-cell lymphoma with rearrangements of MYC and BCL2 (stage IV, International Prognostic Index = 4 points, age-adjusted International Prognostic Index = 3 points) (involving multiple lymph nodes, the bilateral chest wall, pleura, pericardium, peritoneum, omentum, mesentery, right breast and whole body skeleton).
TREATMENT
Considering the patient’s rapidly progressing condition and severe systemic symptoms, we explained the treatment options and possible risks to the patient and her husband, and then informed consent was obtained to perform rivanol-induced labor. The patient also received a blood transfusion and anti-infection, expectorant and other symptomatic treatments. After consultation, we performed ultrasound-guided puncture catheter drainage in the abdominal cavity and right thoracic cavity due to massive abdominal and pleural effusion. A large amount of yellowish chyliform fluid was drained (Figure 2). Because of severe abdominal distension and difficulty associated with enema administration, we carried out ultrasound-guided puncture biopsy of the pelvic masses rather than colonoscopy with biopsy.
Figure 2 Yellowish chyliform fluid drained from the abdomen.
The patient was immediately referred and admitted to the Department of Oncology and Hematology for chemotherapy. First, she received rituximab plus cyclo-phosphamide, doxorubicin, vincristine and prednisone (R-CHOP) chemotherapy. One course later, chemotherapy was adjusted to dose-adjusted R-EPOCH (DA-R-EPOCH) because of grade IV myelosuppression. The patient then achieved complete remission (CR) after four courses. Two months later, the disease relapsed. She received rituximab, dexamethasone, ifosfamide, cisplatin, etoposide + lenalidomide, R-DICE and the treatment of chimeric antigen receptor T-cell therapy and achieved CR again. Two months later, the lymphoma relapsed again, and the patient received rituximab combined with a Btk inhibitor, gemcitabine + oxaliplatin, combined with azacytidine chemotherapy, oral ibrutinib and a combination of methotrexate + rituximab + gemcitabine + oxaliplatin + azacytidine.
OUTCOME AND FOLLOW-UP
The patient achieved CR following treatment but relapsed so rapidly that chemotherapy was continuously adjusted. At present, the patient remains in treatment and close follow-up.
DISCUSSION
The median age of onset for DHL is 51-67 years. DHL is characterized by a high level of LDH, an elevated Ki-67 index, a high-risk International Prognostic Index score and susceptibility to extranodal invasion, especially bone marrow and central nervous system (CNS) involvement[3]. The onset of lymphoma during pregnancy is insidious without typical symptoms. Lymphoma is often accompanied by systemic symptoms, such as fatigue, shortness of breath and night sweats, which is similar to physiological changes during pregnancy and is often ignored. Therefore, patients do not often visit a doctor until severe clinical symptoms appear, which may postpone the diagnosis and optimal treatment. The proportion of reproductive organs involved in non-Hodgkin lymphoma (NHL) is higher during pregnancy than during nonpregnancy and commonly involves invasion of the breast followed by the ovaries and uterus[4]. Because pelvic blood flow and lymphatic drainage are abundant during pregnancy and might enhance the growth and spread of tumor cells, pregnancy may promote the occurrence and development of lymphoma. Our patient developed symptoms at 19 wk of gestation and was found to have ovarian masses reaching the frozen pelvis approximately 4 wk later. However, ultrasound showed no mass in the bilateral adnexal area at 14+6 wk of gestation. DHL progressed rapidly because pregnancy may have accelerated tumor growth and spread.
A pathological examination, including lymph node biopsy and tissue biopsy, which can be performed safely during pregnancy, is the principal means of lymphoma diagnosis. DHL can be diagnosed by fluorescent in situ hybridization[5]. Concerning the immunophenotype, B-cell markers, including CD19, CD20, CD22, CD79a and CD45, are generally positive in these lymphomas, and high CD38 expression is usually observed[5]. For pregnant patients with lymphoma, it is advisable to evaluate the condition by ultrasound, MRI, a chest X-ray examination with an abdomen shield and CT or PET-CT after delivery. Bone marrow biopsy is critical to the diagnosis and staging of lymphoma and is safe during pregnancy[6]. It should be noted that when ovarian tumors are suspected to be malignant, we often perform an exploratory laparotomy. However, for young women with acute onset, rapid progression and increasing chylous pleural effusion containing abundant lymphocytes, biopsy of the lesion should be considered to avoid an unnecessary radical surgery.
As DHL is associated with a poor prognosis during pregnancy, it is necessary to consider many factors, including the stage of pregnancy, pathological type, current feasible treatment methods and patients’ willingness, when making treatment plans. Indolent NHL, with gradual progression can be monitored closely before treatment begins in the second and third trimesters[7]. For most aggressive and highly aggressive NHLs, it is crucial to begin combination chemotherapy immediately and terminate the pregnancy during early pregnancy[7]. For young women who require that their reproductive function be preserved, we should take relevant measures.
These individuals respond poorly to traditional R-CHOP alone and rapidly develop resistance to cytotoxic chemotherapy, which can result in an increased risk of relapse and a poor prognosis[5]. Recently, several centers have used DA-R-EPOCH as DHL’s preferred induction scheme[8]. A retrospective study at the MD Anderson Cancer Center showed that the DA-R-EPOCH regimen could prolong the progression-free survival (PFS) and overall survival (OS) of DHL patients compared with the chemotherapy regimens such as R-CHOP and rituximab, hyperfractionated cyclophosphamide, vincristine, doxorubicin, dexamethasone, alternating with cytarabine + methotrexate[9]. A large multicenter retrospective study showed that high-intensity induction programs such as DA-R-EPOCH, rituximab, hyperfractionated cyclophosphamide, vincristine, doxorubicin, dexamethasone, alternating with cytarabine + methotrexate and cyclophosphamide, vincristine, doxorubicin, high-dose methotrexate/ifosfamide, etoposide, high-dose cytarabine could better prolong PFS in patients than R-CHOP, but there was no difference in OS[10].
Rosenthal et al[11] recommended CNS prevention for all patients with DHL. CNS prophylaxis with intravenous high-dose methotrexate should be given only after delivery[4]. Cellular therapies such as CAR-T-cell therapy can be considered in patients with refractory or repeatedly relapsed disease, preferably in the context of a clinical trial[5]. In addition, targeted agents for MYC, BCL-2 and/or BCL-6 provide new ideas for clinical research and treatment. The patient described herein had a poor response to R-CHOP therapy but was sensitive to the DA-R-EPOCH regimen and CAR-T therapy. The patient achieved CR but relapsed rapidly due to the extremely invasive nature of the tumor.
In summary, DHL is highly aggressive and malignant and responds poorly to standard R-CHOP chemotherapy. In contrast, it is sensitive to high-intensity induction chemotherapy, yet there is a high risk of recurrence after achieving CR. Therefore, it is suggested to closely monitor patients who achieve CR and adjust the chemotherapy plan when conditions change. However, more clinical trials and studies are needed to identify effective therapies.
CONCLUSION
As obstetricians and gynecologists, we should be well aware of the gynecological manifestations of lymphoma and consider it in the differential diagnosis of pelvic tumors. It is necessary to be aware of the occurrence of lymphoma when faced with unexplained abdominal distension and fatigue, a fast-growing pelvic mass, increasing hydrothorax and ascites containing many lymphocytes. Then, biopsy might be a good choice to avoid an unnecessary or excessive radical surgery. The early detection and accurate diagnosis of lymphoma during pregnancy can help expedite proper multidisciplinary treatment to delay progression and decrease the mortality rate.
ACKNOWLEDGEMENTS
We thank the family who participated in this study.
Informed consent statement: Informed written consent was obtained from the patient for publication of this report and any accompanying images.
Conflict-of-interest statement: The authors declare that they have no conflict of interest.
CARE Checklist (2016) statement: The authors have read the CARE Checklist (2016), and the manuscript was prepared and revised according to the CARE Checklist (2016).
Manuscript source: Unsolicited manuscript
Peer-review started: September 11, 2020
First decision: November 14, 2020
Article in press: November 21, 2020
Specialty type: Medicine, research and experimental
Country/Territory of origin: China
Peer-review report’s scientific quality classification
Grade A (Excellent): 0
Grade B (Very good): B
Grade C (Good): 0
Grade D (Fair): 0
Grade E (Poor): 0
P-Reviewer: Ristic-Medic D S-Editor: Huang P L-Editor: Filipodia P-Editor: Ma YJ | Not recovered | ReactionOutcome | CC BY-NC | 33521119 | 19,011,051 | 2021-01-16 |
Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Diffuse large B-cell lymphoma'. | Acetabular Insufficiency Fractures in the Setting of Graft vs Host Disease: A Report of Two Cases.
We report a case series of 2 patients with unilateral acetabular insufficiency fractures who received allogeneic peripheral blood stem cell transplantation for hematologic malignancies complicated by chronic graft vs host disease. These were managed with uncemented cup and cage total hip arthroplasty and stabilization of posterior column with plating. Osteonecrosis of the acetabulum is an uncommon musculoskeletal complication of chronic graft vs host disease. The orthopedic impact of this disease should not be overlooked. Surgical intervention with this construct can provide necessary stability to improve patient function.
Introduction
Graft vs host disease (GVHD) can manifest with multisystemic effects. GVHD can occur after allogeneic peripheral blood stem cell transplantation (PBSCT) and can have orthopedic implications such as osteonecrosis. The incidence of osteonecrosis after allogeneic stem cell transplantation is 4-19% [[1], [2], [3], [4]], and the risk is increased in patients with GVHD [5]. Most studies described involve the femoral head [[1], [2], [3], [4],[6], [7], [8], [9], [10], [11], [12]]. Osteonecrosis of the acetabulum, although rare, can lead to significant complications. These include interruption of the articular surface, insufficiency fracture, and protrusio acetabulum. Osteonecrosis of the acetabulum presents particular difficulty in fixation; poor bone quality can impact long-term patient outcomes and implant survivorship. Implant survivorship of THA in patients with allogeneic peripheral stem cell transplantation at 5 years is up to 93% [11], although it can be as low as 74.8% at 10 years [13]. Therefore, THA and fracture fixation in this setting require an approach that combines primary and revision arthroplasty skills to enable immediate weight bearing and pain relief. We present 2 cases of allogeneic PBSCT complicated by GVHD, with resultant acetabular osteonecrosis leading to acetabular insufficiency fracture and the surgical reconstruction that followed.
Case histories
Case 1
Case 1 is a 60-year-old woman with a history of diffuse large B-cell lymphoma who underwent 8 cycles of R-CHOP (rituximab, cyclophosphamide, hydroxydaunorubicin, oncovin [vincristine], and prednisolone). Her disease recurred and was treated with radiolabeled tositumomab with maintenance on rituximab. Relapse occurred once more, and she received salvage chemotherapy with R-ICE (rituximab, ifosfamide, etoposide, carboplatin) followed by autologous PBSCT. She underwent human leukocyte antigen (HLA)-matched allogeneic PBSCT after fludarabine-melphalan conditioning for relapse involving the central nervous system. This was complicated by GVHD, primarily affecting the gastrointestinal tract, that improved with 20-mg prednisone BID (0.5 mg/kg/day). After several dose escalations and relapses, she was tapered off prednisone three times, but after two severe episodes of pericarditis in the absence of steroids, she remained on 10-mg prednisone daily.
She presented to orthopedics with 1 month of acute, “aching” left-sided groin pain, global left hip weakness, difficulty ambulating (newly required a four-wheel walker), and ecchymosis in her inguinal crease. Physical examination revealed severe pain with hip internal and external rotation, as well as adduction and abduction. She could conduct passive hip flexion to 90 degrees but had pain with resisted hip flexion. Magnetic resonance imaging (MRI) of the pelvis and hip was obtained by her primary care provider before orthopedic referral, and AP of the pelvis was obtained as seen in Figure 1. Initial radiography in Figure 1 and MRI demonstrated comminuted minimally displaced fracture of the acetabulum involving the anterior and posterior columns with acetabular protrusio fracture and superior displacement of the femur of 3.5 cm. Interruption of the anterior and posterior columns is better visualized on iliac oblique and obturator oblique views seen in Figure 2, Figure 3.Figure 1 AP pelvis x-ray upon initial presentation showed displaced acetabular fracture and interruption of the femoroacetabular joint space.
Figure 2 Left obturator oblique better demonstrates insufficiency fracture of the posterior wall and anterior column.
Figure 3 Left iliac oblique further demonstrates osteonecrosis of the acetabulum and fracture extending through the posterior column.
Owing to severe disability and pain, and acetabular insufficiency (pathologic) fracture and joint collapse, posterior THA and posterior column stabilization was undertaken. Posterolateral approach was taken to optimize exposure of acetabular fracture and perform THA. Complex THA was performed using a cage construct. Pelvic size thwarted the use of a cup and cage construct. Findings include fragmentation of medial acetabulum with transverse-type insufficiency or pathologic fracture. Acetabular pathologic fracture was repaired, or stabilized, with 8-hole reconstruction plate bent for the left posterior column. Morselized femoral head autograft was placed at the base of the protruded acetabulum. Dome screws of antiprotrusio cage were placed before ilium cage screws, and 5 mL of synthetic bone graft and 30 mL of cancellous bone allograft was injected behind cage. Postoperative x-ray is demonstrated in Figure 4. Her postoperative activity restrictions included posterior hip precautions, and weightbearing as tolerated with an assistive device, with weaning as she was able.Figure 4 Day 0 postoperative AP pelvis x-ray. THA with cage construct and iliac plating.
At her 3-month follow-up visit, she was able to fully weight bear on her left lower extremity without pain or assistive device. Imaging obtained at that time is seen in Figure 5. At 5 months postoperatively, she underwent right total knee arthroplasty because of osteoarthritis present before the acetabular osteonecrosis and was progressing very well with physical therapy. Unfortunately, 16 months after complex left THA, she succumbed to complications of diffuse large B-cell lymphoma and GVHD.Figure 5 Three months postoperative AP pelvis. Revealed intact cage hardware, posterior column plating, and THA. Interval ileum healing was perceived.
Case 2
Case 2 is a 51-year-old woman with a history of acute myelogenous leukemia (AML), secondary myelodysplastic syndrome (MDS), GVHD, steroid-induced diabetes, and restrictive pulmonary disease. Autologous PBSCT was undertaken for AML 9 years before presentation. Matched unrelated donor PBSCT was conducted 1 year before presentation, after fludarabine-melphalan conditioning. GVHD characterized by gastrointestinal symptoms and florid skin rash complicated PBSCT 4 months before presentation. Steroid dosage during GVHD was started at 1 mg/kg/day (60 mg BID) with rapid resolution of symptoms leading to taper of steroids down to 0.5 mg/kg/day after 1 week. She developed recurrence of pulmonary symptoms and gastrointestinal symptoms with tapering and was restarted on 1 mg/kg/day.
She presented to orthopedics with 2 months of right hip pain, primarily in her deep inguinal crease. She required a walker for ambulation and was limited to very short distances because of pain. The examination was remarkable for BMI = 44, anasarca, and painful and limited right hip rotation with only 10 degrees of passive external and internal rotation. Radiographs taken at that time are seen in Figure 6. MRI performed at that time showed hypointensity of the supra-acetabular ilium with some T2 hyperintensity measuring 2.5 cm transverse × 2.4 cm AP suggestive of osteonecrosis, although without collapse. There was also osteonecrosis of the left femoral head, without collapse. Given significant comorbid conditions including bilateral lower extremity edema and severe open-leg ulcerations, surgery was not initially recommended.Figure 6 AP right hip obtained upon initial presentation to PCP with right hip pain. Revealing subchondral lucency of the right femoral head. No acetabular involvement noted.
Given ongoing severe pain and disability, she underwent medical optimization taking 13 months, although during that time, she developed progressive osteonecrosis of the acetabulum. The progression of this can be seen in Figure 7, Figure 8 obtained 1 month later. Her fracture initially demonstrated disruption of the right iliopubic line with sclerosis of the supraacetabular ilium with superior displacement of the femoral head into the ilium consistent with protrusio fracture. This was further evaluated with a CT of the pelvis, which demonstrated comminution of anterior and posterior columns and 14 gapping of articular surface along anterosuperior acetabulum and medullary sclerosis of the surrounding ilium. Follow-up radiography seen in Figure 8 demonstrated increased displacement of anterior and posterior columns with medial acetabular wall displacement measuring 8 mm. Figure 8 was ultimately used for templating her implants. Iliac oblique and obturator oblique views at this time seen in Figure 9, Figure 10 better demonstrate involvement of the anterior and posterior column, medial protrusion of the acetabulum. She was no longer able to ambulate with a walker and was wheelchair bound. Her steroid dose then was 5 mg, 5 days per week, and 10 mg, 2 days per week. Treatment options discussed with patient included Girdlestone resection, THA, and THA with antiprotrusio cage or cup and cage construct. Reconstruction was preferred by patient over Girdlestone resection as she was hoping to resume ambulation and activities of daily living (ADLs). Surgery was pursued with posterior THA, with cage construct and posterior column plating. This fixation was used as the size of the pelvis was not large enough to facilitate a cup/cage construct. Medial acetabulum bony deficiency with both columns, or transverse-type insufficiency fracture or pelvic discontinuity variant, was encountered. After femoral neck cut was made, A 7-hole pelvic reconstruction plate was contoured, and a posterior column plated from ischium to ileum with good fixation using 4 small fragment screws. After the cage was placed, 10 mL of synthetic bone graft with 30 mL of allograft cancellous chips was placed posteriorly to cage. There were no intraoperative complications, and she was discharged home after 2 days. Two weeks postoperatively, she had a 2-day admission for viral gastroenteritis. She also underwent kyphoplasty for three (T9, T11, L1) vertebral compression fractures 2 months postoperatively. There were no readmissions or emergency department visits for postoperative complications.Figure 7 AP pelvic x-ray 6 months since onset of symptoms and 10 months preoperatively. Revealing displaced healing right acetabular fracture. Disruption of the right iliopubic line and sclerosis of the right supra-acetabular ilium. Sclerosis of the right femoral head was also observed.
Figure 8 AP pelvis x-ray 13 months since onset of symptoms and 1.5 months preoperatively. Showing comminuted displaced right acetabular transverse fracture also involving the posterior and medial acetabular walls. Right femoral head is also eroded and aspherical. This film was used for templating.
Figure 9 Right iliac oblique x-ray 13 months since onset of symptoms and 1.5 months preoperatively demonstrating transverse plus posterior acetabular wall fracture with 1.5 cm medial displacement of medial acetabular wall.
Figure 10 Right obturator oblique x-ray 13 months since onset of symptoms and 1.5 months preoperatively. Further demonstrating comminuted posterior acetabular wall insufficiency fracture, aspherical and eroded femoral head, and some bony callus.
One-month postoperatively, her pain was decreasing, and function with ADLs increased, although she required a walker because of back pain and deconditioning. Her gait was smooth, not antalgic, with the walker. Two views of AP pelvis performed at that time are seen in Figure 11. One-year postoperatively, her pain had resolved, she still required a walker, and she was noted to have Trendelenburg gait. AP pelvis 1 year postoperatively, seen in Figure 12, showed well-positioned THA with no lucencies or subsidence. Unfortunately, 3 years postoperatively, she died of causes related to her MDS and GVHD.Figure 11 Portable pelvis x-ray 1-month postoperatively. Intact cup and cage construct implants, near anatomic alignment of acetabular fracture.
Figure 12 AP pelvis x-rays 1-year postoperatively. Interval acetabular healing was seen. Diffuse osteopenia but no evidence of implant failure.
Discussion
Patients with hematologic malignancies are having increased remission and survivorship after autologous and allogenic hematopoietic stem cell transplantations [14,15]. Allogeneic stem cell transplantation is unique as opposed to autologous transplant as it can lead to GVHD. GVHD is a systemic immune reaction by donor cells against host cells [16]. Several studies have demonstrated the increased risk of osteonecrosis because of GVHD [5,9,11,17,18]. GVHD is thought to cause osteonecrosis because of an inflammatory process in the intraosseous vasculature. Sixou et al. [19] found histologic evidence of vasculitis attributed to GVHD. This vasculitis exacerbates risk factors associated with osteonecrosis inclusive to patients with hematologic malignancies including systemic glucocorticoids, chemotherapeutics, and irradiation [5].
Unique to the presented cases is osteonecrosis of the acetabulum and the timeline to develop osteonecrosis. Case 1 took 5 years for manifestation of acetabular osteonecrosis after initiation of steroids for GVHD. Case 2 took 13 months until acetabular osteonecrosis began after onset of GVHD. In 11 patients (19 hips, 8 patients with bilateral osteonecrosis) studied by Schulte and Beelen, onset of osteonecrosis after allogeneic stem cell transplant ranged from 5 to 57 months, with an average of 25 months [9,18]. However, all these cases were of the femoral head, and the hematologic malignancies were AML, MDS, CML, and ALL. It is unclear in the presented cases what circumstances led to osteonecrosis of the acetabulum. Location and timeline could be attributed to age. Bizot et al. [17] had 16 patients with osteonecrosis secondary to GVHD, although the oldest patient was 47 years old at the time of surgery (average age 13 ± 8 years). The patients presented were 60 and 52 years old at the time of surgery.
Several other studies have identified osteonecrosis risk factors in hematologic malignancies; Schulte and Beelen demonstrated that the most impactful risk factors were chronic GVHD and cumulative steroid intake, followed by female gender, younger age, and conditioning therapy before transplant. Advanced disease stages, bone mineral density, and body composition did not have a significant impact on osteonecrosis [9,18]. The disease process of lymphoma itself may contribute; Chalmers et al. showed that lymphoma was the underlying diagnosis in 33% of THAs in patients with a history of stem cell transplant. However, not all of these patients had a history of GVHD [13].
In these cases, owing to the insufficiency fractures of the acetabular with effective pelvic discontinuity (PD) and the tenuous vascular supply of surrounding bone, THA was conducted with cage construct and bridge plating of the posterior column. This construct has shown efficacy in cases with PD and severe acetabular bone loss in revision THA [[20], [21], [22], [23]]. Plating is primarily studied in revision arthroplasty cases with PD [24,25]. Plating was chosen to restore continuity, optimize contact of viable bone, and add stability to the reconstruction. This fixation technique of posterior column plating with antiprotrusion cage placement led to stability with improved ADLs, restoration of ambulation with full weightbearing, and resolution of pain at 1 year for both cases. Certainly, the perioperative risk of significant surgical or medical complications is high for patients with GVHD; therefore, this technique should be considered in situations with tenuous blood supply and insufficiency fractures in the setting of hematologic malignancy and GVHD.
Summary
These cases are unique reports of osteonecrosis focal to the acetabulum, in patients with history of stem cell transplant and subsequent GVHD. The impact of this disease process should not be overlooked in patients with hematologic malignances and GVHD. Surgical treatment with multifaceted construct, in these cases with an antiprotrusio cage bolstered by posterior column plating, can relieve pain and improve mobility.
Conflict of interest
Dr. Schabel obtains research support from Zimmer Biomet, unrelated to this work. She is also a board member for the Oregon Association of Orthopaedists.
Supplementary data
Conflict of Interest Statement for Nielsen
Conflict of Interest Statement for Schabel
Statements of informed consent were obtained from patients and family members of deceased patients. | FLUDARABINE PHOSPHATE, MELPHALAN, PREDNISONE | DrugsGivenReaction | CC BY-NC-ND | 33521198 | 18,925,490 | 2021-02 |
Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Gastroenteritis viral'. | Acetabular Insufficiency Fractures in the Setting of Graft vs Host Disease: A Report of Two Cases.
We report a case series of 2 patients with unilateral acetabular insufficiency fractures who received allogeneic peripheral blood stem cell transplantation for hematologic malignancies complicated by chronic graft vs host disease. These were managed with uncemented cup and cage total hip arthroplasty and stabilization of posterior column with plating. Osteonecrosis of the acetabulum is an uncommon musculoskeletal complication of chronic graft vs host disease. The orthopedic impact of this disease should not be overlooked. Surgical intervention with this construct can provide necessary stability to improve patient function.
Introduction
Graft vs host disease (GVHD) can manifest with multisystemic effects. GVHD can occur after allogeneic peripheral blood stem cell transplantation (PBSCT) and can have orthopedic implications such as osteonecrosis. The incidence of osteonecrosis after allogeneic stem cell transplantation is 4-19% [[1], [2], [3], [4]], and the risk is increased in patients with GVHD [5]. Most studies described involve the femoral head [[1], [2], [3], [4],[6], [7], [8], [9], [10], [11], [12]]. Osteonecrosis of the acetabulum, although rare, can lead to significant complications. These include interruption of the articular surface, insufficiency fracture, and protrusio acetabulum. Osteonecrosis of the acetabulum presents particular difficulty in fixation; poor bone quality can impact long-term patient outcomes and implant survivorship. Implant survivorship of THA in patients with allogeneic peripheral stem cell transplantation at 5 years is up to 93% [11], although it can be as low as 74.8% at 10 years [13]. Therefore, THA and fracture fixation in this setting require an approach that combines primary and revision arthroplasty skills to enable immediate weight bearing and pain relief. We present 2 cases of allogeneic PBSCT complicated by GVHD, with resultant acetabular osteonecrosis leading to acetabular insufficiency fracture and the surgical reconstruction that followed.
Case histories
Case 1
Case 1 is a 60-year-old woman with a history of diffuse large B-cell lymphoma who underwent 8 cycles of R-CHOP (rituximab, cyclophosphamide, hydroxydaunorubicin, oncovin [vincristine], and prednisolone). Her disease recurred and was treated with radiolabeled tositumomab with maintenance on rituximab. Relapse occurred once more, and she received salvage chemotherapy with R-ICE (rituximab, ifosfamide, etoposide, carboplatin) followed by autologous PBSCT. She underwent human leukocyte antigen (HLA)-matched allogeneic PBSCT after fludarabine-melphalan conditioning for relapse involving the central nervous system. This was complicated by GVHD, primarily affecting the gastrointestinal tract, that improved with 20-mg prednisone BID (0.5 mg/kg/day). After several dose escalations and relapses, she was tapered off prednisone three times, but after two severe episodes of pericarditis in the absence of steroids, she remained on 10-mg prednisone daily.
She presented to orthopedics with 1 month of acute, “aching” left-sided groin pain, global left hip weakness, difficulty ambulating (newly required a four-wheel walker), and ecchymosis in her inguinal crease. Physical examination revealed severe pain with hip internal and external rotation, as well as adduction and abduction. She could conduct passive hip flexion to 90 degrees but had pain with resisted hip flexion. Magnetic resonance imaging (MRI) of the pelvis and hip was obtained by her primary care provider before orthopedic referral, and AP of the pelvis was obtained as seen in Figure 1. Initial radiography in Figure 1 and MRI demonstrated comminuted minimally displaced fracture of the acetabulum involving the anterior and posterior columns with acetabular protrusio fracture and superior displacement of the femur of 3.5 cm. Interruption of the anterior and posterior columns is better visualized on iliac oblique and obturator oblique views seen in Figure 2, Figure 3.Figure 1 AP pelvis x-ray upon initial presentation showed displaced acetabular fracture and interruption of the femoroacetabular joint space.
Figure 2 Left obturator oblique better demonstrates insufficiency fracture of the posterior wall and anterior column.
Figure 3 Left iliac oblique further demonstrates osteonecrosis of the acetabulum and fracture extending through the posterior column.
Owing to severe disability and pain, and acetabular insufficiency (pathologic) fracture and joint collapse, posterior THA and posterior column stabilization was undertaken. Posterolateral approach was taken to optimize exposure of acetabular fracture and perform THA. Complex THA was performed using a cage construct. Pelvic size thwarted the use of a cup and cage construct. Findings include fragmentation of medial acetabulum with transverse-type insufficiency or pathologic fracture. Acetabular pathologic fracture was repaired, or stabilized, with 8-hole reconstruction plate bent for the left posterior column. Morselized femoral head autograft was placed at the base of the protruded acetabulum. Dome screws of antiprotrusio cage were placed before ilium cage screws, and 5 mL of synthetic bone graft and 30 mL of cancellous bone allograft was injected behind cage. Postoperative x-ray is demonstrated in Figure 4. Her postoperative activity restrictions included posterior hip precautions, and weightbearing as tolerated with an assistive device, with weaning as she was able.Figure 4 Day 0 postoperative AP pelvis x-ray. THA with cage construct and iliac plating.
At her 3-month follow-up visit, she was able to fully weight bear on her left lower extremity without pain or assistive device. Imaging obtained at that time is seen in Figure 5. At 5 months postoperatively, she underwent right total knee arthroplasty because of osteoarthritis present before the acetabular osteonecrosis and was progressing very well with physical therapy. Unfortunately, 16 months after complex left THA, she succumbed to complications of diffuse large B-cell lymphoma and GVHD.Figure 5 Three months postoperative AP pelvis. Revealed intact cage hardware, posterior column plating, and THA. Interval ileum healing was perceived.
Case 2
Case 2 is a 51-year-old woman with a history of acute myelogenous leukemia (AML), secondary myelodysplastic syndrome (MDS), GVHD, steroid-induced diabetes, and restrictive pulmonary disease. Autologous PBSCT was undertaken for AML 9 years before presentation. Matched unrelated donor PBSCT was conducted 1 year before presentation, after fludarabine-melphalan conditioning. GVHD characterized by gastrointestinal symptoms and florid skin rash complicated PBSCT 4 months before presentation. Steroid dosage during GVHD was started at 1 mg/kg/day (60 mg BID) with rapid resolution of symptoms leading to taper of steroids down to 0.5 mg/kg/day after 1 week. She developed recurrence of pulmonary symptoms and gastrointestinal symptoms with tapering and was restarted on 1 mg/kg/day.
She presented to orthopedics with 2 months of right hip pain, primarily in her deep inguinal crease. She required a walker for ambulation and was limited to very short distances because of pain. The examination was remarkable for BMI = 44, anasarca, and painful and limited right hip rotation with only 10 degrees of passive external and internal rotation. Radiographs taken at that time are seen in Figure 6. MRI performed at that time showed hypointensity of the supra-acetabular ilium with some T2 hyperintensity measuring 2.5 cm transverse × 2.4 cm AP suggestive of osteonecrosis, although without collapse. There was also osteonecrosis of the left femoral head, without collapse. Given significant comorbid conditions including bilateral lower extremity edema and severe open-leg ulcerations, surgery was not initially recommended.Figure 6 AP right hip obtained upon initial presentation to PCP with right hip pain. Revealing subchondral lucency of the right femoral head. No acetabular involvement noted.
Given ongoing severe pain and disability, she underwent medical optimization taking 13 months, although during that time, she developed progressive osteonecrosis of the acetabulum. The progression of this can be seen in Figure 7, Figure 8 obtained 1 month later. Her fracture initially demonstrated disruption of the right iliopubic line with sclerosis of the supraacetabular ilium with superior displacement of the femoral head into the ilium consistent with protrusio fracture. This was further evaluated with a CT of the pelvis, which demonstrated comminution of anterior and posterior columns and 14 gapping of articular surface along anterosuperior acetabulum and medullary sclerosis of the surrounding ilium. Follow-up radiography seen in Figure 8 demonstrated increased displacement of anterior and posterior columns with medial acetabular wall displacement measuring 8 mm. Figure 8 was ultimately used for templating her implants. Iliac oblique and obturator oblique views at this time seen in Figure 9, Figure 10 better demonstrate involvement of the anterior and posterior column, medial protrusion of the acetabulum. She was no longer able to ambulate with a walker and was wheelchair bound. Her steroid dose then was 5 mg, 5 days per week, and 10 mg, 2 days per week. Treatment options discussed with patient included Girdlestone resection, THA, and THA with antiprotrusio cage or cup and cage construct. Reconstruction was preferred by patient over Girdlestone resection as she was hoping to resume ambulation and activities of daily living (ADLs). Surgery was pursued with posterior THA, with cage construct and posterior column plating. This fixation was used as the size of the pelvis was not large enough to facilitate a cup/cage construct. Medial acetabulum bony deficiency with both columns, or transverse-type insufficiency fracture or pelvic discontinuity variant, was encountered. After femoral neck cut was made, A 7-hole pelvic reconstruction plate was contoured, and a posterior column plated from ischium to ileum with good fixation using 4 small fragment screws. After the cage was placed, 10 mL of synthetic bone graft with 30 mL of allograft cancellous chips was placed posteriorly to cage. There were no intraoperative complications, and she was discharged home after 2 days. Two weeks postoperatively, she had a 2-day admission for viral gastroenteritis. She also underwent kyphoplasty for three (T9, T11, L1) vertebral compression fractures 2 months postoperatively. There were no readmissions or emergency department visits for postoperative complications.Figure 7 AP pelvic x-ray 6 months since onset of symptoms and 10 months preoperatively. Revealing displaced healing right acetabular fracture. Disruption of the right iliopubic line and sclerosis of the right supra-acetabular ilium. Sclerosis of the right femoral head was also observed.
Figure 8 AP pelvis x-ray 13 months since onset of symptoms and 1.5 months preoperatively. Showing comminuted displaced right acetabular transverse fracture also involving the posterior and medial acetabular walls. Right femoral head is also eroded and aspherical. This film was used for templating.
Figure 9 Right iliac oblique x-ray 13 months since onset of symptoms and 1.5 months preoperatively demonstrating transverse plus posterior acetabular wall fracture with 1.5 cm medial displacement of medial acetabular wall.
Figure 10 Right obturator oblique x-ray 13 months since onset of symptoms and 1.5 months preoperatively. Further demonstrating comminuted posterior acetabular wall insufficiency fracture, aspherical and eroded femoral head, and some bony callus.
One-month postoperatively, her pain was decreasing, and function with ADLs increased, although she required a walker because of back pain and deconditioning. Her gait was smooth, not antalgic, with the walker. Two views of AP pelvis performed at that time are seen in Figure 11. One-year postoperatively, her pain had resolved, she still required a walker, and she was noted to have Trendelenburg gait. AP pelvis 1 year postoperatively, seen in Figure 12, showed well-positioned THA with no lucencies or subsidence. Unfortunately, 3 years postoperatively, she died of causes related to her MDS and GVHD.Figure 11 Portable pelvis x-ray 1-month postoperatively. Intact cup and cage construct implants, near anatomic alignment of acetabular fracture.
Figure 12 AP pelvis x-rays 1-year postoperatively. Interval acetabular healing was seen. Diffuse osteopenia but no evidence of implant failure.
Discussion
Patients with hematologic malignancies are having increased remission and survivorship after autologous and allogenic hematopoietic stem cell transplantations [14,15]. Allogeneic stem cell transplantation is unique as opposed to autologous transplant as it can lead to GVHD. GVHD is a systemic immune reaction by donor cells against host cells [16]. Several studies have demonstrated the increased risk of osteonecrosis because of GVHD [5,9,11,17,18]. GVHD is thought to cause osteonecrosis because of an inflammatory process in the intraosseous vasculature. Sixou et al. [19] found histologic evidence of vasculitis attributed to GVHD. This vasculitis exacerbates risk factors associated with osteonecrosis inclusive to patients with hematologic malignancies including systemic glucocorticoids, chemotherapeutics, and irradiation [5].
Unique to the presented cases is osteonecrosis of the acetabulum and the timeline to develop osteonecrosis. Case 1 took 5 years for manifestation of acetabular osteonecrosis after initiation of steroids for GVHD. Case 2 took 13 months until acetabular osteonecrosis began after onset of GVHD. In 11 patients (19 hips, 8 patients with bilateral osteonecrosis) studied by Schulte and Beelen, onset of osteonecrosis after allogeneic stem cell transplant ranged from 5 to 57 months, with an average of 25 months [9,18]. However, all these cases were of the femoral head, and the hematologic malignancies were AML, MDS, CML, and ALL. It is unclear in the presented cases what circumstances led to osteonecrosis of the acetabulum. Location and timeline could be attributed to age. Bizot et al. [17] had 16 patients with osteonecrosis secondary to GVHD, although the oldest patient was 47 years old at the time of surgery (average age 13 ± 8 years). The patients presented were 60 and 52 years old at the time of surgery.
Several other studies have identified osteonecrosis risk factors in hematologic malignancies; Schulte and Beelen demonstrated that the most impactful risk factors were chronic GVHD and cumulative steroid intake, followed by female gender, younger age, and conditioning therapy before transplant. Advanced disease stages, bone mineral density, and body composition did not have a significant impact on osteonecrosis [9,18]. The disease process of lymphoma itself may contribute; Chalmers et al. showed that lymphoma was the underlying diagnosis in 33% of THAs in patients with a history of stem cell transplant. However, not all of these patients had a history of GVHD [13].
In these cases, owing to the insufficiency fractures of the acetabular with effective pelvic discontinuity (PD) and the tenuous vascular supply of surrounding bone, THA was conducted with cage construct and bridge plating of the posterior column. This construct has shown efficacy in cases with PD and severe acetabular bone loss in revision THA [[20], [21], [22], [23]]. Plating is primarily studied in revision arthroplasty cases with PD [24,25]. Plating was chosen to restore continuity, optimize contact of viable bone, and add stability to the reconstruction. This fixation technique of posterior column plating with antiprotrusion cage placement led to stability with improved ADLs, restoration of ambulation with full weightbearing, and resolution of pain at 1 year for both cases. Certainly, the perioperative risk of significant surgical or medical complications is high for patients with GVHD; therefore, this technique should be considered in situations with tenuous blood supply and insufficiency fractures in the setting of hematologic malignancy and GVHD.
Summary
These cases are unique reports of osteonecrosis focal to the acetabulum, in patients with history of stem cell transplant and subsequent GVHD. The impact of this disease process should not be overlooked in patients with hematologic malignances and GVHD. Surgical treatment with multifaceted construct, in these cases with an antiprotrusio cage bolstered by posterior column plating, can relieve pain and improve mobility.
Conflict of interest
Dr. Schabel obtains research support from Zimmer Biomet, unrelated to this work. She is also a board member for the Oregon Association of Orthopaedists.
Supplementary data
Conflict of Interest Statement for Nielsen
Conflict of Interest Statement for Schabel
Statements of informed consent were obtained from patients and family members of deceased patients. | FLUDARABINE PHOSPHATE, MELPHALAN HYDROCHLORIDE | DrugsGivenReaction | CC BY-NC-ND | 33521198 | 18,921,443 | 2021-02 |
Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Generalised oedema'. | Acetabular Insufficiency Fractures in the Setting of Graft vs Host Disease: A Report of Two Cases.
We report a case series of 2 patients with unilateral acetabular insufficiency fractures who received allogeneic peripheral blood stem cell transplantation for hematologic malignancies complicated by chronic graft vs host disease. These were managed with uncemented cup and cage total hip arthroplasty and stabilization of posterior column with plating. Osteonecrosis of the acetabulum is an uncommon musculoskeletal complication of chronic graft vs host disease. The orthopedic impact of this disease should not be overlooked. Surgical intervention with this construct can provide necessary stability to improve patient function.
Introduction
Graft vs host disease (GVHD) can manifest with multisystemic effects. GVHD can occur after allogeneic peripheral blood stem cell transplantation (PBSCT) and can have orthopedic implications such as osteonecrosis. The incidence of osteonecrosis after allogeneic stem cell transplantation is 4-19% [[1], [2], [3], [4]], and the risk is increased in patients with GVHD [5]. Most studies described involve the femoral head [[1], [2], [3], [4],[6], [7], [8], [9], [10], [11], [12]]. Osteonecrosis of the acetabulum, although rare, can lead to significant complications. These include interruption of the articular surface, insufficiency fracture, and protrusio acetabulum. Osteonecrosis of the acetabulum presents particular difficulty in fixation; poor bone quality can impact long-term patient outcomes and implant survivorship. Implant survivorship of THA in patients with allogeneic peripheral stem cell transplantation at 5 years is up to 93% [11], although it can be as low as 74.8% at 10 years [13]. Therefore, THA and fracture fixation in this setting require an approach that combines primary and revision arthroplasty skills to enable immediate weight bearing and pain relief. We present 2 cases of allogeneic PBSCT complicated by GVHD, with resultant acetabular osteonecrosis leading to acetabular insufficiency fracture and the surgical reconstruction that followed.
Case histories
Case 1
Case 1 is a 60-year-old woman with a history of diffuse large B-cell lymphoma who underwent 8 cycles of R-CHOP (rituximab, cyclophosphamide, hydroxydaunorubicin, oncovin [vincristine], and prednisolone). Her disease recurred and was treated with radiolabeled tositumomab with maintenance on rituximab. Relapse occurred once more, and she received salvage chemotherapy with R-ICE (rituximab, ifosfamide, etoposide, carboplatin) followed by autologous PBSCT. She underwent human leukocyte antigen (HLA)-matched allogeneic PBSCT after fludarabine-melphalan conditioning for relapse involving the central nervous system. This was complicated by GVHD, primarily affecting the gastrointestinal tract, that improved with 20-mg prednisone BID (0.5 mg/kg/day). After several dose escalations and relapses, she was tapered off prednisone three times, but after two severe episodes of pericarditis in the absence of steroids, she remained on 10-mg prednisone daily.
She presented to orthopedics with 1 month of acute, “aching” left-sided groin pain, global left hip weakness, difficulty ambulating (newly required a four-wheel walker), and ecchymosis in her inguinal crease. Physical examination revealed severe pain with hip internal and external rotation, as well as adduction and abduction. She could conduct passive hip flexion to 90 degrees but had pain with resisted hip flexion. Magnetic resonance imaging (MRI) of the pelvis and hip was obtained by her primary care provider before orthopedic referral, and AP of the pelvis was obtained as seen in Figure 1. Initial radiography in Figure 1 and MRI demonstrated comminuted minimally displaced fracture of the acetabulum involving the anterior and posterior columns with acetabular protrusio fracture and superior displacement of the femur of 3.5 cm. Interruption of the anterior and posterior columns is better visualized on iliac oblique and obturator oblique views seen in Figure 2, Figure 3.Figure 1 AP pelvis x-ray upon initial presentation showed displaced acetabular fracture and interruption of the femoroacetabular joint space.
Figure 2 Left obturator oblique better demonstrates insufficiency fracture of the posterior wall and anterior column.
Figure 3 Left iliac oblique further demonstrates osteonecrosis of the acetabulum and fracture extending through the posterior column.
Owing to severe disability and pain, and acetabular insufficiency (pathologic) fracture and joint collapse, posterior THA and posterior column stabilization was undertaken. Posterolateral approach was taken to optimize exposure of acetabular fracture and perform THA. Complex THA was performed using a cage construct. Pelvic size thwarted the use of a cup and cage construct. Findings include fragmentation of medial acetabulum with transverse-type insufficiency or pathologic fracture. Acetabular pathologic fracture was repaired, or stabilized, with 8-hole reconstruction plate bent for the left posterior column. Morselized femoral head autograft was placed at the base of the protruded acetabulum. Dome screws of antiprotrusio cage were placed before ilium cage screws, and 5 mL of synthetic bone graft and 30 mL of cancellous bone allograft was injected behind cage. Postoperative x-ray is demonstrated in Figure 4. Her postoperative activity restrictions included posterior hip precautions, and weightbearing as tolerated with an assistive device, with weaning as she was able.Figure 4 Day 0 postoperative AP pelvis x-ray. THA with cage construct and iliac plating.
At her 3-month follow-up visit, she was able to fully weight bear on her left lower extremity without pain or assistive device. Imaging obtained at that time is seen in Figure 5. At 5 months postoperatively, she underwent right total knee arthroplasty because of osteoarthritis present before the acetabular osteonecrosis and was progressing very well with physical therapy. Unfortunately, 16 months after complex left THA, she succumbed to complications of diffuse large B-cell lymphoma and GVHD.Figure 5 Three months postoperative AP pelvis. Revealed intact cage hardware, posterior column plating, and THA. Interval ileum healing was perceived.
Case 2
Case 2 is a 51-year-old woman with a history of acute myelogenous leukemia (AML), secondary myelodysplastic syndrome (MDS), GVHD, steroid-induced diabetes, and restrictive pulmonary disease. Autologous PBSCT was undertaken for AML 9 years before presentation. Matched unrelated donor PBSCT was conducted 1 year before presentation, after fludarabine-melphalan conditioning. GVHD characterized by gastrointestinal symptoms and florid skin rash complicated PBSCT 4 months before presentation. Steroid dosage during GVHD was started at 1 mg/kg/day (60 mg BID) with rapid resolution of symptoms leading to taper of steroids down to 0.5 mg/kg/day after 1 week. She developed recurrence of pulmonary symptoms and gastrointestinal symptoms with tapering and was restarted on 1 mg/kg/day.
She presented to orthopedics with 2 months of right hip pain, primarily in her deep inguinal crease. She required a walker for ambulation and was limited to very short distances because of pain. The examination was remarkable for BMI = 44, anasarca, and painful and limited right hip rotation with only 10 degrees of passive external and internal rotation. Radiographs taken at that time are seen in Figure 6. MRI performed at that time showed hypointensity of the supra-acetabular ilium with some T2 hyperintensity measuring 2.5 cm transverse × 2.4 cm AP suggestive of osteonecrosis, although without collapse. There was also osteonecrosis of the left femoral head, without collapse. Given significant comorbid conditions including bilateral lower extremity edema and severe open-leg ulcerations, surgery was not initially recommended.Figure 6 AP right hip obtained upon initial presentation to PCP with right hip pain. Revealing subchondral lucency of the right femoral head. No acetabular involvement noted.
Given ongoing severe pain and disability, she underwent medical optimization taking 13 months, although during that time, she developed progressive osteonecrosis of the acetabulum. The progression of this can be seen in Figure 7, Figure 8 obtained 1 month later. Her fracture initially demonstrated disruption of the right iliopubic line with sclerosis of the supraacetabular ilium with superior displacement of the femoral head into the ilium consistent with protrusio fracture. This was further evaluated with a CT of the pelvis, which demonstrated comminution of anterior and posterior columns and 14 gapping of articular surface along anterosuperior acetabulum and medullary sclerosis of the surrounding ilium. Follow-up radiography seen in Figure 8 demonstrated increased displacement of anterior and posterior columns with medial acetabular wall displacement measuring 8 mm. Figure 8 was ultimately used for templating her implants. Iliac oblique and obturator oblique views at this time seen in Figure 9, Figure 10 better demonstrate involvement of the anterior and posterior column, medial protrusion of the acetabulum. She was no longer able to ambulate with a walker and was wheelchair bound. Her steroid dose then was 5 mg, 5 days per week, and 10 mg, 2 days per week. Treatment options discussed with patient included Girdlestone resection, THA, and THA with antiprotrusio cage or cup and cage construct. Reconstruction was preferred by patient over Girdlestone resection as she was hoping to resume ambulation and activities of daily living (ADLs). Surgery was pursued with posterior THA, with cage construct and posterior column plating. This fixation was used as the size of the pelvis was not large enough to facilitate a cup/cage construct. Medial acetabulum bony deficiency with both columns, or transverse-type insufficiency fracture or pelvic discontinuity variant, was encountered. After femoral neck cut was made, A 7-hole pelvic reconstruction plate was contoured, and a posterior column plated from ischium to ileum with good fixation using 4 small fragment screws. After the cage was placed, 10 mL of synthetic bone graft with 30 mL of allograft cancellous chips was placed posteriorly to cage. There were no intraoperative complications, and she was discharged home after 2 days. Two weeks postoperatively, she had a 2-day admission for viral gastroenteritis. She also underwent kyphoplasty for three (T9, T11, L1) vertebral compression fractures 2 months postoperatively. There were no readmissions or emergency department visits for postoperative complications.Figure 7 AP pelvic x-ray 6 months since onset of symptoms and 10 months preoperatively. Revealing displaced healing right acetabular fracture. Disruption of the right iliopubic line and sclerosis of the right supra-acetabular ilium. Sclerosis of the right femoral head was also observed.
Figure 8 AP pelvis x-ray 13 months since onset of symptoms and 1.5 months preoperatively. Showing comminuted displaced right acetabular transverse fracture also involving the posterior and medial acetabular walls. Right femoral head is also eroded and aspherical. This film was used for templating.
Figure 9 Right iliac oblique x-ray 13 months since onset of symptoms and 1.5 months preoperatively demonstrating transverse plus posterior acetabular wall fracture with 1.5 cm medial displacement of medial acetabular wall.
Figure 10 Right obturator oblique x-ray 13 months since onset of symptoms and 1.5 months preoperatively. Further demonstrating comminuted posterior acetabular wall insufficiency fracture, aspherical and eroded femoral head, and some bony callus.
One-month postoperatively, her pain was decreasing, and function with ADLs increased, although she required a walker because of back pain and deconditioning. Her gait was smooth, not antalgic, with the walker. Two views of AP pelvis performed at that time are seen in Figure 11. One-year postoperatively, her pain had resolved, she still required a walker, and she was noted to have Trendelenburg gait. AP pelvis 1 year postoperatively, seen in Figure 12, showed well-positioned THA with no lucencies or subsidence. Unfortunately, 3 years postoperatively, she died of causes related to her MDS and GVHD.Figure 11 Portable pelvis x-ray 1-month postoperatively. Intact cup and cage construct implants, near anatomic alignment of acetabular fracture.
Figure 12 AP pelvis x-rays 1-year postoperatively. Interval acetabular healing was seen. Diffuse osteopenia but no evidence of implant failure.
Discussion
Patients with hematologic malignancies are having increased remission and survivorship after autologous and allogenic hematopoietic stem cell transplantations [14,15]. Allogeneic stem cell transplantation is unique as opposed to autologous transplant as it can lead to GVHD. GVHD is a systemic immune reaction by donor cells against host cells [16]. Several studies have demonstrated the increased risk of osteonecrosis because of GVHD [5,9,11,17,18]. GVHD is thought to cause osteonecrosis because of an inflammatory process in the intraosseous vasculature. Sixou et al. [19] found histologic evidence of vasculitis attributed to GVHD. This vasculitis exacerbates risk factors associated with osteonecrosis inclusive to patients with hematologic malignancies including systemic glucocorticoids, chemotherapeutics, and irradiation [5].
Unique to the presented cases is osteonecrosis of the acetabulum and the timeline to develop osteonecrosis. Case 1 took 5 years for manifestation of acetabular osteonecrosis after initiation of steroids for GVHD. Case 2 took 13 months until acetabular osteonecrosis began after onset of GVHD. In 11 patients (19 hips, 8 patients with bilateral osteonecrosis) studied by Schulte and Beelen, onset of osteonecrosis after allogeneic stem cell transplant ranged from 5 to 57 months, with an average of 25 months [9,18]. However, all these cases were of the femoral head, and the hematologic malignancies were AML, MDS, CML, and ALL. It is unclear in the presented cases what circumstances led to osteonecrosis of the acetabulum. Location and timeline could be attributed to age. Bizot et al. [17] had 16 patients with osteonecrosis secondary to GVHD, although the oldest patient was 47 years old at the time of surgery (average age 13 ± 8 years). The patients presented were 60 and 52 years old at the time of surgery.
Several other studies have identified osteonecrosis risk factors in hematologic malignancies; Schulte and Beelen demonstrated that the most impactful risk factors were chronic GVHD and cumulative steroid intake, followed by female gender, younger age, and conditioning therapy before transplant. Advanced disease stages, bone mineral density, and body composition did not have a significant impact on osteonecrosis [9,18]. The disease process of lymphoma itself may contribute; Chalmers et al. showed that lymphoma was the underlying diagnosis in 33% of THAs in patients with a history of stem cell transplant. However, not all of these patients had a history of GVHD [13].
In these cases, owing to the insufficiency fractures of the acetabular with effective pelvic discontinuity (PD) and the tenuous vascular supply of surrounding bone, THA was conducted with cage construct and bridge plating of the posterior column. This construct has shown efficacy in cases with PD and severe acetabular bone loss in revision THA [[20], [21], [22], [23]]. Plating is primarily studied in revision arthroplasty cases with PD [24,25]. Plating was chosen to restore continuity, optimize contact of viable bone, and add stability to the reconstruction. This fixation technique of posterior column plating with antiprotrusion cage placement led to stability with improved ADLs, restoration of ambulation with full weightbearing, and resolution of pain at 1 year for both cases. Certainly, the perioperative risk of significant surgical or medical complications is high for patients with GVHD; therefore, this technique should be considered in situations with tenuous blood supply and insufficiency fractures in the setting of hematologic malignancy and GVHD.
Summary
These cases are unique reports of osteonecrosis focal to the acetabulum, in patients with history of stem cell transplant and subsequent GVHD. The impact of this disease process should not be overlooked in patients with hematologic malignances and GVHD. Surgical treatment with multifaceted construct, in these cases with an antiprotrusio cage bolstered by posterior column plating, can relieve pain and improve mobility.
Conflict of interest
Dr. Schabel obtains research support from Zimmer Biomet, unrelated to this work. She is also a board member for the Oregon Association of Orthopaedists.
Supplementary data
Conflict of Interest Statement for Nielsen
Conflict of Interest Statement for Schabel
Statements of informed consent were obtained from patients and family members of deceased patients. | FLUDARABINE PHOSPHATE, MELPHALAN HYDROCHLORIDE | DrugsGivenReaction | CC BY-NC-ND | 33521198 | 18,921,443 | 2021-02 |
Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Joint dislocation'. | Acetabular Insufficiency Fractures in the Setting of Graft vs Host Disease: A Report of Two Cases.
We report a case series of 2 patients with unilateral acetabular insufficiency fractures who received allogeneic peripheral blood stem cell transplantation for hematologic malignancies complicated by chronic graft vs host disease. These were managed with uncemented cup and cage total hip arthroplasty and stabilization of posterior column with plating. Osteonecrosis of the acetabulum is an uncommon musculoskeletal complication of chronic graft vs host disease. The orthopedic impact of this disease should not be overlooked. Surgical intervention with this construct can provide necessary stability to improve patient function.
Introduction
Graft vs host disease (GVHD) can manifest with multisystemic effects. GVHD can occur after allogeneic peripheral blood stem cell transplantation (PBSCT) and can have orthopedic implications such as osteonecrosis. The incidence of osteonecrosis after allogeneic stem cell transplantation is 4-19% [[1], [2], [3], [4]], and the risk is increased in patients with GVHD [5]. Most studies described involve the femoral head [[1], [2], [3], [4],[6], [7], [8], [9], [10], [11], [12]]. Osteonecrosis of the acetabulum, although rare, can lead to significant complications. These include interruption of the articular surface, insufficiency fracture, and protrusio acetabulum. Osteonecrosis of the acetabulum presents particular difficulty in fixation; poor bone quality can impact long-term patient outcomes and implant survivorship. Implant survivorship of THA in patients with allogeneic peripheral stem cell transplantation at 5 years is up to 93% [11], although it can be as low as 74.8% at 10 years [13]. Therefore, THA and fracture fixation in this setting require an approach that combines primary and revision arthroplasty skills to enable immediate weight bearing and pain relief. We present 2 cases of allogeneic PBSCT complicated by GVHD, with resultant acetabular osteonecrosis leading to acetabular insufficiency fracture and the surgical reconstruction that followed.
Case histories
Case 1
Case 1 is a 60-year-old woman with a history of diffuse large B-cell lymphoma who underwent 8 cycles of R-CHOP (rituximab, cyclophosphamide, hydroxydaunorubicin, oncovin [vincristine], and prednisolone). Her disease recurred and was treated with radiolabeled tositumomab with maintenance on rituximab. Relapse occurred once more, and she received salvage chemotherapy with R-ICE (rituximab, ifosfamide, etoposide, carboplatin) followed by autologous PBSCT. She underwent human leukocyte antigen (HLA)-matched allogeneic PBSCT after fludarabine-melphalan conditioning for relapse involving the central nervous system. This was complicated by GVHD, primarily affecting the gastrointestinal tract, that improved with 20-mg prednisone BID (0.5 mg/kg/day). After several dose escalations and relapses, she was tapered off prednisone three times, but after two severe episodes of pericarditis in the absence of steroids, she remained on 10-mg prednisone daily.
She presented to orthopedics with 1 month of acute, “aching” left-sided groin pain, global left hip weakness, difficulty ambulating (newly required a four-wheel walker), and ecchymosis in her inguinal crease. Physical examination revealed severe pain with hip internal and external rotation, as well as adduction and abduction. She could conduct passive hip flexion to 90 degrees but had pain with resisted hip flexion. Magnetic resonance imaging (MRI) of the pelvis and hip was obtained by her primary care provider before orthopedic referral, and AP of the pelvis was obtained as seen in Figure 1. Initial radiography in Figure 1 and MRI demonstrated comminuted minimally displaced fracture of the acetabulum involving the anterior and posterior columns with acetabular protrusio fracture and superior displacement of the femur of 3.5 cm. Interruption of the anterior and posterior columns is better visualized on iliac oblique and obturator oblique views seen in Figure 2, Figure 3.Figure 1 AP pelvis x-ray upon initial presentation showed displaced acetabular fracture and interruption of the femoroacetabular joint space.
Figure 2 Left obturator oblique better demonstrates insufficiency fracture of the posterior wall and anterior column.
Figure 3 Left iliac oblique further demonstrates osteonecrosis of the acetabulum and fracture extending through the posterior column.
Owing to severe disability and pain, and acetabular insufficiency (pathologic) fracture and joint collapse, posterior THA and posterior column stabilization was undertaken. Posterolateral approach was taken to optimize exposure of acetabular fracture and perform THA. Complex THA was performed using a cage construct. Pelvic size thwarted the use of a cup and cage construct. Findings include fragmentation of medial acetabulum with transverse-type insufficiency or pathologic fracture. Acetabular pathologic fracture was repaired, or stabilized, with 8-hole reconstruction plate bent for the left posterior column. Morselized femoral head autograft was placed at the base of the protruded acetabulum. Dome screws of antiprotrusio cage were placed before ilium cage screws, and 5 mL of synthetic bone graft and 30 mL of cancellous bone allograft was injected behind cage. Postoperative x-ray is demonstrated in Figure 4. Her postoperative activity restrictions included posterior hip precautions, and weightbearing as tolerated with an assistive device, with weaning as she was able.Figure 4 Day 0 postoperative AP pelvis x-ray. THA with cage construct and iliac plating.
At her 3-month follow-up visit, she was able to fully weight bear on her left lower extremity without pain or assistive device. Imaging obtained at that time is seen in Figure 5. At 5 months postoperatively, she underwent right total knee arthroplasty because of osteoarthritis present before the acetabular osteonecrosis and was progressing very well with physical therapy. Unfortunately, 16 months after complex left THA, she succumbed to complications of diffuse large B-cell lymphoma and GVHD.Figure 5 Three months postoperative AP pelvis. Revealed intact cage hardware, posterior column plating, and THA. Interval ileum healing was perceived.
Case 2
Case 2 is a 51-year-old woman with a history of acute myelogenous leukemia (AML), secondary myelodysplastic syndrome (MDS), GVHD, steroid-induced diabetes, and restrictive pulmonary disease. Autologous PBSCT was undertaken for AML 9 years before presentation. Matched unrelated donor PBSCT was conducted 1 year before presentation, after fludarabine-melphalan conditioning. GVHD characterized by gastrointestinal symptoms and florid skin rash complicated PBSCT 4 months before presentation. Steroid dosage during GVHD was started at 1 mg/kg/day (60 mg BID) with rapid resolution of symptoms leading to taper of steroids down to 0.5 mg/kg/day after 1 week. She developed recurrence of pulmonary symptoms and gastrointestinal symptoms with tapering and was restarted on 1 mg/kg/day.
She presented to orthopedics with 2 months of right hip pain, primarily in her deep inguinal crease. She required a walker for ambulation and was limited to very short distances because of pain. The examination was remarkable for BMI = 44, anasarca, and painful and limited right hip rotation with only 10 degrees of passive external and internal rotation. Radiographs taken at that time are seen in Figure 6. MRI performed at that time showed hypointensity of the supra-acetabular ilium with some T2 hyperintensity measuring 2.5 cm transverse × 2.4 cm AP suggestive of osteonecrosis, although without collapse. There was also osteonecrosis of the left femoral head, without collapse. Given significant comorbid conditions including bilateral lower extremity edema and severe open-leg ulcerations, surgery was not initially recommended.Figure 6 AP right hip obtained upon initial presentation to PCP with right hip pain. Revealing subchondral lucency of the right femoral head. No acetabular involvement noted.
Given ongoing severe pain and disability, she underwent medical optimization taking 13 months, although during that time, she developed progressive osteonecrosis of the acetabulum. The progression of this can be seen in Figure 7, Figure 8 obtained 1 month later. Her fracture initially demonstrated disruption of the right iliopubic line with sclerosis of the supraacetabular ilium with superior displacement of the femoral head into the ilium consistent with protrusio fracture. This was further evaluated with a CT of the pelvis, which demonstrated comminution of anterior and posterior columns and 14 gapping of articular surface along anterosuperior acetabulum and medullary sclerosis of the surrounding ilium. Follow-up radiography seen in Figure 8 demonstrated increased displacement of anterior and posterior columns with medial acetabular wall displacement measuring 8 mm. Figure 8 was ultimately used for templating her implants. Iliac oblique and obturator oblique views at this time seen in Figure 9, Figure 10 better demonstrate involvement of the anterior and posterior column, medial protrusion of the acetabulum. She was no longer able to ambulate with a walker and was wheelchair bound. Her steroid dose then was 5 mg, 5 days per week, and 10 mg, 2 days per week. Treatment options discussed with patient included Girdlestone resection, THA, and THA with antiprotrusio cage or cup and cage construct. Reconstruction was preferred by patient over Girdlestone resection as she was hoping to resume ambulation and activities of daily living (ADLs). Surgery was pursued with posterior THA, with cage construct and posterior column plating. This fixation was used as the size of the pelvis was not large enough to facilitate a cup/cage construct. Medial acetabulum bony deficiency with both columns, or transverse-type insufficiency fracture or pelvic discontinuity variant, was encountered. After femoral neck cut was made, A 7-hole pelvic reconstruction plate was contoured, and a posterior column plated from ischium to ileum with good fixation using 4 small fragment screws. After the cage was placed, 10 mL of synthetic bone graft with 30 mL of allograft cancellous chips was placed posteriorly to cage. There were no intraoperative complications, and she was discharged home after 2 days. Two weeks postoperatively, she had a 2-day admission for viral gastroenteritis. She also underwent kyphoplasty for three (T9, T11, L1) vertebral compression fractures 2 months postoperatively. There were no readmissions or emergency department visits for postoperative complications.Figure 7 AP pelvic x-ray 6 months since onset of symptoms and 10 months preoperatively. Revealing displaced healing right acetabular fracture. Disruption of the right iliopubic line and sclerosis of the right supra-acetabular ilium. Sclerosis of the right femoral head was also observed.
Figure 8 AP pelvis x-ray 13 months since onset of symptoms and 1.5 months preoperatively. Showing comminuted displaced right acetabular transverse fracture also involving the posterior and medial acetabular walls. Right femoral head is also eroded and aspherical. This film was used for templating.
Figure 9 Right iliac oblique x-ray 13 months since onset of symptoms and 1.5 months preoperatively demonstrating transverse plus posterior acetabular wall fracture with 1.5 cm medial displacement of medial acetabular wall.
Figure 10 Right obturator oblique x-ray 13 months since onset of symptoms and 1.5 months preoperatively. Further demonstrating comminuted posterior acetabular wall insufficiency fracture, aspherical and eroded femoral head, and some bony callus.
One-month postoperatively, her pain was decreasing, and function with ADLs increased, although she required a walker because of back pain and deconditioning. Her gait was smooth, not antalgic, with the walker. Two views of AP pelvis performed at that time are seen in Figure 11. One-year postoperatively, her pain had resolved, she still required a walker, and she was noted to have Trendelenburg gait. AP pelvis 1 year postoperatively, seen in Figure 12, showed well-positioned THA with no lucencies or subsidence. Unfortunately, 3 years postoperatively, she died of causes related to her MDS and GVHD.Figure 11 Portable pelvis x-ray 1-month postoperatively. Intact cup and cage construct implants, near anatomic alignment of acetabular fracture.
Figure 12 AP pelvis x-rays 1-year postoperatively. Interval acetabular healing was seen. Diffuse osteopenia but no evidence of implant failure.
Discussion
Patients with hematologic malignancies are having increased remission and survivorship after autologous and allogenic hematopoietic stem cell transplantations [14,15]. Allogeneic stem cell transplantation is unique as opposed to autologous transplant as it can lead to GVHD. GVHD is a systemic immune reaction by donor cells against host cells [16]. Several studies have demonstrated the increased risk of osteonecrosis because of GVHD [5,9,11,17,18]. GVHD is thought to cause osteonecrosis because of an inflammatory process in the intraosseous vasculature. Sixou et al. [19] found histologic evidence of vasculitis attributed to GVHD. This vasculitis exacerbates risk factors associated with osteonecrosis inclusive to patients with hematologic malignancies including systemic glucocorticoids, chemotherapeutics, and irradiation [5].
Unique to the presented cases is osteonecrosis of the acetabulum and the timeline to develop osteonecrosis. Case 1 took 5 years for manifestation of acetabular osteonecrosis after initiation of steroids for GVHD. Case 2 took 13 months until acetabular osteonecrosis began after onset of GVHD. In 11 patients (19 hips, 8 patients with bilateral osteonecrosis) studied by Schulte and Beelen, onset of osteonecrosis after allogeneic stem cell transplant ranged from 5 to 57 months, with an average of 25 months [9,18]. However, all these cases were of the femoral head, and the hematologic malignancies were AML, MDS, CML, and ALL. It is unclear in the presented cases what circumstances led to osteonecrosis of the acetabulum. Location and timeline could be attributed to age. Bizot et al. [17] had 16 patients with osteonecrosis secondary to GVHD, although the oldest patient was 47 years old at the time of surgery (average age 13 ± 8 years). The patients presented were 60 and 52 years old at the time of surgery.
Several other studies have identified osteonecrosis risk factors in hematologic malignancies; Schulte and Beelen demonstrated that the most impactful risk factors were chronic GVHD and cumulative steroid intake, followed by female gender, younger age, and conditioning therapy before transplant. Advanced disease stages, bone mineral density, and body composition did not have a significant impact on osteonecrosis [9,18]. The disease process of lymphoma itself may contribute; Chalmers et al. showed that lymphoma was the underlying diagnosis in 33% of THAs in patients with a history of stem cell transplant. However, not all of these patients had a history of GVHD [13].
In these cases, owing to the insufficiency fractures of the acetabular with effective pelvic discontinuity (PD) and the tenuous vascular supply of surrounding bone, THA was conducted with cage construct and bridge plating of the posterior column. This construct has shown efficacy in cases with PD and severe acetabular bone loss in revision THA [[20], [21], [22], [23]]. Plating is primarily studied in revision arthroplasty cases with PD [24,25]. Plating was chosen to restore continuity, optimize contact of viable bone, and add stability to the reconstruction. This fixation technique of posterior column plating with antiprotrusion cage placement led to stability with improved ADLs, restoration of ambulation with full weightbearing, and resolution of pain at 1 year for both cases. Certainly, the perioperative risk of significant surgical or medical complications is high for patients with GVHD; therefore, this technique should be considered in situations with tenuous blood supply and insufficiency fractures in the setting of hematologic malignancy and GVHD.
Summary
These cases are unique reports of osteonecrosis focal to the acetabulum, in patients with history of stem cell transplant and subsequent GVHD. The impact of this disease process should not be overlooked in patients with hematologic malignances and GVHD. Surgical treatment with multifaceted construct, in these cases with an antiprotrusio cage bolstered by posterior column plating, can relieve pain and improve mobility.
Conflict of interest
Dr. Schabel obtains research support from Zimmer Biomet, unrelated to this work. She is also a board member for the Oregon Association of Orthopaedists.
Supplementary data
Conflict of Interest Statement for Nielsen
Conflict of Interest Statement for Schabel
Statements of informed consent were obtained from patients and family members of deceased patients. | CARBOPLATIN, CYCLOPHOSPHAMIDE, DOXORUBICIN, ETOPOSIDE, FLUDARABINE PHOSPHATE, IFOSFAMIDE, MELPHALAN, PREDNISOLONE, PREDNISONE, RITUXIMAB, TOSITUMOMAB, VINCRISTINE SULFATE | DrugsGivenReaction | CC BY-NC-ND | 33521198 | 18,981,647 | 2021-02 |
Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Oedema peripheral'. | Acetabular Insufficiency Fractures in the Setting of Graft vs Host Disease: A Report of Two Cases.
We report a case series of 2 patients with unilateral acetabular insufficiency fractures who received allogeneic peripheral blood stem cell transplantation for hematologic malignancies complicated by chronic graft vs host disease. These were managed with uncemented cup and cage total hip arthroplasty and stabilization of posterior column with plating. Osteonecrosis of the acetabulum is an uncommon musculoskeletal complication of chronic graft vs host disease. The orthopedic impact of this disease should not be overlooked. Surgical intervention with this construct can provide necessary stability to improve patient function.
Introduction
Graft vs host disease (GVHD) can manifest with multisystemic effects. GVHD can occur after allogeneic peripheral blood stem cell transplantation (PBSCT) and can have orthopedic implications such as osteonecrosis. The incidence of osteonecrosis after allogeneic stem cell transplantation is 4-19% [[1], [2], [3], [4]], and the risk is increased in patients with GVHD [5]. Most studies described involve the femoral head [[1], [2], [3], [4],[6], [7], [8], [9], [10], [11], [12]]. Osteonecrosis of the acetabulum, although rare, can lead to significant complications. These include interruption of the articular surface, insufficiency fracture, and protrusio acetabulum. Osteonecrosis of the acetabulum presents particular difficulty in fixation; poor bone quality can impact long-term patient outcomes and implant survivorship. Implant survivorship of THA in patients with allogeneic peripheral stem cell transplantation at 5 years is up to 93% [11], although it can be as low as 74.8% at 10 years [13]. Therefore, THA and fracture fixation in this setting require an approach that combines primary and revision arthroplasty skills to enable immediate weight bearing and pain relief. We present 2 cases of allogeneic PBSCT complicated by GVHD, with resultant acetabular osteonecrosis leading to acetabular insufficiency fracture and the surgical reconstruction that followed.
Case histories
Case 1
Case 1 is a 60-year-old woman with a history of diffuse large B-cell lymphoma who underwent 8 cycles of R-CHOP (rituximab, cyclophosphamide, hydroxydaunorubicin, oncovin [vincristine], and prednisolone). Her disease recurred and was treated with radiolabeled tositumomab with maintenance on rituximab. Relapse occurred once more, and she received salvage chemotherapy with R-ICE (rituximab, ifosfamide, etoposide, carboplatin) followed by autologous PBSCT. She underwent human leukocyte antigen (HLA)-matched allogeneic PBSCT after fludarabine-melphalan conditioning for relapse involving the central nervous system. This was complicated by GVHD, primarily affecting the gastrointestinal tract, that improved with 20-mg prednisone BID (0.5 mg/kg/day). After several dose escalations and relapses, she was tapered off prednisone three times, but after two severe episodes of pericarditis in the absence of steroids, she remained on 10-mg prednisone daily.
She presented to orthopedics with 1 month of acute, “aching” left-sided groin pain, global left hip weakness, difficulty ambulating (newly required a four-wheel walker), and ecchymosis in her inguinal crease. Physical examination revealed severe pain with hip internal and external rotation, as well as adduction and abduction. She could conduct passive hip flexion to 90 degrees but had pain with resisted hip flexion. Magnetic resonance imaging (MRI) of the pelvis and hip was obtained by her primary care provider before orthopedic referral, and AP of the pelvis was obtained as seen in Figure 1. Initial radiography in Figure 1 and MRI demonstrated comminuted minimally displaced fracture of the acetabulum involving the anterior and posterior columns with acetabular protrusio fracture and superior displacement of the femur of 3.5 cm. Interruption of the anterior and posterior columns is better visualized on iliac oblique and obturator oblique views seen in Figure 2, Figure 3.Figure 1 AP pelvis x-ray upon initial presentation showed displaced acetabular fracture and interruption of the femoroacetabular joint space.
Figure 2 Left obturator oblique better demonstrates insufficiency fracture of the posterior wall and anterior column.
Figure 3 Left iliac oblique further demonstrates osteonecrosis of the acetabulum and fracture extending through the posterior column.
Owing to severe disability and pain, and acetabular insufficiency (pathologic) fracture and joint collapse, posterior THA and posterior column stabilization was undertaken. Posterolateral approach was taken to optimize exposure of acetabular fracture and perform THA. Complex THA was performed using a cage construct. Pelvic size thwarted the use of a cup and cage construct. Findings include fragmentation of medial acetabulum with transverse-type insufficiency or pathologic fracture. Acetabular pathologic fracture was repaired, or stabilized, with 8-hole reconstruction plate bent for the left posterior column. Morselized femoral head autograft was placed at the base of the protruded acetabulum. Dome screws of antiprotrusio cage were placed before ilium cage screws, and 5 mL of synthetic bone graft and 30 mL of cancellous bone allograft was injected behind cage. Postoperative x-ray is demonstrated in Figure 4. Her postoperative activity restrictions included posterior hip precautions, and weightbearing as tolerated with an assistive device, with weaning as she was able.Figure 4 Day 0 postoperative AP pelvis x-ray. THA with cage construct and iliac plating.
At her 3-month follow-up visit, she was able to fully weight bear on her left lower extremity without pain or assistive device. Imaging obtained at that time is seen in Figure 5. At 5 months postoperatively, she underwent right total knee arthroplasty because of osteoarthritis present before the acetabular osteonecrosis and was progressing very well with physical therapy. Unfortunately, 16 months after complex left THA, she succumbed to complications of diffuse large B-cell lymphoma and GVHD.Figure 5 Three months postoperative AP pelvis. Revealed intact cage hardware, posterior column plating, and THA. Interval ileum healing was perceived.
Case 2
Case 2 is a 51-year-old woman with a history of acute myelogenous leukemia (AML), secondary myelodysplastic syndrome (MDS), GVHD, steroid-induced diabetes, and restrictive pulmonary disease. Autologous PBSCT was undertaken for AML 9 years before presentation. Matched unrelated donor PBSCT was conducted 1 year before presentation, after fludarabine-melphalan conditioning. GVHD characterized by gastrointestinal symptoms and florid skin rash complicated PBSCT 4 months before presentation. Steroid dosage during GVHD was started at 1 mg/kg/day (60 mg BID) with rapid resolution of symptoms leading to taper of steroids down to 0.5 mg/kg/day after 1 week. She developed recurrence of pulmonary symptoms and gastrointestinal symptoms with tapering and was restarted on 1 mg/kg/day.
She presented to orthopedics with 2 months of right hip pain, primarily in her deep inguinal crease. She required a walker for ambulation and was limited to very short distances because of pain. The examination was remarkable for BMI = 44, anasarca, and painful and limited right hip rotation with only 10 degrees of passive external and internal rotation. Radiographs taken at that time are seen in Figure 6. MRI performed at that time showed hypointensity of the supra-acetabular ilium with some T2 hyperintensity measuring 2.5 cm transverse × 2.4 cm AP suggestive of osteonecrosis, although without collapse. There was also osteonecrosis of the left femoral head, without collapse. Given significant comorbid conditions including bilateral lower extremity edema and severe open-leg ulcerations, surgery was not initially recommended.Figure 6 AP right hip obtained upon initial presentation to PCP with right hip pain. Revealing subchondral lucency of the right femoral head. No acetabular involvement noted.
Given ongoing severe pain and disability, she underwent medical optimization taking 13 months, although during that time, she developed progressive osteonecrosis of the acetabulum. The progression of this can be seen in Figure 7, Figure 8 obtained 1 month later. Her fracture initially demonstrated disruption of the right iliopubic line with sclerosis of the supraacetabular ilium with superior displacement of the femoral head into the ilium consistent with protrusio fracture. This was further evaluated with a CT of the pelvis, which demonstrated comminution of anterior and posterior columns and 14 gapping of articular surface along anterosuperior acetabulum and medullary sclerosis of the surrounding ilium. Follow-up radiography seen in Figure 8 demonstrated increased displacement of anterior and posterior columns with medial acetabular wall displacement measuring 8 mm. Figure 8 was ultimately used for templating her implants. Iliac oblique and obturator oblique views at this time seen in Figure 9, Figure 10 better demonstrate involvement of the anterior and posterior column, medial protrusion of the acetabulum. She was no longer able to ambulate with a walker and was wheelchair bound. Her steroid dose then was 5 mg, 5 days per week, and 10 mg, 2 days per week. Treatment options discussed with patient included Girdlestone resection, THA, and THA with antiprotrusio cage or cup and cage construct. Reconstruction was preferred by patient over Girdlestone resection as she was hoping to resume ambulation and activities of daily living (ADLs). Surgery was pursued with posterior THA, with cage construct and posterior column plating. This fixation was used as the size of the pelvis was not large enough to facilitate a cup/cage construct. Medial acetabulum bony deficiency with both columns, or transverse-type insufficiency fracture or pelvic discontinuity variant, was encountered. After femoral neck cut was made, A 7-hole pelvic reconstruction plate was contoured, and a posterior column plated from ischium to ileum with good fixation using 4 small fragment screws. After the cage was placed, 10 mL of synthetic bone graft with 30 mL of allograft cancellous chips was placed posteriorly to cage. There were no intraoperative complications, and she was discharged home after 2 days. Two weeks postoperatively, she had a 2-day admission for viral gastroenteritis. She also underwent kyphoplasty for three (T9, T11, L1) vertebral compression fractures 2 months postoperatively. There were no readmissions or emergency department visits for postoperative complications.Figure 7 AP pelvic x-ray 6 months since onset of symptoms and 10 months preoperatively. Revealing displaced healing right acetabular fracture. Disruption of the right iliopubic line and sclerosis of the right supra-acetabular ilium. Sclerosis of the right femoral head was also observed.
Figure 8 AP pelvis x-ray 13 months since onset of symptoms and 1.5 months preoperatively. Showing comminuted displaced right acetabular transverse fracture also involving the posterior and medial acetabular walls. Right femoral head is also eroded and aspherical. This film was used for templating.
Figure 9 Right iliac oblique x-ray 13 months since onset of symptoms and 1.5 months preoperatively demonstrating transverse plus posterior acetabular wall fracture with 1.5 cm medial displacement of medial acetabular wall.
Figure 10 Right obturator oblique x-ray 13 months since onset of symptoms and 1.5 months preoperatively. Further demonstrating comminuted posterior acetabular wall insufficiency fracture, aspherical and eroded femoral head, and some bony callus.
One-month postoperatively, her pain was decreasing, and function with ADLs increased, although she required a walker because of back pain and deconditioning. Her gait was smooth, not antalgic, with the walker. Two views of AP pelvis performed at that time are seen in Figure 11. One-year postoperatively, her pain had resolved, she still required a walker, and she was noted to have Trendelenburg gait. AP pelvis 1 year postoperatively, seen in Figure 12, showed well-positioned THA with no lucencies or subsidence. Unfortunately, 3 years postoperatively, she died of causes related to her MDS and GVHD.Figure 11 Portable pelvis x-ray 1-month postoperatively. Intact cup and cage construct implants, near anatomic alignment of acetabular fracture.
Figure 12 AP pelvis x-rays 1-year postoperatively. Interval acetabular healing was seen. Diffuse osteopenia but no evidence of implant failure.
Discussion
Patients with hematologic malignancies are having increased remission and survivorship after autologous and allogenic hematopoietic stem cell transplantations [14,15]. Allogeneic stem cell transplantation is unique as opposed to autologous transplant as it can lead to GVHD. GVHD is a systemic immune reaction by donor cells against host cells [16]. Several studies have demonstrated the increased risk of osteonecrosis because of GVHD [5,9,11,17,18]. GVHD is thought to cause osteonecrosis because of an inflammatory process in the intraosseous vasculature. Sixou et al. [19] found histologic evidence of vasculitis attributed to GVHD. This vasculitis exacerbates risk factors associated with osteonecrosis inclusive to patients with hematologic malignancies including systemic glucocorticoids, chemotherapeutics, and irradiation [5].
Unique to the presented cases is osteonecrosis of the acetabulum and the timeline to develop osteonecrosis. Case 1 took 5 years for manifestation of acetabular osteonecrosis after initiation of steroids for GVHD. Case 2 took 13 months until acetabular osteonecrosis began after onset of GVHD. In 11 patients (19 hips, 8 patients with bilateral osteonecrosis) studied by Schulte and Beelen, onset of osteonecrosis after allogeneic stem cell transplant ranged from 5 to 57 months, with an average of 25 months [9,18]. However, all these cases were of the femoral head, and the hematologic malignancies were AML, MDS, CML, and ALL. It is unclear in the presented cases what circumstances led to osteonecrosis of the acetabulum. Location and timeline could be attributed to age. Bizot et al. [17] had 16 patients with osteonecrosis secondary to GVHD, although the oldest patient was 47 years old at the time of surgery (average age 13 ± 8 years). The patients presented were 60 and 52 years old at the time of surgery.
Several other studies have identified osteonecrosis risk factors in hematologic malignancies; Schulte and Beelen demonstrated that the most impactful risk factors were chronic GVHD and cumulative steroid intake, followed by female gender, younger age, and conditioning therapy before transplant. Advanced disease stages, bone mineral density, and body composition did not have a significant impact on osteonecrosis [9,18]. The disease process of lymphoma itself may contribute; Chalmers et al. showed that lymphoma was the underlying diagnosis in 33% of THAs in patients with a history of stem cell transplant. However, not all of these patients had a history of GVHD [13].
In these cases, owing to the insufficiency fractures of the acetabular with effective pelvic discontinuity (PD) and the tenuous vascular supply of surrounding bone, THA was conducted with cage construct and bridge plating of the posterior column. This construct has shown efficacy in cases with PD and severe acetabular bone loss in revision THA [[20], [21], [22], [23]]. Plating is primarily studied in revision arthroplasty cases with PD [24,25]. Plating was chosen to restore continuity, optimize contact of viable bone, and add stability to the reconstruction. This fixation technique of posterior column plating with antiprotrusion cage placement led to stability with improved ADLs, restoration of ambulation with full weightbearing, and resolution of pain at 1 year for both cases. Certainly, the perioperative risk of significant surgical or medical complications is high for patients with GVHD; therefore, this technique should be considered in situations with tenuous blood supply and insufficiency fractures in the setting of hematologic malignancy and GVHD.
Summary
These cases are unique reports of osteonecrosis focal to the acetabulum, in patients with history of stem cell transplant and subsequent GVHD. The impact of this disease process should not be overlooked in patients with hematologic malignances and GVHD. Surgical treatment with multifaceted construct, in these cases with an antiprotrusio cage bolstered by posterior column plating, can relieve pain and improve mobility.
Conflict of interest
Dr. Schabel obtains research support from Zimmer Biomet, unrelated to this work. She is also a board member for the Oregon Association of Orthopaedists.
Supplementary data
Conflict of Interest Statement for Nielsen
Conflict of Interest Statement for Schabel
Statements of informed consent were obtained from patients and family members of deceased patients. | FLUDARABINE PHOSPHATE, MELPHALAN HYDROCHLORIDE | DrugsGivenReaction | CC BY-NC-ND | 33521198 | 18,921,443 | 2021-02 |
Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Ulcer'. | Acetabular Insufficiency Fractures in the Setting of Graft vs Host Disease: A Report of Two Cases.
We report a case series of 2 patients with unilateral acetabular insufficiency fractures who received allogeneic peripheral blood stem cell transplantation for hematologic malignancies complicated by chronic graft vs host disease. These were managed with uncemented cup and cage total hip arthroplasty and stabilization of posterior column with plating. Osteonecrosis of the acetabulum is an uncommon musculoskeletal complication of chronic graft vs host disease. The orthopedic impact of this disease should not be overlooked. Surgical intervention with this construct can provide necessary stability to improve patient function.
Introduction
Graft vs host disease (GVHD) can manifest with multisystemic effects. GVHD can occur after allogeneic peripheral blood stem cell transplantation (PBSCT) and can have orthopedic implications such as osteonecrosis. The incidence of osteonecrosis after allogeneic stem cell transplantation is 4-19% [[1], [2], [3], [4]], and the risk is increased in patients with GVHD [5]. Most studies described involve the femoral head [[1], [2], [3], [4],[6], [7], [8], [9], [10], [11], [12]]. Osteonecrosis of the acetabulum, although rare, can lead to significant complications. These include interruption of the articular surface, insufficiency fracture, and protrusio acetabulum. Osteonecrosis of the acetabulum presents particular difficulty in fixation; poor bone quality can impact long-term patient outcomes and implant survivorship. Implant survivorship of THA in patients with allogeneic peripheral stem cell transplantation at 5 years is up to 93% [11], although it can be as low as 74.8% at 10 years [13]. Therefore, THA and fracture fixation in this setting require an approach that combines primary and revision arthroplasty skills to enable immediate weight bearing and pain relief. We present 2 cases of allogeneic PBSCT complicated by GVHD, with resultant acetabular osteonecrosis leading to acetabular insufficiency fracture and the surgical reconstruction that followed.
Case histories
Case 1
Case 1 is a 60-year-old woman with a history of diffuse large B-cell lymphoma who underwent 8 cycles of R-CHOP (rituximab, cyclophosphamide, hydroxydaunorubicin, oncovin [vincristine], and prednisolone). Her disease recurred and was treated with radiolabeled tositumomab with maintenance on rituximab. Relapse occurred once more, and she received salvage chemotherapy with R-ICE (rituximab, ifosfamide, etoposide, carboplatin) followed by autologous PBSCT. She underwent human leukocyte antigen (HLA)-matched allogeneic PBSCT after fludarabine-melphalan conditioning for relapse involving the central nervous system. This was complicated by GVHD, primarily affecting the gastrointestinal tract, that improved with 20-mg prednisone BID (0.5 mg/kg/day). After several dose escalations and relapses, she was tapered off prednisone three times, but after two severe episodes of pericarditis in the absence of steroids, she remained on 10-mg prednisone daily.
She presented to orthopedics with 1 month of acute, “aching” left-sided groin pain, global left hip weakness, difficulty ambulating (newly required a four-wheel walker), and ecchymosis in her inguinal crease. Physical examination revealed severe pain with hip internal and external rotation, as well as adduction and abduction. She could conduct passive hip flexion to 90 degrees but had pain with resisted hip flexion. Magnetic resonance imaging (MRI) of the pelvis and hip was obtained by her primary care provider before orthopedic referral, and AP of the pelvis was obtained as seen in Figure 1. Initial radiography in Figure 1 and MRI demonstrated comminuted minimally displaced fracture of the acetabulum involving the anterior and posterior columns with acetabular protrusio fracture and superior displacement of the femur of 3.5 cm. Interruption of the anterior and posterior columns is better visualized on iliac oblique and obturator oblique views seen in Figure 2, Figure 3.Figure 1 AP pelvis x-ray upon initial presentation showed displaced acetabular fracture and interruption of the femoroacetabular joint space.
Figure 2 Left obturator oblique better demonstrates insufficiency fracture of the posterior wall and anterior column.
Figure 3 Left iliac oblique further demonstrates osteonecrosis of the acetabulum and fracture extending through the posterior column.
Owing to severe disability and pain, and acetabular insufficiency (pathologic) fracture and joint collapse, posterior THA and posterior column stabilization was undertaken. Posterolateral approach was taken to optimize exposure of acetabular fracture and perform THA. Complex THA was performed using a cage construct. Pelvic size thwarted the use of a cup and cage construct. Findings include fragmentation of medial acetabulum with transverse-type insufficiency or pathologic fracture. Acetabular pathologic fracture was repaired, or stabilized, with 8-hole reconstruction plate bent for the left posterior column. Morselized femoral head autograft was placed at the base of the protruded acetabulum. Dome screws of antiprotrusio cage were placed before ilium cage screws, and 5 mL of synthetic bone graft and 30 mL of cancellous bone allograft was injected behind cage. Postoperative x-ray is demonstrated in Figure 4. Her postoperative activity restrictions included posterior hip precautions, and weightbearing as tolerated with an assistive device, with weaning as she was able.Figure 4 Day 0 postoperative AP pelvis x-ray. THA with cage construct and iliac plating.
At her 3-month follow-up visit, she was able to fully weight bear on her left lower extremity without pain or assistive device. Imaging obtained at that time is seen in Figure 5. At 5 months postoperatively, she underwent right total knee arthroplasty because of osteoarthritis present before the acetabular osteonecrosis and was progressing very well with physical therapy. Unfortunately, 16 months after complex left THA, she succumbed to complications of diffuse large B-cell lymphoma and GVHD.Figure 5 Three months postoperative AP pelvis. Revealed intact cage hardware, posterior column plating, and THA. Interval ileum healing was perceived.
Case 2
Case 2 is a 51-year-old woman with a history of acute myelogenous leukemia (AML), secondary myelodysplastic syndrome (MDS), GVHD, steroid-induced diabetes, and restrictive pulmonary disease. Autologous PBSCT was undertaken for AML 9 years before presentation. Matched unrelated donor PBSCT was conducted 1 year before presentation, after fludarabine-melphalan conditioning. GVHD characterized by gastrointestinal symptoms and florid skin rash complicated PBSCT 4 months before presentation. Steroid dosage during GVHD was started at 1 mg/kg/day (60 mg BID) with rapid resolution of symptoms leading to taper of steroids down to 0.5 mg/kg/day after 1 week. She developed recurrence of pulmonary symptoms and gastrointestinal symptoms with tapering and was restarted on 1 mg/kg/day.
She presented to orthopedics with 2 months of right hip pain, primarily in her deep inguinal crease. She required a walker for ambulation and was limited to very short distances because of pain. The examination was remarkable for BMI = 44, anasarca, and painful and limited right hip rotation with only 10 degrees of passive external and internal rotation. Radiographs taken at that time are seen in Figure 6. MRI performed at that time showed hypointensity of the supra-acetabular ilium with some T2 hyperintensity measuring 2.5 cm transverse × 2.4 cm AP suggestive of osteonecrosis, although without collapse. There was also osteonecrosis of the left femoral head, without collapse. Given significant comorbid conditions including bilateral lower extremity edema and severe open-leg ulcerations, surgery was not initially recommended.Figure 6 AP right hip obtained upon initial presentation to PCP with right hip pain. Revealing subchondral lucency of the right femoral head. No acetabular involvement noted.
Given ongoing severe pain and disability, she underwent medical optimization taking 13 months, although during that time, she developed progressive osteonecrosis of the acetabulum. The progression of this can be seen in Figure 7, Figure 8 obtained 1 month later. Her fracture initially demonstrated disruption of the right iliopubic line with sclerosis of the supraacetabular ilium with superior displacement of the femoral head into the ilium consistent with protrusio fracture. This was further evaluated with a CT of the pelvis, which demonstrated comminution of anterior and posterior columns and 14 gapping of articular surface along anterosuperior acetabulum and medullary sclerosis of the surrounding ilium. Follow-up radiography seen in Figure 8 demonstrated increased displacement of anterior and posterior columns with medial acetabular wall displacement measuring 8 mm. Figure 8 was ultimately used for templating her implants. Iliac oblique and obturator oblique views at this time seen in Figure 9, Figure 10 better demonstrate involvement of the anterior and posterior column, medial protrusion of the acetabulum. She was no longer able to ambulate with a walker and was wheelchair bound. Her steroid dose then was 5 mg, 5 days per week, and 10 mg, 2 days per week. Treatment options discussed with patient included Girdlestone resection, THA, and THA with antiprotrusio cage or cup and cage construct. Reconstruction was preferred by patient over Girdlestone resection as she was hoping to resume ambulation and activities of daily living (ADLs). Surgery was pursued with posterior THA, with cage construct and posterior column plating. This fixation was used as the size of the pelvis was not large enough to facilitate a cup/cage construct. Medial acetabulum bony deficiency with both columns, or transverse-type insufficiency fracture or pelvic discontinuity variant, was encountered. After femoral neck cut was made, A 7-hole pelvic reconstruction plate was contoured, and a posterior column plated from ischium to ileum with good fixation using 4 small fragment screws. After the cage was placed, 10 mL of synthetic bone graft with 30 mL of allograft cancellous chips was placed posteriorly to cage. There were no intraoperative complications, and she was discharged home after 2 days. Two weeks postoperatively, she had a 2-day admission for viral gastroenteritis. She also underwent kyphoplasty for three (T9, T11, L1) vertebral compression fractures 2 months postoperatively. There were no readmissions or emergency department visits for postoperative complications.Figure 7 AP pelvic x-ray 6 months since onset of symptoms and 10 months preoperatively. Revealing displaced healing right acetabular fracture. Disruption of the right iliopubic line and sclerosis of the right supra-acetabular ilium. Sclerosis of the right femoral head was also observed.
Figure 8 AP pelvis x-ray 13 months since onset of symptoms and 1.5 months preoperatively. Showing comminuted displaced right acetabular transverse fracture also involving the posterior and medial acetabular walls. Right femoral head is also eroded and aspherical. This film was used for templating.
Figure 9 Right iliac oblique x-ray 13 months since onset of symptoms and 1.5 months preoperatively demonstrating transverse plus posterior acetabular wall fracture with 1.5 cm medial displacement of medial acetabular wall.
Figure 10 Right obturator oblique x-ray 13 months since onset of symptoms and 1.5 months preoperatively. Further demonstrating comminuted posterior acetabular wall insufficiency fracture, aspherical and eroded femoral head, and some bony callus.
One-month postoperatively, her pain was decreasing, and function with ADLs increased, although she required a walker because of back pain and deconditioning. Her gait was smooth, not antalgic, with the walker. Two views of AP pelvis performed at that time are seen in Figure 11. One-year postoperatively, her pain had resolved, she still required a walker, and she was noted to have Trendelenburg gait. AP pelvis 1 year postoperatively, seen in Figure 12, showed well-positioned THA with no lucencies or subsidence. Unfortunately, 3 years postoperatively, she died of causes related to her MDS and GVHD.Figure 11 Portable pelvis x-ray 1-month postoperatively. Intact cup and cage construct implants, near anatomic alignment of acetabular fracture.
Figure 12 AP pelvis x-rays 1-year postoperatively. Interval acetabular healing was seen. Diffuse osteopenia but no evidence of implant failure.
Discussion
Patients with hematologic malignancies are having increased remission and survivorship after autologous and allogenic hematopoietic stem cell transplantations [14,15]. Allogeneic stem cell transplantation is unique as opposed to autologous transplant as it can lead to GVHD. GVHD is a systemic immune reaction by donor cells against host cells [16]. Several studies have demonstrated the increased risk of osteonecrosis because of GVHD [5,9,11,17,18]. GVHD is thought to cause osteonecrosis because of an inflammatory process in the intraosseous vasculature. Sixou et al. [19] found histologic evidence of vasculitis attributed to GVHD. This vasculitis exacerbates risk factors associated with osteonecrosis inclusive to patients with hematologic malignancies including systemic glucocorticoids, chemotherapeutics, and irradiation [5].
Unique to the presented cases is osteonecrosis of the acetabulum and the timeline to develop osteonecrosis. Case 1 took 5 years for manifestation of acetabular osteonecrosis after initiation of steroids for GVHD. Case 2 took 13 months until acetabular osteonecrosis began after onset of GVHD. In 11 patients (19 hips, 8 patients with bilateral osteonecrosis) studied by Schulte and Beelen, onset of osteonecrosis after allogeneic stem cell transplant ranged from 5 to 57 months, with an average of 25 months [9,18]. However, all these cases were of the femoral head, and the hematologic malignancies were AML, MDS, CML, and ALL. It is unclear in the presented cases what circumstances led to osteonecrosis of the acetabulum. Location and timeline could be attributed to age. Bizot et al. [17] had 16 patients with osteonecrosis secondary to GVHD, although the oldest patient was 47 years old at the time of surgery (average age 13 ± 8 years). The patients presented were 60 and 52 years old at the time of surgery.
Several other studies have identified osteonecrosis risk factors in hematologic malignancies; Schulte and Beelen demonstrated that the most impactful risk factors were chronic GVHD and cumulative steroid intake, followed by female gender, younger age, and conditioning therapy before transplant. Advanced disease stages, bone mineral density, and body composition did not have a significant impact on osteonecrosis [9,18]. The disease process of lymphoma itself may contribute; Chalmers et al. showed that lymphoma was the underlying diagnosis in 33% of THAs in patients with a history of stem cell transplant. However, not all of these patients had a history of GVHD [13].
In these cases, owing to the insufficiency fractures of the acetabular with effective pelvic discontinuity (PD) and the tenuous vascular supply of surrounding bone, THA was conducted with cage construct and bridge plating of the posterior column. This construct has shown efficacy in cases with PD and severe acetabular bone loss in revision THA [[20], [21], [22], [23]]. Plating is primarily studied in revision arthroplasty cases with PD [24,25]. Plating was chosen to restore continuity, optimize contact of viable bone, and add stability to the reconstruction. This fixation technique of posterior column plating with antiprotrusion cage placement led to stability with improved ADLs, restoration of ambulation with full weightbearing, and resolution of pain at 1 year for both cases. Certainly, the perioperative risk of significant surgical or medical complications is high for patients with GVHD; therefore, this technique should be considered in situations with tenuous blood supply and insufficiency fractures in the setting of hematologic malignancy and GVHD.
Summary
These cases are unique reports of osteonecrosis focal to the acetabulum, in patients with history of stem cell transplant and subsequent GVHD. The impact of this disease process should not be overlooked in patients with hematologic malignances and GVHD. Surgical treatment with multifaceted construct, in these cases with an antiprotrusio cage bolstered by posterior column plating, can relieve pain and improve mobility.
Conflict of interest
Dr. Schabel obtains research support from Zimmer Biomet, unrelated to this work. She is also a board member for the Oregon Association of Orthopaedists.
Supplementary data
Conflict of Interest Statement for Nielsen
Conflict of Interest Statement for Schabel
Statements of informed consent were obtained from patients and family members of deceased patients. | FLUDARABINE PHOSPHATE, MELPHALAN HYDROCHLORIDE | DrugsGivenReaction | CC BY-NC-ND | 33521198 | 18,921,443 | 2021-02 |
What was the dosage of drug 'CYCLOPHOSPHAMIDE'? | Acetabular Insufficiency Fractures in the Setting of Graft vs Host Disease: A Report of Two Cases.
We report a case series of 2 patients with unilateral acetabular insufficiency fractures who received allogeneic peripheral blood stem cell transplantation for hematologic malignancies complicated by chronic graft vs host disease. These were managed with uncemented cup and cage total hip arthroplasty and stabilization of posterior column with plating. Osteonecrosis of the acetabulum is an uncommon musculoskeletal complication of chronic graft vs host disease. The orthopedic impact of this disease should not be overlooked. Surgical intervention with this construct can provide necessary stability to improve patient function.
Introduction
Graft vs host disease (GVHD) can manifest with multisystemic effects. GVHD can occur after allogeneic peripheral blood stem cell transplantation (PBSCT) and can have orthopedic implications such as osteonecrosis. The incidence of osteonecrosis after allogeneic stem cell transplantation is 4-19% [[1], [2], [3], [4]], and the risk is increased in patients with GVHD [5]. Most studies described involve the femoral head [[1], [2], [3], [4],[6], [7], [8], [9], [10], [11], [12]]. Osteonecrosis of the acetabulum, although rare, can lead to significant complications. These include interruption of the articular surface, insufficiency fracture, and protrusio acetabulum. Osteonecrosis of the acetabulum presents particular difficulty in fixation; poor bone quality can impact long-term patient outcomes and implant survivorship. Implant survivorship of THA in patients with allogeneic peripheral stem cell transplantation at 5 years is up to 93% [11], although it can be as low as 74.8% at 10 years [13]. Therefore, THA and fracture fixation in this setting require an approach that combines primary and revision arthroplasty skills to enable immediate weight bearing and pain relief. We present 2 cases of allogeneic PBSCT complicated by GVHD, with resultant acetabular osteonecrosis leading to acetabular insufficiency fracture and the surgical reconstruction that followed.
Case histories
Case 1
Case 1 is a 60-year-old woman with a history of diffuse large B-cell lymphoma who underwent 8 cycles of R-CHOP (rituximab, cyclophosphamide, hydroxydaunorubicin, oncovin [vincristine], and prednisolone). Her disease recurred and was treated with radiolabeled tositumomab with maintenance on rituximab. Relapse occurred once more, and she received salvage chemotherapy with R-ICE (rituximab, ifosfamide, etoposide, carboplatin) followed by autologous PBSCT. She underwent human leukocyte antigen (HLA)-matched allogeneic PBSCT after fludarabine-melphalan conditioning for relapse involving the central nervous system. This was complicated by GVHD, primarily affecting the gastrointestinal tract, that improved with 20-mg prednisone BID (0.5 mg/kg/day). After several dose escalations and relapses, she was tapered off prednisone three times, but after two severe episodes of pericarditis in the absence of steroids, she remained on 10-mg prednisone daily.
She presented to orthopedics with 1 month of acute, “aching” left-sided groin pain, global left hip weakness, difficulty ambulating (newly required a four-wheel walker), and ecchymosis in her inguinal crease. Physical examination revealed severe pain with hip internal and external rotation, as well as adduction and abduction. She could conduct passive hip flexion to 90 degrees but had pain with resisted hip flexion. Magnetic resonance imaging (MRI) of the pelvis and hip was obtained by her primary care provider before orthopedic referral, and AP of the pelvis was obtained as seen in Figure 1. Initial radiography in Figure 1 and MRI demonstrated comminuted minimally displaced fracture of the acetabulum involving the anterior and posterior columns with acetabular protrusio fracture and superior displacement of the femur of 3.5 cm. Interruption of the anterior and posterior columns is better visualized on iliac oblique and obturator oblique views seen in Figure 2, Figure 3.Figure 1 AP pelvis x-ray upon initial presentation showed displaced acetabular fracture and interruption of the femoroacetabular joint space.
Figure 2 Left obturator oblique better demonstrates insufficiency fracture of the posterior wall and anterior column.
Figure 3 Left iliac oblique further demonstrates osteonecrosis of the acetabulum and fracture extending through the posterior column.
Owing to severe disability and pain, and acetabular insufficiency (pathologic) fracture and joint collapse, posterior THA and posterior column stabilization was undertaken. Posterolateral approach was taken to optimize exposure of acetabular fracture and perform THA. Complex THA was performed using a cage construct. Pelvic size thwarted the use of a cup and cage construct. Findings include fragmentation of medial acetabulum with transverse-type insufficiency or pathologic fracture. Acetabular pathologic fracture was repaired, or stabilized, with 8-hole reconstruction plate bent for the left posterior column. Morselized femoral head autograft was placed at the base of the protruded acetabulum. Dome screws of antiprotrusio cage were placed before ilium cage screws, and 5 mL of synthetic bone graft and 30 mL of cancellous bone allograft was injected behind cage. Postoperative x-ray is demonstrated in Figure 4. Her postoperative activity restrictions included posterior hip precautions, and weightbearing as tolerated with an assistive device, with weaning as she was able.Figure 4 Day 0 postoperative AP pelvis x-ray. THA with cage construct and iliac plating.
At her 3-month follow-up visit, she was able to fully weight bear on her left lower extremity without pain or assistive device. Imaging obtained at that time is seen in Figure 5. At 5 months postoperatively, she underwent right total knee arthroplasty because of osteoarthritis present before the acetabular osteonecrosis and was progressing very well with physical therapy. Unfortunately, 16 months after complex left THA, she succumbed to complications of diffuse large B-cell lymphoma and GVHD.Figure 5 Three months postoperative AP pelvis. Revealed intact cage hardware, posterior column plating, and THA. Interval ileum healing was perceived.
Case 2
Case 2 is a 51-year-old woman with a history of acute myelogenous leukemia (AML), secondary myelodysplastic syndrome (MDS), GVHD, steroid-induced diabetes, and restrictive pulmonary disease. Autologous PBSCT was undertaken for AML 9 years before presentation. Matched unrelated donor PBSCT was conducted 1 year before presentation, after fludarabine-melphalan conditioning. GVHD characterized by gastrointestinal symptoms and florid skin rash complicated PBSCT 4 months before presentation. Steroid dosage during GVHD was started at 1 mg/kg/day (60 mg BID) with rapid resolution of symptoms leading to taper of steroids down to 0.5 mg/kg/day after 1 week. She developed recurrence of pulmonary symptoms and gastrointestinal symptoms with tapering and was restarted on 1 mg/kg/day.
She presented to orthopedics with 2 months of right hip pain, primarily in her deep inguinal crease. She required a walker for ambulation and was limited to very short distances because of pain. The examination was remarkable for BMI = 44, anasarca, and painful and limited right hip rotation with only 10 degrees of passive external and internal rotation. Radiographs taken at that time are seen in Figure 6. MRI performed at that time showed hypointensity of the supra-acetabular ilium with some T2 hyperintensity measuring 2.5 cm transverse × 2.4 cm AP suggestive of osteonecrosis, although without collapse. There was also osteonecrosis of the left femoral head, without collapse. Given significant comorbid conditions including bilateral lower extremity edema and severe open-leg ulcerations, surgery was not initially recommended.Figure 6 AP right hip obtained upon initial presentation to PCP with right hip pain. Revealing subchondral lucency of the right femoral head. No acetabular involvement noted.
Given ongoing severe pain and disability, she underwent medical optimization taking 13 months, although during that time, she developed progressive osteonecrosis of the acetabulum. The progression of this can be seen in Figure 7, Figure 8 obtained 1 month later. Her fracture initially demonstrated disruption of the right iliopubic line with sclerosis of the supraacetabular ilium with superior displacement of the femoral head into the ilium consistent with protrusio fracture. This was further evaluated with a CT of the pelvis, which demonstrated comminution of anterior and posterior columns and 14 gapping of articular surface along anterosuperior acetabulum and medullary sclerosis of the surrounding ilium. Follow-up radiography seen in Figure 8 demonstrated increased displacement of anterior and posterior columns with medial acetabular wall displacement measuring 8 mm. Figure 8 was ultimately used for templating her implants. Iliac oblique and obturator oblique views at this time seen in Figure 9, Figure 10 better demonstrate involvement of the anterior and posterior column, medial protrusion of the acetabulum. She was no longer able to ambulate with a walker and was wheelchair bound. Her steroid dose then was 5 mg, 5 days per week, and 10 mg, 2 days per week. Treatment options discussed with patient included Girdlestone resection, THA, and THA with antiprotrusio cage or cup and cage construct. Reconstruction was preferred by patient over Girdlestone resection as she was hoping to resume ambulation and activities of daily living (ADLs). Surgery was pursued with posterior THA, with cage construct and posterior column plating. This fixation was used as the size of the pelvis was not large enough to facilitate a cup/cage construct. Medial acetabulum bony deficiency with both columns, or transverse-type insufficiency fracture or pelvic discontinuity variant, was encountered. After femoral neck cut was made, A 7-hole pelvic reconstruction plate was contoured, and a posterior column plated from ischium to ileum with good fixation using 4 small fragment screws. After the cage was placed, 10 mL of synthetic bone graft with 30 mL of allograft cancellous chips was placed posteriorly to cage. There were no intraoperative complications, and she was discharged home after 2 days. Two weeks postoperatively, she had a 2-day admission for viral gastroenteritis. She also underwent kyphoplasty for three (T9, T11, L1) vertebral compression fractures 2 months postoperatively. There were no readmissions or emergency department visits for postoperative complications.Figure 7 AP pelvic x-ray 6 months since onset of symptoms and 10 months preoperatively. Revealing displaced healing right acetabular fracture. Disruption of the right iliopubic line and sclerosis of the right supra-acetabular ilium. Sclerosis of the right femoral head was also observed.
Figure 8 AP pelvis x-ray 13 months since onset of symptoms and 1.5 months preoperatively. Showing comminuted displaced right acetabular transverse fracture also involving the posterior and medial acetabular walls. Right femoral head is also eroded and aspherical. This film was used for templating.
Figure 9 Right iliac oblique x-ray 13 months since onset of symptoms and 1.5 months preoperatively demonstrating transverse plus posterior acetabular wall fracture with 1.5 cm medial displacement of medial acetabular wall.
Figure 10 Right obturator oblique x-ray 13 months since onset of symptoms and 1.5 months preoperatively. Further demonstrating comminuted posterior acetabular wall insufficiency fracture, aspherical and eroded femoral head, and some bony callus.
One-month postoperatively, her pain was decreasing, and function with ADLs increased, although she required a walker because of back pain and deconditioning. Her gait was smooth, not antalgic, with the walker. Two views of AP pelvis performed at that time are seen in Figure 11. One-year postoperatively, her pain had resolved, she still required a walker, and she was noted to have Trendelenburg gait. AP pelvis 1 year postoperatively, seen in Figure 12, showed well-positioned THA with no lucencies or subsidence. Unfortunately, 3 years postoperatively, she died of causes related to her MDS and GVHD.Figure 11 Portable pelvis x-ray 1-month postoperatively. Intact cup and cage construct implants, near anatomic alignment of acetabular fracture.
Figure 12 AP pelvis x-rays 1-year postoperatively. Interval acetabular healing was seen. Diffuse osteopenia but no evidence of implant failure.
Discussion
Patients with hematologic malignancies are having increased remission and survivorship after autologous and allogenic hematopoietic stem cell transplantations [14,15]. Allogeneic stem cell transplantation is unique as opposed to autologous transplant as it can lead to GVHD. GVHD is a systemic immune reaction by donor cells against host cells [16]. Several studies have demonstrated the increased risk of osteonecrosis because of GVHD [5,9,11,17,18]. GVHD is thought to cause osteonecrosis because of an inflammatory process in the intraosseous vasculature. Sixou et al. [19] found histologic evidence of vasculitis attributed to GVHD. This vasculitis exacerbates risk factors associated with osteonecrosis inclusive to patients with hematologic malignancies including systemic glucocorticoids, chemotherapeutics, and irradiation [5].
Unique to the presented cases is osteonecrosis of the acetabulum and the timeline to develop osteonecrosis. Case 1 took 5 years for manifestation of acetabular osteonecrosis after initiation of steroids for GVHD. Case 2 took 13 months until acetabular osteonecrosis began after onset of GVHD. In 11 patients (19 hips, 8 patients with bilateral osteonecrosis) studied by Schulte and Beelen, onset of osteonecrosis after allogeneic stem cell transplant ranged from 5 to 57 months, with an average of 25 months [9,18]. However, all these cases were of the femoral head, and the hematologic malignancies were AML, MDS, CML, and ALL. It is unclear in the presented cases what circumstances led to osteonecrosis of the acetabulum. Location and timeline could be attributed to age. Bizot et al. [17] had 16 patients with osteonecrosis secondary to GVHD, although the oldest patient was 47 years old at the time of surgery (average age 13 ± 8 years). The patients presented were 60 and 52 years old at the time of surgery.
Several other studies have identified osteonecrosis risk factors in hematologic malignancies; Schulte and Beelen demonstrated that the most impactful risk factors were chronic GVHD and cumulative steroid intake, followed by female gender, younger age, and conditioning therapy before transplant. Advanced disease stages, bone mineral density, and body composition did not have a significant impact on osteonecrosis [9,18]. The disease process of lymphoma itself may contribute; Chalmers et al. showed that lymphoma was the underlying diagnosis in 33% of THAs in patients with a history of stem cell transplant. However, not all of these patients had a history of GVHD [13].
In these cases, owing to the insufficiency fractures of the acetabular with effective pelvic discontinuity (PD) and the tenuous vascular supply of surrounding bone, THA was conducted with cage construct and bridge plating of the posterior column. This construct has shown efficacy in cases with PD and severe acetabular bone loss in revision THA [[20], [21], [22], [23]]. Plating is primarily studied in revision arthroplasty cases with PD [24,25]. Plating was chosen to restore continuity, optimize contact of viable bone, and add stability to the reconstruction. This fixation technique of posterior column plating with antiprotrusion cage placement led to stability with improved ADLs, restoration of ambulation with full weightbearing, and resolution of pain at 1 year for both cases. Certainly, the perioperative risk of significant surgical or medical complications is high for patients with GVHD; therefore, this technique should be considered in situations with tenuous blood supply and insufficiency fractures in the setting of hematologic malignancy and GVHD.
Summary
These cases are unique reports of osteonecrosis focal to the acetabulum, in patients with history of stem cell transplant and subsequent GVHD. The impact of this disease process should not be overlooked in patients with hematologic malignances and GVHD. Surgical treatment with multifaceted construct, in these cases with an antiprotrusio cage bolstered by posterior column plating, can relieve pain and improve mobility.
Conflict of interest
Dr. Schabel obtains research support from Zimmer Biomet, unrelated to this work. She is also a board member for the Oregon Association of Orthopaedists.
Supplementary data
Conflict of Interest Statement for Nielsen
Conflict of Interest Statement for Schabel
Statements of informed consent were obtained from patients and family members of deceased patients. | PART OF R?CHOP REGIMEN | DrugDosageText | CC BY-NC-ND | 33521198 | 18,981,647 | 2021-02 |
What was the dosage of drug 'PREDNISOLONE'? | Acetabular Insufficiency Fractures in the Setting of Graft vs Host Disease: A Report of Two Cases.
We report a case series of 2 patients with unilateral acetabular insufficiency fractures who received allogeneic peripheral blood stem cell transplantation for hematologic malignancies complicated by chronic graft vs host disease. These were managed with uncemented cup and cage total hip arthroplasty and stabilization of posterior column with plating. Osteonecrosis of the acetabulum is an uncommon musculoskeletal complication of chronic graft vs host disease. The orthopedic impact of this disease should not be overlooked. Surgical intervention with this construct can provide necessary stability to improve patient function.
Introduction
Graft vs host disease (GVHD) can manifest with multisystemic effects. GVHD can occur after allogeneic peripheral blood stem cell transplantation (PBSCT) and can have orthopedic implications such as osteonecrosis. The incidence of osteonecrosis after allogeneic stem cell transplantation is 4-19% [[1], [2], [3], [4]], and the risk is increased in patients with GVHD [5]. Most studies described involve the femoral head [[1], [2], [3], [4],[6], [7], [8], [9], [10], [11], [12]]. Osteonecrosis of the acetabulum, although rare, can lead to significant complications. These include interruption of the articular surface, insufficiency fracture, and protrusio acetabulum. Osteonecrosis of the acetabulum presents particular difficulty in fixation; poor bone quality can impact long-term patient outcomes and implant survivorship. Implant survivorship of THA in patients with allogeneic peripheral stem cell transplantation at 5 years is up to 93% [11], although it can be as low as 74.8% at 10 years [13]. Therefore, THA and fracture fixation in this setting require an approach that combines primary and revision arthroplasty skills to enable immediate weight bearing and pain relief. We present 2 cases of allogeneic PBSCT complicated by GVHD, with resultant acetabular osteonecrosis leading to acetabular insufficiency fracture and the surgical reconstruction that followed.
Case histories
Case 1
Case 1 is a 60-year-old woman with a history of diffuse large B-cell lymphoma who underwent 8 cycles of R-CHOP (rituximab, cyclophosphamide, hydroxydaunorubicin, oncovin [vincristine], and prednisolone). Her disease recurred and was treated with radiolabeled tositumomab with maintenance on rituximab. Relapse occurred once more, and she received salvage chemotherapy with R-ICE (rituximab, ifosfamide, etoposide, carboplatin) followed by autologous PBSCT. She underwent human leukocyte antigen (HLA)-matched allogeneic PBSCT after fludarabine-melphalan conditioning for relapse involving the central nervous system. This was complicated by GVHD, primarily affecting the gastrointestinal tract, that improved with 20-mg prednisone BID (0.5 mg/kg/day). After several dose escalations and relapses, she was tapered off prednisone three times, but after two severe episodes of pericarditis in the absence of steroids, she remained on 10-mg prednisone daily.
She presented to orthopedics with 1 month of acute, “aching” left-sided groin pain, global left hip weakness, difficulty ambulating (newly required a four-wheel walker), and ecchymosis in her inguinal crease. Physical examination revealed severe pain with hip internal and external rotation, as well as adduction and abduction. She could conduct passive hip flexion to 90 degrees but had pain with resisted hip flexion. Magnetic resonance imaging (MRI) of the pelvis and hip was obtained by her primary care provider before orthopedic referral, and AP of the pelvis was obtained as seen in Figure 1. Initial radiography in Figure 1 and MRI demonstrated comminuted minimally displaced fracture of the acetabulum involving the anterior and posterior columns with acetabular protrusio fracture and superior displacement of the femur of 3.5 cm. Interruption of the anterior and posterior columns is better visualized on iliac oblique and obturator oblique views seen in Figure 2, Figure 3.Figure 1 AP pelvis x-ray upon initial presentation showed displaced acetabular fracture and interruption of the femoroacetabular joint space.
Figure 2 Left obturator oblique better demonstrates insufficiency fracture of the posterior wall and anterior column.
Figure 3 Left iliac oblique further demonstrates osteonecrosis of the acetabulum and fracture extending through the posterior column.
Owing to severe disability and pain, and acetabular insufficiency (pathologic) fracture and joint collapse, posterior THA and posterior column stabilization was undertaken. Posterolateral approach was taken to optimize exposure of acetabular fracture and perform THA. Complex THA was performed using a cage construct. Pelvic size thwarted the use of a cup and cage construct. Findings include fragmentation of medial acetabulum with transverse-type insufficiency or pathologic fracture. Acetabular pathologic fracture was repaired, or stabilized, with 8-hole reconstruction plate bent for the left posterior column. Morselized femoral head autograft was placed at the base of the protruded acetabulum. Dome screws of antiprotrusio cage were placed before ilium cage screws, and 5 mL of synthetic bone graft and 30 mL of cancellous bone allograft was injected behind cage. Postoperative x-ray is demonstrated in Figure 4. Her postoperative activity restrictions included posterior hip precautions, and weightbearing as tolerated with an assistive device, with weaning as she was able.Figure 4 Day 0 postoperative AP pelvis x-ray. THA with cage construct and iliac plating.
At her 3-month follow-up visit, she was able to fully weight bear on her left lower extremity without pain or assistive device. Imaging obtained at that time is seen in Figure 5. At 5 months postoperatively, she underwent right total knee arthroplasty because of osteoarthritis present before the acetabular osteonecrosis and was progressing very well with physical therapy. Unfortunately, 16 months after complex left THA, she succumbed to complications of diffuse large B-cell lymphoma and GVHD.Figure 5 Three months postoperative AP pelvis. Revealed intact cage hardware, posterior column plating, and THA. Interval ileum healing was perceived.
Case 2
Case 2 is a 51-year-old woman with a history of acute myelogenous leukemia (AML), secondary myelodysplastic syndrome (MDS), GVHD, steroid-induced diabetes, and restrictive pulmonary disease. Autologous PBSCT was undertaken for AML 9 years before presentation. Matched unrelated donor PBSCT was conducted 1 year before presentation, after fludarabine-melphalan conditioning. GVHD characterized by gastrointestinal symptoms and florid skin rash complicated PBSCT 4 months before presentation. Steroid dosage during GVHD was started at 1 mg/kg/day (60 mg BID) with rapid resolution of symptoms leading to taper of steroids down to 0.5 mg/kg/day after 1 week. She developed recurrence of pulmonary symptoms and gastrointestinal symptoms with tapering and was restarted on 1 mg/kg/day.
She presented to orthopedics with 2 months of right hip pain, primarily in her deep inguinal crease. She required a walker for ambulation and was limited to very short distances because of pain. The examination was remarkable for BMI = 44, anasarca, and painful and limited right hip rotation with only 10 degrees of passive external and internal rotation. Radiographs taken at that time are seen in Figure 6. MRI performed at that time showed hypointensity of the supra-acetabular ilium with some T2 hyperintensity measuring 2.5 cm transverse × 2.4 cm AP suggestive of osteonecrosis, although without collapse. There was also osteonecrosis of the left femoral head, without collapse. Given significant comorbid conditions including bilateral lower extremity edema and severe open-leg ulcerations, surgery was not initially recommended.Figure 6 AP right hip obtained upon initial presentation to PCP with right hip pain. Revealing subchondral lucency of the right femoral head. No acetabular involvement noted.
Given ongoing severe pain and disability, she underwent medical optimization taking 13 months, although during that time, she developed progressive osteonecrosis of the acetabulum. The progression of this can be seen in Figure 7, Figure 8 obtained 1 month later. Her fracture initially demonstrated disruption of the right iliopubic line with sclerosis of the supraacetabular ilium with superior displacement of the femoral head into the ilium consistent with protrusio fracture. This was further evaluated with a CT of the pelvis, which demonstrated comminution of anterior and posterior columns and 14 gapping of articular surface along anterosuperior acetabulum and medullary sclerosis of the surrounding ilium. Follow-up radiography seen in Figure 8 demonstrated increased displacement of anterior and posterior columns with medial acetabular wall displacement measuring 8 mm. Figure 8 was ultimately used for templating her implants. Iliac oblique and obturator oblique views at this time seen in Figure 9, Figure 10 better demonstrate involvement of the anterior and posterior column, medial protrusion of the acetabulum. She was no longer able to ambulate with a walker and was wheelchair bound. Her steroid dose then was 5 mg, 5 days per week, and 10 mg, 2 days per week. Treatment options discussed with patient included Girdlestone resection, THA, and THA with antiprotrusio cage or cup and cage construct. Reconstruction was preferred by patient over Girdlestone resection as she was hoping to resume ambulation and activities of daily living (ADLs). Surgery was pursued with posterior THA, with cage construct and posterior column plating. This fixation was used as the size of the pelvis was not large enough to facilitate a cup/cage construct. Medial acetabulum bony deficiency with both columns, or transverse-type insufficiency fracture or pelvic discontinuity variant, was encountered. After femoral neck cut was made, A 7-hole pelvic reconstruction plate was contoured, and a posterior column plated from ischium to ileum with good fixation using 4 small fragment screws. After the cage was placed, 10 mL of synthetic bone graft with 30 mL of allograft cancellous chips was placed posteriorly to cage. There were no intraoperative complications, and she was discharged home after 2 days. Two weeks postoperatively, she had a 2-day admission for viral gastroenteritis. She also underwent kyphoplasty for three (T9, T11, L1) vertebral compression fractures 2 months postoperatively. There were no readmissions or emergency department visits for postoperative complications.Figure 7 AP pelvic x-ray 6 months since onset of symptoms and 10 months preoperatively. Revealing displaced healing right acetabular fracture. Disruption of the right iliopubic line and sclerosis of the right supra-acetabular ilium. Sclerosis of the right femoral head was also observed.
Figure 8 AP pelvis x-ray 13 months since onset of symptoms and 1.5 months preoperatively. Showing comminuted displaced right acetabular transverse fracture also involving the posterior and medial acetabular walls. Right femoral head is also eroded and aspherical. This film was used for templating.
Figure 9 Right iliac oblique x-ray 13 months since onset of symptoms and 1.5 months preoperatively demonstrating transverse plus posterior acetabular wall fracture with 1.5 cm medial displacement of medial acetabular wall.
Figure 10 Right obturator oblique x-ray 13 months since onset of symptoms and 1.5 months preoperatively. Further demonstrating comminuted posterior acetabular wall insufficiency fracture, aspherical and eroded femoral head, and some bony callus.
One-month postoperatively, her pain was decreasing, and function with ADLs increased, although she required a walker because of back pain and deconditioning. Her gait was smooth, not antalgic, with the walker. Two views of AP pelvis performed at that time are seen in Figure 11. One-year postoperatively, her pain had resolved, she still required a walker, and she was noted to have Trendelenburg gait. AP pelvis 1 year postoperatively, seen in Figure 12, showed well-positioned THA with no lucencies or subsidence. Unfortunately, 3 years postoperatively, she died of causes related to her MDS and GVHD.Figure 11 Portable pelvis x-ray 1-month postoperatively. Intact cup and cage construct implants, near anatomic alignment of acetabular fracture.
Figure 12 AP pelvis x-rays 1-year postoperatively. Interval acetabular healing was seen. Diffuse osteopenia but no evidence of implant failure.
Discussion
Patients with hematologic malignancies are having increased remission and survivorship after autologous and allogenic hematopoietic stem cell transplantations [14,15]. Allogeneic stem cell transplantation is unique as opposed to autologous transplant as it can lead to GVHD. GVHD is a systemic immune reaction by donor cells against host cells [16]. Several studies have demonstrated the increased risk of osteonecrosis because of GVHD [5,9,11,17,18]. GVHD is thought to cause osteonecrosis because of an inflammatory process in the intraosseous vasculature. Sixou et al. [19] found histologic evidence of vasculitis attributed to GVHD. This vasculitis exacerbates risk factors associated with osteonecrosis inclusive to patients with hematologic malignancies including systemic glucocorticoids, chemotherapeutics, and irradiation [5].
Unique to the presented cases is osteonecrosis of the acetabulum and the timeline to develop osteonecrosis. Case 1 took 5 years for manifestation of acetabular osteonecrosis after initiation of steroids for GVHD. Case 2 took 13 months until acetabular osteonecrosis began after onset of GVHD. In 11 patients (19 hips, 8 patients with bilateral osteonecrosis) studied by Schulte and Beelen, onset of osteonecrosis after allogeneic stem cell transplant ranged from 5 to 57 months, with an average of 25 months [9,18]. However, all these cases were of the femoral head, and the hematologic malignancies were AML, MDS, CML, and ALL. It is unclear in the presented cases what circumstances led to osteonecrosis of the acetabulum. Location and timeline could be attributed to age. Bizot et al. [17] had 16 patients with osteonecrosis secondary to GVHD, although the oldest patient was 47 years old at the time of surgery (average age 13 ± 8 years). The patients presented were 60 and 52 years old at the time of surgery.
Several other studies have identified osteonecrosis risk factors in hematologic malignancies; Schulte and Beelen demonstrated that the most impactful risk factors were chronic GVHD and cumulative steroid intake, followed by female gender, younger age, and conditioning therapy before transplant. Advanced disease stages, bone mineral density, and body composition did not have a significant impact on osteonecrosis [9,18]. The disease process of lymphoma itself may contribute; Chalmers et al. showed that lymphoma was the underlying diagnosis in 33% of THAs in patients with a history of stem cell transplant. However, not all of these patients had a history of GVHD [13].
In these cases, owing to the insufficiency fractures of the acetabular with effective pelvic discontinuity (PD) and the tenuous vascular supply of surrounding bone, THA was conducted with cage construct and bridge plating of the posterior column. This construct has shown efficacy in cases with PD and severe acetabular bone loss in revision THA [[20], [21], [22], [23]]. Plating is primarily studied in revision arthroplasty cases with PD [24,25]. Plating was chosen to restore continuity, optimize contact of viable bone, and add stability to the reconstruction. This fixation technique of posterior column plating with antiprotrusion cage placement led to stability with improved ADLs, restoration of ambulation with full weightbearing, and resolution of pain at 1 year for both cases. Certainly, the perioperative risk of significant surgical or medical complications is high for patients with GVHD; therefore, this technique should be considered in situations with tenuous blood supply and insufficiency fractures in the setting of hematologic malignancy and GVHD.
Summary
These cases are unique reports of osteonecrosis focal to the acetabulum, in patients with history of stem cell transplant and subsequent GVHD. The impact of this disease process should not be overlooked in patients with hematologic malignances and GVHD. Surgical treatment with multifaceted construct, in these cases with an antiprotrusio cage bolstered by posterior column plating, can relieve pain and improve mobility.
Conflict of interest
Dr. Schabel obtains research support from Zimmer Biomet, unrelated to this work. She is also a board member for the Oregon Association of Orthopaedists.
Supplementary data
Conflict of Interest Statement for Nielsen
Conflict of Interest Statement for Schabel
Statements of informed consent were obtained from patients and family members of deceased patients. | PART OF R?CHOP REGIMEN | DrugDosageText | CC BY-NC-ND | 33521198 | 18,981,647 | 2021-02 |
What was the dosage of drug 'VINCRISTINE SULFATE'? | Acetabular Insufficiency Fractures in the Setting of Graft vs Host Disease: A Report of Two Cases.
We report a case series of 2 patients with unilateral acetabular insufficiency fractures who received allogeneic peripheral blood stem cell transplantation for hematologic malignancies complicated by chronic graft vs host disease. These were managed with uncemented cup and cage total hip arthroplasty and stabilization of posterior column with plating. Osteonecrosis of the acetabulum is an uncommon musculoskeletal complication of chronic graft vs host disease. The orthopedic impact of this disease should not be overlooked. Surgical intervention with this construct can provide necessary stability to improve patient function.
Introduction
Graft vs host disease (GVHD) can manifest with multisystemic effects. GVHD can occur after allogeneic peripheral blood stem cell transplantation (PBSCT) and can have orthopedic implications such as osteonecrosis. The incidence of osteonecrosis after allogeneic stem cell transplantation is 4-19% [[1], [2], [3], [4]], and the risk is increased in patients with GVHD [5]. Most studies described involve the femoral head [[1], [2], [3], [4],[6], [7], [8], [9], [10], [11], [12]]. Osteonecrosis of the acetabulum, although rare, can lead to significant complications. These include interruption of the articular surface, insufficiency fracture, and protrusio acetabulum. Osteonecrosis of the acetabulum presents particular difficulty in fixation; poor bone quality can impact long-term patient outcomes and implant survivorship. Implant survivorship of THA in patients with allogeneic peripheral stem cell transplantation at 5 years is up to 93% [11], although it can be as low as 74.8% at 10 years [13]. Therefore, THA and fracture fixation in this setting require an approach that combines primary and revision arthroplasty skills to enable immediate weight bearing and pain relief. We present 2 cases of allogeneic PBSCT complicated by GVHD, with resultant acetabular osteonecrosis leading to acetabular insufficiency fracture and the surgical reconstruction that followed.
Case histories
Case 1
Case 1 is a 60-year-old woman with a history of diffuse large B-cell lymphoma who underwent 8 cycles of R-CHOP (rituximab, cyclophosphamide, hydroxydaunorubicin, oncovin [vincristine], and prednisolone). Her disease recurred and was treated with radiolabeled tositumomab with maintenance on rituximab. Relapse occurred once more, and she received salvage chemotherapy with R-ICE (rituximab, ifosfamide, etoposide, carboplatin) followed by autologous PBSCT. She underwent human leukocyte antigen (HLA)-matched allogeneic PBSCT after fludarabine-melphalan conditioning for relapse involving the central nervous system. This was complicated by GVHD, primarily affecting the gastrointestinal tract, that improved with 20-mg prednisone BID (0.5 mg/kg/day). After several dose escalations and relapses, she was tapered off prednisone three times, but after two severe episodes of pericarditis in the absence of steroids, she remained on 10-mg prednisone daily.
She presented to orthopedics with 1 month of acute, “aching” left-sided groin pain, global left hip weakness, difficulty ambulating (newly required a four-wheel walker), and ecchymosis in her inguinal crease. Physical examination revealed severe pain with hip internal and external rotation, as well as adduction and abduction. She could conduct passive hip flexion to 90 degrees but had pain with resisted hip flexion. Magnetic resonance imaging (MRI) of the pelvis and hip was obtained by her primary care provider before orthopedic referral, and AP of the pelvis was obtained as seen in Figure 1. Initial radiography in Figure 1 and MRI demonstrated comminuted minimally displaced fracture of the acetabulum involving the anterior and posterior columns with acetabular protrusio fracture and superior displacement of the femur of 3.5 cm. Interruption of the anterior and posterior columns is better visualized on iliac oblique and obturator oblique views seen in Figure 2, Figure 3.Figure 1 AP pelvis x-ray upon initial presentation showed displaced acetabular fracture and interruption of the femoroacetabular joint space.
Figure 2 Left obturator oblique better demonstrates insufficiency fracture of the posterior wall and anterior column.
Figure 3 Left iliac oblique further demonstrates osteonecrosis of the acetabulum and fracture extending through the posterior column.
Owing to severe disability and pain, and acetabular insufficiency (pathologic) fracture and joint collapse, posterior THA and posterior column stabilization was undertaken. Posterolateral approach was taken to optimize exposure of acetabular fracture and perform THA. Complex THA was performed using a cage construct. Pelvic size thwarted the use of a cup and cage construct. Findings include fragmentation of medial acetabulum with transverse-type insufficiency or pathologic fracture. Acetabular pathologic fracture was repaired, or stabilized, with 8-hole reconstruction plate bent for the left posterior column. Morselized femoral head autograft was placed at the base of the protruded acetabulum. Dome screws of antiprotrusio cage were placed before ilium cage screws, and 5 mL of synthetic bone graft and 30 mL of cancellous bone allograft was injected behind cage. Postoperative x-ray is demonstrated in Figure 4. Her postoperative activity restrictions included posterior hip precautions, and weightbearing as tolerated with an assistive device, with weaning as she was able.Figure 4 Day 0 postoperative AP pelvis x-ray. THA with cage construct and iliac plating.
At her 3-month follow-up visit, she was able to fully weight bear on her left lower extremity without pain or assistive device. Imaging obtained at that time is seen in Figure 5. At 5 months postoperatively, she underwent right total knee arthroplasty because of osteoarthritis present before the acetabular osteonecrosis and was progressing very well with physical therapy. Unfortunately, 16 months after complex left THA, she succumbed to complications of diffuse large B-cell lymphoma and GVHD.Figure 5 Three months postoperative AP pelvis. Revealed intact cage hardware, posterior column plating, and THA. Interval ileum healing was perceived.
Case 2
Case 2 is a 51-year-old woman with a history of acute myelogenous leukemia (AML), secondary myelodysplastic syndrome (MDS), GVHD, steroid-induced diabetes, and restrictive pulmonary disease. Autologous PBSCT was undertaken for AML 9 years before presentation. Matched unrelated donor PBSCT was conducted 1 year before presentation, after fludarabine-melphalan conditioning. GVHD characterized by gastrointestinal symptoms and florid skin rash complicated PBSCT 4 months before presentation. Steroid dosage during GVHD was started at 1 mg/kg/day (60 mg BID) with rapid resolution of symptoms leading to taper of steroids down to 0.5 mg/kg/day after 1 week. She developed recurrence of pulmonary symptoms and gastrointestinal symptoms with tapering and was restarted on 1 mg/kg/day.
She presented to orthopedics with 2 months of right hip pain, primarily in her deep inguinal crease. She required a walker for ambulation and was limited to very short distances because of pain. The examination was remarkable for BMI = 44, anasarca, and painful and limited right hip rotation with only 10 degrees of passive external and internal rotation. Radiographs taken at that time are seen in Figure 6. MRI performed at that time showed hypointensity of the supra-acetabular ilium with some T2 hyperintensity measuring 2.5 cm transverse × 2.4 cm AP suggestive of osteonecrosis, although without collapse. There was also osteonecrosis of the left femoral head, without collapse. Given significant comorbid conditions including bilateral lower extremity edema and severe open-leg ulcerations, surgery was not initially recommended.Figure 6 AP right hip obtained upon initial presentation to PCP with right hip pain. Revealing subchondral lucency of the right femoral head. No acetabular involvement noted.
Given ongoing severe pain and disability, she underwent medical optimization taking 13 months, although during that time, she developed progressive osteonecrosis of the acetabulum. The progression of this can be seen in Figure 7, Figure 8 obtained 1 month later. Her fracture initially demonstrated disruption of the right iliopubic line with sclerosis of the supraacetabular ilium with superior displacement of the femoral head into the ilium consistent with protrusio fracture. This was further evaluated with a CT of the pelvis, which demonstrated comminution of anterior and posterior columns and 14 gapping of articular surface along anterosuperior acetabulum and medullary sclerosis of the surrounding ilium. Follow-up radiography seen in Figure 8 demonstrated increased displacement of anterior and posterior columns with medial acetabular wall displacement measuring 8 mm. Figure 8 was ultimately used for templating her implants. Iliac oblique and obturator oblique views at this time seen in Figure 9, Figure 10 better demonstrate involvement of the anterior and posterior column, medial protrusion of the acetabulum. She was no longer able to ambulate with a walker and was wheelchair bound. Her steroid dose then was 5 mg, 5 days per week, and 10 mg, 2 days per week. Treatment options discussed with patient included Girdlestone resection, THA, and THA with antiprotrusio cage or cup and cage construct. Reconstruction was preferred by patient over Girdlestone resection as she was hoping to resume ambulation and activities of daily living (ADLs). Surgery was pursued with posterior THA, with cage construct and posterior column plating. This fixation was used as the size of the pelvis was not large enough to facilitate a cup/cage construct. Medial acetabulum bony deficiency with both columns, or transverse-type insufficiency fracture or pelvic discontinuity variant, was encountered. After femoral neck cut was made, A 7-hole pelvic reconstruction plate was contoured, and a posterior column plated from ischium to ileum with good fixation using 4 small fragment screws. After the cage was placed, 10 mL of synthetic bone graft with 30 mL of allograft cancellous chips was placed posteriorly to cage. There were no intraoperative complications, and she was discharged home after 2 days. Two weeks postoperatively, she had a 2-day admission for viral gastroenteritis. She also underwent kyphoplasty for three (T9, T11, L1) vertebral compression fractures 2 months postoperatively. There were no readmissions or emergency department visits for postoperative complications.Figure 7 AP pelvic x-ray 6 months since onset of symptoms and 10 months preoperatively. Revealing displaced healing right acetabular fracture. Disruption of the right iliopubic line and sclerosis of the right supra-acetabular ilium. Sclerosis of the right femoral head was also observed.
Figure 8 AP pelvis x-ray 13 months since onset of symptoms and 1.5 months preoperatively. Showing comminuted displaced right acetabular transverse fracture also involving the posterior and medial acetabular walls. Right femoral head is also eroded and aspherical. This film was used for templating.
Figure 9 Right iliac oblique x-ray 13 months since onset of symptoms and 1.5 months preoperatively demonstrating transverse plus posterior acetabular wall fracture with 1.5 cm medial displacement of medial acetabular wall.
Figure 10 Right obturator oblique x-ray 13 months since onset of symptoms and 1.5 months preoperatively. Further demonstrating comminuted posterior acetabular wall insufficiency fracture, aspherical and eroded femoral head, and some bony callus.
One-month postoperatively, her pain was decreasing, and function with ADLs increased, although she required a walker because of back pain and deconditioning. Her gait was smooth, not antalgic, with the walker. Two views of AP pelvis performed at that time are seen in Figure 11. One-year postoperatively, her pain had resolved, she still required a walker, and she was noted to have Trendelenburg gait. AP pelvis 1 year postoperatively, seen in Figure 12, showed well-positioned THA with no lucencies or subsidence. Unfortunately, 3 years postoperatively, she died of causes related to her MDS and GVHD.Figure 11 Portable pelvis x-ray 1-month postoperatively. Intact cup and cage construct implants, near anatomic alignment of acetabular fracture.
Figure 12 AP pelvis x-rays 1-year postoperatively. Interval acetabular healing was seen. Diffuse osteopenia but no evidence of implant failure.
Discussion
Patients with hematologic malignancies are having increased remission and survivorship after autologous and allogenic hematopoietic stem cell transplantations [14,15]. Allogeneic stem cell transplantation is unique as opposed to autologous transplant as it can lead to GVHD. GVHD is a systemic immune reaction by donor cells against host cells [16]. Several studies have demonstrated the increased risk of osteonecrosis because of GVHD [5,9,11,17,18]. GVHD is thought to cause osteonecrosis because of an inflammatory process in the intraosseous vasculature. Sixou et al. [19] found histologic evidence of vasculitis attributed to GVHD. This vasculitis exacerbates risk factors associated with osteonecrosis inclusive to patients with hematologic malignancies including systemic glucocorticoids, chemotherapeutics, and irradiation [5].
Unique to the presented cases is osteonecrosis of the acetabulum and the timeline to develop osteonecrosis. Case 1 took 5 years for manifestation of acetabular osteonecrosis after initiation of steroids for GVHD. Case 2 took 13 months until acetabular osteonecrosis began after onset of GVHD. In 11 patients (19 hips, 8 patients with bilateral osteonecrosis) studied by Schulte and Beelen, onset of osteonecrosis after allogeneic stem cell transplant ranged from 5 to 57 months, with an average of 25 months [9,18]. However, all these cases were of the femoral head, and the hematologic malignancies were AML, MDS, CML, and ALL. It is unclear in the presented cases what circumstances led to osteonecrosis of the acetabulum. Location and timeline could be attributed to age. Bizot et al. [17] had 16 patients with osteonecrosis secondary to GVHD, although the oldest patient was 47 years old at the time of surgery (average age 13 ± 8 years). The patients presented were 60 and 52 years old at the time of surgery.
Several other studies have identified osteonecrosis risk factors in hematologic malignancies; Schulte and Beelen demonstrated that the most impactful risk factors were chronic GVHD and cumulative steroid intake, followed by female gender, younger age, and conditioning therapy before transplant. Advanced disease stages, bone mineral density, and body composition did not have a significant impact on osteonecrosis [9,18]. The disease process of lymphoma itself may contribute; Chalmers et al. showed that lymphoma was the underlying diagnosis in 33% of THAs in patients with a history of stem cell transplant. However, not all of these patients had a history of GVHD [13].
In these cases, owing to the insufficiency fractures of the acetabular with effective pelvic discontinuity (PD) and the tenuous vascular supply of surrounding bone, THA was conducted with cage construct and bridge plating of the posterior column. This construct has shown efficacy in cases with PD and severe acetabular bone loss in revision THA [[20], [21], [22], [23]]. Plating is primarily studied in revision arthroplasty cases with PD [24,25]. Plating was chosen to restore continuity, optimize contact of viable bone, and add stability to the reconstruction. This fixation technique of posterior column plating with antiprotrusion cage placement led to stability with improved ADLs, restoration of ambulation with full weightbearing, and resolution of pain at 1 year for both cases. Certainly, the perioperative risk of significant surgical or medical complications is high for patients with GVHD; therefore, this technique should be considered in situations with tenuous blood supply and insufficiency fractures in the setting of hematologic malignancy and GVHD.
Summary
These cases are unique reports of osteonecrosis focal to the acetabulum, in patients with history of stem cell transplant and subsequent GVHD. The impact of this disease process should not be overlooked in patients with hematologic malignances and GVHD. Surgical treatment with multifaceted construct, in these cases with an antiprotrusio cage bolstered by posterior column plating, can relieve pain and improve mobility.
Conflict of interest
Dr. Schabel obtains research support from Zimmer Biomet, unrelated to this work. She is also a board member for the Oregon Association of Orthopaedists.
Supplementary data
Conflict of Interest Statement for Nielsen
Conflict of Interest Statement for Schabel
Statements of informed consent were obtained from patients and family members of deceased patients. | PART OF R?CHOP REGIMEN | DrugDosageText | CC BY-NC-ND | 33521198 | 18,981,647 | 2021-02 |
What was the outcome of reaction 'Arthropathy'? | Acetabular Insufficiency Fractures in the Setting of Graft vs Host Disease: A Report of Two Cases.
We report a case series of 2 patients with unilateral acetabular insufficiency fractures who received allogeneic peripheral blood stem cell transplantation for hematologic malignancies complicated by chronic graft vs host disease. These were managed with uncemented cup and cage total hip arthroplasty and stabilization of posterior column with plating. Osteonecrosis of the acetabulum is an uncommon musculoskeletal complication of chronic graft vs host disease. The orthopedic impact of this disease should not be overlooked. Surgical intervention with this construct can provide necessary stability to improve patient function.
Introduction
Graft vs host disease (GVHD) can manifest with multisystemic effects. GVHD can occur after allogeneic peripheral blood stem cell transplantation (PBSCT) and can have orthopedic implications such as osteonecrosis. The incidence of osteonecrosis after allogeneic stem cell transplantation is 4-19% [[1], [2], [3], [4]], and the risk is increased in patients with GVHD [5]. Most studies described involve the femoral head [[1], [2], [3], [4],[6], [7], [8], [9], [10], [11], [12]]. Osteonecrosis of the acetabulum, although rare, can lead to significant complications. These include interruption of the articular surface, insufficiency fracture, and protrusio acetabulum. Osteonecrosis of the acetabulum presents particular difficulty in fixation; poor bone quality can impact long-term patient outcomes and implant survivorship. Implant survivorship of THA in patients with allogeneic peripheral stem cell transplantation at 5 years is up to 93% [11], although it can be as low as 74.8% at 10 years [13]. Therefore, THA and fracture fixation in this setting require an approach that combines primary and revision arthroplasty skills to enable immediate weight bearing and pain relief. We present 2 cases of allogeneic PBSCT complicated by GVHD, with resultant acetabular osteonecrosis leading to acetabular insufficiency fracture and the surgical reconstruction that followed.
Case histories
Case 1
Case 1 is a 60-year-old woman with a history of diffuse large B-cell lymphoma who underwent 8 cycles of R-CHOP (rituximab, cyclophosphamide, hydroxydaunorubicin, oncovin [vincristine], and prednisolone). Her disease recurred and was treated with radiolabeled tositumomab with maintenance on rituximab. Relapse occurred once more, and she received salvage chemotherapy with R-ICE (rituximab, ifosfamide, etoposide, carboplatin) followed by autologous PBSCT. She underwent human leukocyte antigen (HLA)-matched allogeneic PBSCT after fludarabine-melphalan conditioning for relapse involving the central nervous system. This was complicated by GVHD, primarily affecting the gastrointestinal tract, that improved with 20-mg prednisone BID (0.5 mg/kg/day). After several dose escalations and relapses, she was tapered off prednisone three times, but after two severe episodes of pericarditis in the absence of steroids, she remained on 10-mg prednisone daily.
She presented to orthopedics with 1 month of acute, “aching” left-sided groin pain, global left hip weakness, difficulty ambulating (newly required a four-wheel walker), and ecchymosis in her inguinal crease. Physical examination revealed severe pain with hip internal and external rotation, as well as adduction and abduction. She could conduct passive hip flexion to 90 degrees but had pain with resisted hip flexion. Magnetic resonance imaging (MRI) of the pelvis and hip was obtained by her primary care provider before orthopedic referral, and AP of the pelvis was obtained as seen in Figure 1. Initial radiography in Figure 1 and MRI demonstrated comminuted minimally displaced fracture of the acetabulum involving the anterior and posterior columns with acetabular protrusio fracture and superior displacement of the femur of 3.5 cm. Interruption of the anterior and posterior columns is better visualized on iliac oblique and obturator oblique views seen in Figure 2, Figure 3.Figure 1 AP pelvis x-ray upon initial presentation showed displaced acetabular fracture and interruption of the femoroacetabular joint space.
Figure 2 Left obturator oblique better demonstrates insufficiency fracture of the posterior wall and anterior column.
Figure 3 Left iliac oblique further demonstrates osteonecrosis of the acetabulum and fracture extending through the posterior column.
Owing to severe disability and pain, and acetabular insufficiency (pathologic) fracture and joint collapse, posterior THA and posterior column stabilization was undertaken. Posterolateral approach was taken to optimize exposure of acetabular fracture and perform THA. Complex THA was performed using a cage construct. Pelvic size thwarted the use of a cup and cage construct. Findings include fragmentation of medial acetabulum with transverse-type insufficiency or pathologic fracture. Acetabular pathologic fracture was repaired, or stabilized, with 8-hole reconstruction plate bent for the left posterior column. Morselized femoral head autograft was placed at the base of the protruded acetabulum. Dome screws of antiprotrusio cage were placed before ilium cage screws, and 5 mL of synthetic bone graft and 30 mL of cancellous bone allograft was injected behind cage. Postoperative x-ray is demonstrated in Figure 4. Her postoperative activity restrictions included posterior hip precautions, and weightbearing as tolerated with an assistive device, with weaning as she was able.Figure 4 Day 0 postoperative AP pelvis x-ray. THA with cage construct and iliac plating.
At her 3-month follow-up visit, she was able to fully weight bear on her left lower extremity without pain or assistive device. Imaging obtained at that time is seen in Figure 5. At 5 months postoperatively, she underwent right total knee arthroplasty because of osteoarthritis present before the acetabular osteonecrosis and was progressing very well with physical therapy. Unfortunately, 16 months after complex left THA, she succumbed to complications of diffuse large B-cell lymphoma and GVHD.Figure 5 Three months postoperative AP pelvis. Revealed intact cage hardware, posterior column plating, and THA. Interval ileum healing was perceived.
Case 2
Case 2 is a 51-year-old woman with a history of acute myelogenous leukemia (AML), secondary myelodysplastic syndrome (MDS), GVHD, steroid-induced diabetes, and restrictive pulmonary disease. Autologous PBSCT was undertaken for AML 9 years before presentation. Matched unrelated donor PBSCT was conducted 1 year before presentation, after fludarabine-melphalan conditioning. GVHD characterized by gastrointestinal symptoms and florid skin rash complicated PBSCT 4 months before presentation. Steroid dosage during GVHD was started at 1 mg/kg/day (60 mg BID) with rapid resolution of symptoms leading to taper of steroids down to 0.5 mg/kg/day after 1 week. She developed recurrence of pulmonary symptoms and gastrointestinal symptoms with tapering and was restarted on 1 mg/kg/day.
She presented to orthopedics with 2 months of right hip pain, primarily in her deep inguinal crease. She required a walker for ambulation and was limited to very short distances because of pain. The examination was remarkable for BMI = 44, anasarca, and painful and limited right hip rotation with only 10 degrees of passive external and internal rotation. Radiographs taken at that time are seen in Figure 6. MRI performed at that time showed hypointensity of the supra-acetabular ilium with some T2 hyperintensity measuring 2.5 cm transverse × 2.4 cm AP suggestive of osteonecrosis, although without collapse. There was also osteonecrosis of the left femoral head, without collapse. Given significant comorbid conditions including bilateral lower extremity edema and severe open-leg ulcerations, surgery was not initially recommended.Figure 6 AP right hip obtained upon initial presentation to PCP with right hip pain. Revealing subchondral lucency of the right femoral head. No acetabular involvement noted.
Given ongoing severe pain and disability, she underwent medical optimization taking 13 months, although during that time, she developed progressive osteonecrosis of the acetabulum. The progression of this can be seen in Figure 7, Figure 8 obtained 1 month later. Her fracture initially demonstrated disruption of the right iliopubic line with sclerosis of the supraacetabular ilium with superior displacement of the femoral head into the ilium consistent with protrusio fracture. This was further evaluated with a CT of the pelvis, which demonstrated comminution of anterior and posterior columns and 14 gapping of articular surface along anterosuperior acetabulum and medullary sclerosis of the surrounding ilium. Follow-up radiography seen in Figure 8 demonstrated increased displacement of anterior and posterior columns with medial acetabular wall displacement measuring 8 mm. Figure 8 was ultimately used for templating her implants. Iliac oblique and obturator oblique views at this time seen in Figure 9, Figure 10 better demonstrate involvement of the anterior and posterior column, medial protrusion of the acetabulum. She was no longer able to ambulate with a walker and was wheelchair bound. Her steroid dose then was 5 mg, 5 days per week, and 10 mg, 2 days per week. Treatment options discussed with patient included Girdlestone resection, THA, and THA with antiprotrusio cage or cup and cage construct. Reconstruction was preferred by patient over Girdlestone resection as she was hoping to resume ambulation and activities of daily living (ADLs). Surgery was pursued with posterior THA, with cage construct and posterior column plating. This fixation was used as the size of the pelvis was not large enough to facilitate a cup/cage construct. Medial acetabulum bony deficiency with both columns, or transverse-type insufficiency fracture or pelvic discontinuity variant, was encountered. After femoral neck cut was made, A 7-hole pelvic reconstruction plate was contoured, and a posterior column plated from ischium to ileum with good fixation using 4 small fragment screws. After the cage was placed, 10 mL of synthetic bone graft with 30 mL of allograft cancellous chips was placed posteriorly to cage. There were no intraoperative complications, and she was discharged home after 2 days. Two weeks postoperatively, she had a 2-day admission for viral gastroenteritis. She also underwent kyphoplasty for three (T9, T11, L1) vertebral compression fractures 2 months postoperatively. There were no readmissions or emergency department visits for postoperative complications.Figure 7 AP pelvic x-ray 6 months since onset of symptoms and 10 months preoperatively. Revealing displaced healing right acetabular fracture. Disruption of the right iliopubic line and sclerosis of the right supra-acetabular ilium. Sclerosis of the right femoral head was also observed.
Figure 8 AP pelvis x-ray 13 months since onset of symptoms and 1.5 months preoperatively. Showing comminuted displaced right acetabular transverse fracture also involving the posterior and medial acetabular walls. Right femoral head is also eroded and aspherical. This film was used for templating.
Figure 9 Right iliac oblique x-ray 13 months since onset of symptoms and 1.5 months preoperatively demonstrating transverse plus posterior acetabular wall fracture with 1.5 cm medial displacement of medial acetabular wall.
Figure 10 Right obturator oblique x-ray 13 months since onset of symptoms and 1.5 months preoperatively. Further demonstrating comminuted posterior acetabular wall insufficiency fracture, aspherical and eroded femoral head, and some bony callus.
One-month postoperatively, her pain was decreasing, and function with ADLs increased, although she required a walker because of back pain and deconditioning. Her gait was smooth, not antalgic, with the walker. Two views of AP pelvis performed at that time are seen in Figure 11. One-year postoperatively, her pain had resolved, she still required a walker, and she was noted to have Trendelenburg gait. AP pelvis 1 year postoperatively, seen in Figure 12, showed well-positioned THA with no lucencies or subsidence. Unfortunately, 3 years postoperatively, she died of causes related to her MDS and GVHD.Figure 11 Portable pelvis x-ray 1-month postoperatively. Intact cup and cage construct implants, near anatomic alignment of acetabular fracture.
Figure 12 AP pelvis x-rays 1-year postoperatively. Interval acetabular healing was seen. Diffuse osteopenia but no evidence of implant failure.
Discussion
Patients with hematologic malignancies are having increased remission and survivorship after autologous and allogenic hematopoietic stem cell transplantations [14,15]. Allogeneic stem cell transplantation is unique as opposed to autologous transplant as it can lead to GVHD. GVHD is a systemic immune reaction by donor cells against host cells [16]. Several studies have demonstrated the increased risk of osteonecrosis because of GVHD [5,9,11,17,18]. GVHD is thought to cause osteonecrosis because of an inflammatory process in the intraosseous vasculature. Sixou et al. [19] found histologic evidence of vasculitis attributed to GVHD. This vasculitis exacerbates risk factors associated with osteonecrosis inclusive to patients with hematologic malignancies including systemic glucocorticoids, chemotherapeutics, and irradiation [5].
Unique to the presented cases is osteonecrosis of the acetabulum and the timeline to develop osteonecrosis. Case 1 took 5 years for manifestation of acetabular osteonecrosis after initiation of steroids for GVHD. Case 2 took 13 months until acetabular osteonecrosis began after onset of GVHD. In 11 patients (19 hips, 8 patients with bilateral osteonecrosis) studied by Schulte and Beelen, onset of osteonecrosis after allogeneic stem cell transplant ranged from 5 to 57 months, with an average of 25 months [9,18]. However, all these cases were of the femoral head, and the hematologic malignancies were AML, MDS, CML, and ALL. It is unclear in the presented cases what circumstances led to osteonecrosis of the acetabulum. Location and timeline could be attributed to age. Bizot et al. [17] had 16 patients with osteonecrosis secondary to GVHD, although the oldest patient was 47 years old at the time of surgery (average age 13 ± 8 years). The patients presented were 60 and 52 years old at the time of surgery.
Several other studies have identified osteonecrosis risk factors in hematologic malignancies; Schulte and Beelen demonstrated that the most impactful risk factors were chronic GVHD and cumulative steroid intake, followed by female gender, younger age, and conditioning therapy before transplant. Advanced disease stages, bone mineral density, and body composition did not have a significant impact on osteonecrosis [9,18]. The disease process of lymphoma itself may contribute; Chalmers et al. showed that lymphoma was the underlying diagnosis in 33% of THAs in patients with a history of stem cell transplant. However, not all of these patients had a history of GVHD [13].
In these cases, owing to the insufficiency fractures of the acetabular with effective pelvic discontinuity (PD) and the tenuous vascular supply of surrounding bone, THA was conducted with cage construct and bridge plating of the posterior column. This construct has shown efficacy in cases with PD and severe acetabular bone loss in revision THA [[20], [21], [22], [23]]. Plating is primarily studied in revision arthroplasty cases with PD [24,25]. Plating was chosen to restore continuity, optimize contact of viable bone, and add stability to the reconstruction. This fixation technique of posterior column plating with antiprotrusion cage placement led to stability with improved ADLs, restoration of ambulation with full weightbearing, and resolution of pain at 1 year for both cases. Certainly, the perioperative risk of significant surgical or medical complications is high for patients with GVHD; therefore, this technique should be considered in situations with tenuous blood supply and insufficiency fractures in the setting of hematologic malignancy and GVHD.
Summary
These cases are unique reports of osteonecrosis focal to the acetabulum, in patients with history of stem cell transplant and subsequent GVHD. The impact of this disease process should not be overlooked in patients with hematologic malignances and GVHD. Surgical treatment with multifaceted construct, in these cases with an antiprotrusio cage bolstered by posterior column plating, can relieve pain and improve mobility.
Conflict of interest
Dr. Schabel obtains research support from Zimmer Biomet, unrelated to this work. She is also a board member for the Oregon Association of Orthopaedists.
Supplementary data
Conflict of Interest Statement for Nielsen
Conflict of Interest Statement for Schabel
Statements of informed consent were obtained from patients and family members of deceased patients. | Recovering | ReactionOutcome | CC BY-NC-ND | 33521198 | 18,981,647 | 2021-02 |
What was the outcome of reaction 'Diffuse large B-cell lymphoma'? | Acetabular Insufficiency Fractures in the Setting of Graft vs Host Disease: A Report of Two Cases.
We report a case series of 2 patients with unilateral acetabular insufficiency fractures who received allogeneic peripheral blood stem cell transplantation for hematologic malignancies complicated by chronic graft vs host disease. These were managed with uncemented cup and cage total hip arthroplasty and stabilization of posterior column with plating. Osteonecrosis of the acetabulum is an uncommon musculoskeletal complication of chronic graft vs host disease. The orthopedic impact of this disease should not be overlooked. Surgical intervention with this construct can provide necessary stability to improve patient function.
Introduction
Graft vs host disease (GVHD) can manifest with multisystemic effects. GVHD can occur after allogeneic peripheral blood stem cell transplantation (PBSCT) and can have orthopedic implications such as osteonecrosis. The incidence of osteonecrosis after allogeneic stem cell transplantation is 4-19% [[1], [2], [3], [4]], and the risk is increased in patients with GVHD [5]. Most studies described involve the femoral head [[1], [2], [3], [4],[6], [7], [8], [9], [10], [11], [12]]. Osteonecrosis of the acetabulum, although rare, can lead to significant complications. These include interruption of the articular surface, insufficiency fracture, and protrusio acetabulum. Osteonecrosis of the acetabulum presents particular difficulty in fixation; poor bone quality can impact long-term patient outcomes and implant survivorship. Implant survivorship of THA in patients with allogeneic peripheral stem cell transplantation at 5 years is up to 93% [11], although it can be as low as 74.8% at 10 years [13]. Therefore, THA and fracture fixation in this setting require an approach that combines primary and revision arthroplasty skills to enable immediate weight bearing and pain relief. We present 2 cases of allogeneic PBSCT complicated by GVHD, with resultant acetabular osteonecrosis leading to acetabular insufficiency fracture and the surgical reconstruction that followed.
Case histories
Case 1
Case 1 is a 60-year-old woman with a history of diffuse large B-cell lymphoma who underwent 8 cycles of R-CHOP (rituximab, cyclophosphamide, hydroxydaunorubicin, oncovin [vincristine], and prednisolone). Her disease recurred and was treated with radiolabeled tositumomab with maintenance on rituximab. Relapse occurred once more, and she received salvage chemotherapy with R-ICE (rituximab, ifosfamide, etoposide, carboplatin) followed by autologous PBSCT. She underwent human leukocyte antigen (HLA)-matched allogeneic PBSCT after fludarabine-melphalan conditioning for relapse involving the central nervous system. This was complicated by GVHD, primarily affecting the gastrointestinal tract, that improved with 20-mg prednisone BID (0.5 mg/kg/day). After several dose escalations and relapses, she was tapered off prednisone three times, but after two severe episodes of pericarditis in the absence of steroids, she remained on 10-mg prednisone daily.
She presented to orthopedics with 1 month of acute, “aching” left-sided groin pain, global left hip weakness, difficulty ambulating (newly required a four-wheel walker), and ecchymosis in her inguinal crease. Physical examination revealed severe pain with hip internal and external rotation, as well as adduction and abduction. She could conduct passive hip flexion to 90 degrees but had pain with resisted hip flexion. Magnetic resonance imaging (MRI) of the pelvis and hip was obtained by her primary care provider before orthopedic referral, and AP of the pelvis was obtained as seen in Figure 1. Initial radiography in Figure 1 and MRI demonstrated comminuted minimally displaced fracture of the acetabulum involving the anterior and posterior columns with acetabular protrusio fracture and superior displacement of the femur of 3.5 cm. Interruption of the anterior and posterior columns is better visualized on iliac oblique and obturator oblique views seen in Figure 2, Figure 3.Figure 1 AP pelvis x-ray upon initial presentation showed displaced acetabular fracture and interruption of the femoroacetabular joint space.
Figure 2 Left obturator oblique better demonstrates insufficiency fracture of the posterior wall and anterior column.
Figure 3 Left iliac oblique further demonstrates osteonecrosis of the acetabulum and fracture extending through the posterior column.
Owing to severe disability and pain, and acetabular insufficiency (pathologic) fracture and joint collapse, posterior THA and posterior column stabilization was undertaken. Posterolateral approach was taken to optimize exposure of acetabular fracture and perform THA. Complex THA was performed using a cage construct. Pelvic size thwarted the use of a cup and cage construct. Findings include fragmentation of medial acetabulum with transverse-type insufficiency or pathologic fracture. Acetabular pathologic fracture was repaired, or stabilized, with 8-hole reconstruction plate bent for the left posterior column. Morselized femoral head autograft was placed at the base of the protruded acetabulum. Dome screws of antiprotrusio cage were placed before ilium cage screws, and 5 mL of synthetic bone graft and 30 mL of cancellous bone allograft was injected behind cage. Postoperative x-ray is demonstrated in Figure 4. Her postoperative activity restrictions included posterior hip precautions, and weightbearing as tolerated with an assistive device, with weaning as she was able.Figure 4 Day 0 postoperative AP pelvis x-ray. THA with cage construct and iliac plating.
At her 3-month follow-up visit, she was able to fully weight bear on her left lower extremity without pain or assistive device. Imaging obtained at that time is seen in Figure 5. At 5 months postoperatively, she underwent right total knee arthroplasty because of osteoarthritis present before the acetabular osteonecrosis and was progressing very well with physical therapy. Unfortunately, 16 months after complex left THA, she succumbed to complications of diffuse large B-cell lymphoma and GVHD.Figure 5 Three months postoperative AP pelvis. Revealed intact cage hardware, posterior column plating, and THA. Interval ileum healing was perceived.
Case 2
Case 2 is a 51-year-old woman with a history of acute myelogenous leukemia (AML), secondary myelodysplastic syndrome (MDS), GVHD, steroid-induced diabetes, and restrictive pulmonary disease. Autologous PBSCT was undertaken for AML 9 years before presentation. Matched unrelated donor PBSCT was conducted 1 year before presentation, after fludarabine-melphalan conditioning. GVHD characterized by gastrointestinal symptoms and florid skin rash complicated PBSCT 4 months before presentation. Steroid dosage during GVHD was started at 1 mg/kg/day (60 mg BID) with rapid resolution of symptoms leading to taper of steroids down to 0.5 mg/kg/day after 1 week. She developed recurrence of pulmonary symptoms and gastrointestinal symptoms with tapering and was restarted on 1 mg/kg/day.
She presented to orthopedics with 2 months of right hip pain, primarily in her deep inguinal crease. She required a walker for ambulation and was limited to very short distances because of pain. The examination was remarkable for BMI = 44, anasarca, and painful and limited right hip rotation with only 10 degrees of passive external and internal rotation. Radiographs taken at that time are seen in Figure 6. MRI performed at that time showed hypointensity of the supra-acetabular ilium with some T2 hyperintensity measuring 2.5 cm transverse × 2.4 cm AP suggestive of osteonecrosis, although without collapse. There was also osteonecrosis of the left femoral head, without collapse. Given significant comorbid conditions including bilateral lower extremity edema and severe open-leg ulcerations, surgery was not initially recommended.Figure 6 AP right hip obtained upon initial presentation to PCP with right hip pain. Revealing subchondral lucency of the right femoral head. No acetabular involvement noted.
Given ongoing severe pain and disability, she underwent medical optimization taking 13 months, although during that time, she developed progressive osteonecrosis of the acetabulum. The progression of this can be seen in Figure 7, Figure 8 obtained 1 month later. Her fracture initially demonstrated disruption of the right iliopubic line with sclerosis of the supraacetabular ilium with superior displacement of the femoral head into the ilium consistent with protrusio fracture. This was further evaluated with a CT of the pelvis, which demonstrated comminution of anterior and posterior columns and 14 gapping of articular surface along anterosuperior acetabulum and medullary sclerosis of the surrounding ilium. Follow-up radiography seen in Figure 8 demonstrated increased displacement of anterior and posterior columns with medial acetabular wall displacement measuring 8 mm. Figure 8 was ultimately used for templating her implants. Iliac oblique and obturator oblique views at this time seen in Figure 9, Figure 10 better demonstrate involvement of the anterior and posterior column, medial protrusion of the acetabulum. She was no longer able to ambulate with a walker and was wheelchair bound. Her steroid dose then was 5 mg, 5 days per week, and 10 mg, 2 days per week. Treatment options discussed with patient included Girdlestone resection, THA, and THA with antiprotrusio cage or cup and cage construct. Reconstruction was preferred by patient over Girdlestone resection as she was hoping to resume ambulation and activities of daily living (ADLs). Surgery was pursued with posterior THA, with cage construct and posterior column plating. This fixation was used as the size of the pelvis was not large enough to facilitate a cup/cage construct. Medial acetabulum bony deficiency with both columns, or transverse-type insufficiency fracture or pelvic discontinuity variant, was encountered. After femoral neck cut was made, A 7-hole pelvic reconstruction plate was contoured, and a posterior column plated from ischium to ileum with good fixation using 4 small fragment screws. After the cage was placed, 10 mL of synthetic bone graft with 30 mL of allograft cancellous chips was placed posteriorly to cage. There were no intraoperative complications, and she was discharged home after 2 days. Two weeks postoperatively, she had a 2-day admission for viral gastroenteritis. She also underwent kyphoplasty for three (T9, T11, L1) vertebral compression fractures 2 months postoperatively. There were no readmissions or emergency department visits for postoperative complications.Figure 7 AP pelvic x-ray 6 months since onset of symptoms and 10 months preoperatively. Revealing displaced healing right acetabular fracture. Disruption of the right iliopubic line and sclerosis of the right supra-acetabular ilium. Sclerosis of the right femoral head was also observed.
Figure 8 AP pelvis x-ray 13 months since onset of symptoms and 1.5 months preoperatively. Showing comminuted displaced right acetabular transverse fracture also involving the posterior and medial acetabular walls. Right femoral head is also eroded and aspherical. This film was used for templating.
Figure 9 Right iliac oblique x-ray 13 months since onset of symptoms and 1.5 months preoperatively demonstrating transverse plus posterior acetabular wall fracture with 1.5 cm medial displacement of medial acetabular wall.
Figure 10 Right obturator oblique x-ray 13 months since onset of symptoms and 1.5 months preoperatively. Further demonstrating comminuted posterior acetabular wall insufficiency fracture, aspherical and eroded femoral head, and some bony callus.
One-month postoperatively, her pain was decreasing, and function with ADLs increased, although she required a walker because of back pain and deconditioning. Her gait was smooth, not antalgic, with the walker. Two views of AP pelvis performed at that time are seen in Figure 11. One-year postoperatively, her pain had resolved, she still required a walker, and she was noted to have Trendelenburg gait. AP pelvis 1 year postoperatively, seen in Figure 12, showed well-positioned THA with no lucencies or subsidence. Unfortunately, 3 years postoperatively, she died of causes related to her MDS and GVHD.Figure 11 Portable pelvis x-ray 1-month postoperatively. Intact cup and cage construct implants, near anatomic alignment of acetabular fracture.
Figure 12 AP pelvis x-rays 1-year postoperatively. Interval acetabular healing was seen. Diffuse osteopenia but no evidence of implant failure.
Discussion
Patients with hematologic malignancies are having increased remission and survivorship after autologous and allogenic hematopoietic stem cell transplantations [14,15]. Allogeneic stem cell transplantation is unique as opposed to autologous transplant as it can lead to GVHD. GVHD is a systemic immune reaction by donor cells against host cells [16]. Several studies have demonstrated the increased risk of osteonecrosis because of GVHD [5,9,11,17,18]. GVHD is thought to cause osteonecrosis because of an inflammatory process in the intraosseous vasculature. Sixou et al. [19] found histologic evidence of vasculitis attributed to GVHD. This vasculitis exacerbates risk factors associated with osteonecrosis inclusive to patients with hematologic malignancies including systemic glucocorticoids, chemotherapeutics, and irradiation [5].
Unique to the presented cases is osteonecrosis of the acetabulum and the timeline to develop osteonecrosis. Case 1 took 5 years for manifestation of acetabular osteonecrosis after initiation of steroids for GVHD. Case 2 took 13 months until acetabular osteonecrosis began after onset of GVHD. In 11 patients (19 hips, 8 patients with bilateral osteonecrosis) studied by Schulte and Beelen, onset of osteonecrosis after allogeneic stem cell transplant ranged from 5 to 57 months, with an average of 25 months [9,18]. However, all these cases were of the femoral head, and the hematologic malignancies were AML, MDS, CML, and ALL. It is unclear in the presented cases what circumstances led to osteonecrosis of the acetabulum. Location and timeline could be attributed to age. Bizot et al. [17] had 16 patients with osteonecrosis secondary to GVHD, although the oldest patient was 47 years old at the time of surgery (average age 13 ± 8 years). The patients presented were 60 and 52 years old at the time of surgery.
Several other studies have identified osteonecrosis risk factors in hematologic malignancies; Schulte and Beelen demonstrated that the most impactful risk factors were chronic GVHD and cumulative steroid intake, followed by female gender, younger age, and conditioning therapy before transplant. Advanced disease stages, bone mineral density, and body composition did not have a significant impact on osteonecrosis [9,18]. The disease process of lymphoma itself may contribute; Chalmers et al. showed that lymphoma was the underlying diagnosis in 33% of THAs in patients with a history of stem cell transplant. However, not all of these patients had a history of GVHD [13].
In these cases, owing to the insufficiency fractures of the acetabular with effective pelvic discontinuity (PD) and the tenuous vascular supply of surrounding bone, THA was conducted with cage construct and bridge plating of the posterior column. This construct has shown efficacy in cases with PD and severe acetabular bone loss in revision THA [[20], [21], [22], [23]]. Plating is primarily studied in revision arthroplasty cases with PD [24,25]. Plating was chosen to restore continuity, optimize contact of viable bone, and add stability to the reconstruction. This fixation technique of posterior column plating with antiprotrusion cage placement led to stability with improved ADLs, restoration of ambulation with full weightbearing, and resolution of pain at 1 year for both cases. Certainly, the perioperative risk of significant surgical or medical complications is high for patients with GVHD; therefore, this technique should be considered in situations with tenuous blood supply and insufficiency fractures in the setting of hematologic malignancy and GVHD.
Summary
These cases are unique reports of osteonecrosis focal to the acetabulum, in patients with history of stem cell transplant and subsequent GVHD. The impact of this disease process should not be overlooked in patients with hematologic malignances and GVHD. Surgical treatment with multifaceted construct, in these cases with an antiprotrusio cage bolstered by posterior column plating, can relieve pain and improve mobility.
Conflict of interest
Dr. Schabel obtains research support from Zimmer Biomet, unrelated to this work. She is also a board member for the Oregon Association of Orthopaedists.
Supplementary data
Conflict of Interest Statement for Nielsen
Conflict of Interest Statement for Schabel
Statements of informed consent were obtained from patients and family members of deceased patients. | Fatal | ReactionOutcome | CC BY-NC-ND | 33521198 | 18,925,490 | 2021-02 |
What was the outcome of reaction 'Graft versus host disease in gastrointestinal tract'? | Acetabular Insufficiency Fractures in the Setting of Graft vs Host Disease: A Report of Two Cases.
We report a case series of 2 patients with unilateral acetabular insufficiency fractures who received allogeneic peripheral blood stem cell transplantation for hematologic malignancies complicated by chronic graft vs host disease. These were managed with uncemented cup and cage total hip arthroplasty and stabilization of posterior column with plating. Osteonecrosis of the acetabulum is an uncommon musculoskeletal complication of chronic graft vs host disease. The orthopedic impact of this disease should not be overlooked. Surgical intervention with this construct can provide necessary stability to improve patient function.
Introduction
Graft vs host disease (GVHD) can manifest with multisystemic effects. GVHD can occur after allogeneic peripheral blood stem cell transplantation (PBSCT) and can have orthopedic implications such as osteonecrosis. The incidence of osteonecrosis after allogeneic stem cell transplantation is 4-19% [[1], [2], [3], [4]], and the risk is increased in patients with GVHD [5]. Most studies described involve the femoral head [[1], [2], [3], [4],[6], [7], [8], [9], [10], [11], [12]]. Osteonecrosis of the acetabulum, although rare, can lead to significant complications. These include interruption of the articular surface, insufficiency fracture, and protrusio acetabulum. Osteonecrosis of the acetabulum presents particular difficulty in fixation; poor bone quality can impact long-term patient outcomes and implant survivorship. Implant survivorship of THA in patients with allogeneic peripheral stem cell transplantation at 5 years is up to 93% [11], although it can be as low as 74.8% at 10 years [13]. Therefore, THA and fracture fixation in this setting require an approach that combines primary and revision arthroplasty skills to enable immediate weight bearing and pain relief. We present 2 cases of allogeneic PBSCT complicated by GVHD, with resultant acetabular osteonecrosis leading to acetabular insufficiency fracture and the surgical reconstruction that followed.
Case histories
Case 1
Case 1 is a 60-year-old woman with a history of diffuse large B-cell lymphoma who underwent 8 cycles of R-CHOP (rituximab, cyclophosphamide, hydroxydaunorubicin, oncovin [vincristine], and prednisolone). Her disease recurred and was treated with radiolabeled tositumomab with maintenance on rituximab. Relapse occurred once more, and she received salvage chemotherapy with R-ICE (rituximab, ifosfamide, etoposide, carboplatin) followed by autologous PBSCT. She underwent human leukocyte antigen (HLA)-matched allogeneic PBSCT after fludarabine-melphalan conditioning for relapse involving the central nervous system. This was complicated by GVHD, primarily affecting the gastrointestinal tract, that improved with 20-mg prednisone BID (0.5 mg/kg/day). After several dose escalations and relapses, she was tapered off prednisone three times, but after two severe episodes of pericarditis in the absence of steroids, she remained on 10-mg prednisone daily.
She presented to orthopedics with 1 month of acute, “aching” left-sided groin pain, global left hip weakness, difficulty ambulating (newly required a four-wheel walker), and ecchymosis in her inguinal crease. Physical examination revealed severe pain with hip internal and external rotation, as well as adduction and abduction. She could conduct passive hip flexion to 90 degrees but had pain with resisted hip flexion. Magnetic resonance imaging (MRI) of the pelvis and hip was obtained by her primary care provider before orthopedic referral, and AP of the pelvis was obtained as seen in Figure 1. Initial radiography in Figure 1 and MRI demonstrated comminuted minimally displaced fracture of the acetabulum involving the anterior and posterior columns with acetabular protrusio fracture and superior displacement of the femur of 3.5 cm. Interruption of the anterior and posterior columns is better visualized on iliac oblique and obturator oblique views seen in Figure 2, Figure 3.Figure 1 AP pelvis x-ray upon initial presentation showed displaced acetabular fracture and interruption of the femoroacetabular joint space.
Figure 2 Left obturator oblique better demonstrates insufficiency fracture of the posterior wall and anterior column.
Figure 3 Left iliac oblique further demonstrates osteonecrosis of the acetabulum and fracture extending through the posterior column.
Owing to severe disability and pain, and acetabular insufficiency (pathologic) fracture and joint collapse, posterior THA and posterior column stabilization was undertaken. Posterolateral approach was taken to optimize exposure of acetabular fracture and perform THA. Complex THA was performed using a cage construct. Pelvic size thwarted the use of a cup and cage construct. Findings include fragmentation of medial acetabulum with transverse-type insufficiency or pathologic fracture. Acetabular pathologic fracture was repaired, or stabilized, with 8-hole reconstruction plate bent for the left posterior column. Morselized femoral head autograft was placed at the base of the protruded acetabulum. Dome screws of antiprotrusio cage were placed before ilium cage screws, and 5 mL of synthetic bone graft and 30 mL of cancellous bone allograft was injected behind cage. Postoperative x-ray is demonstrated in Figure 4. Her postoperative activity restrictions included posterior hip precautions, and weightbearing as tolerated with an assistive device, with weaning as she was able.Figure 4 Day 0 postoperative AP pelvis x-ray. THA with cage construct and iliac plating.
At her 3-month follow-up visit, she was able to fully weight bear on her left lower extremity without pain or assistive device. Imaging obtained at that time is seen in Figure 5. At 5 months postoperatively, she underwent right total knee arthroplasty because of osteoarthritis present before the acetabular osteonecrosis and was progressing very well with physical therapy. Unfortunately, 16 months after complex left THA, she succumbed to complications of diffuse large B-cell lymphoma and GVHD.Figure 5 Three months postoperative AP pelvis. Revealed intact cage hardware, posterior column plating, and THA. Interval ileum healing was perceived.
Case 2
Case 2 is a 51-year-old woman with a history of acute myelogenous leukemia (AML), secondary myelodysplastic syndrome (MDS), GVHD, steroid-induced diabetes, and restrictive pulmonary disease. Autologous PBSCT was undertaken for AML 9 years before presentation. Matched unrelated donor PBSCT was conducted 1 year before presentation, after fludarabine-melphalan conditioning. GVHD characterized by gastrointestinal symptoms and florid skin rash complicated PBSCT 4 months before presentation. Steroid dosage during GVHD was started at 1 mg/kg/day (60 mg BID) with rapid resolution of symptoms leading to taper of steroids down to 0.5 mg/kg/day after 1 week. She developed recurrence of pulmonary symptoms and gastrointestinal symptoms with tapering and was restarted on 1 mg/kg/day.
She presented to orthopedics with 2 months of right hip pain, primarily in her deep inguinal crease. She required a walker for ambulation and was limited to very short distances because of pain. The examination was remarkable for BMI = 44, anasarca, and painful and limited right hip rotation with only 10 degrees of passive external and internal rotation. Radiographs taken at that time are seen in Figure 6. MRI performed at that time showed hypointensity of the supra-acetabular ilium with some T2 hyperintensity measuring 2.5 cm transverse × 2.4 cm AP suggestive of osteonecrosis, although without collapse. There was also osteonecrosis of the left femoral head, without collapse. Given significant comorbid conditions including bilateral lower extremity edema and severe open-leg ulcerations, surgery was not initially recommended.Figure 6 AP right hip obtained upon initial presentation to PCP with right hip pain. Revealing subchondral lucency of the right femoral head. No acetabular involvement noted.
Given ongoing severe pain and disability, she underwent medical optimization taking 13 months, although during that time, she developed progressive osteonecrosis of the acetabulum. The progression of this can be seen in Figure 7, Figure 8 obtained 1 month later. Her fracture initially demonstrated disruption of the right iliopubic line with sclerosis of the supraacetabular ilium with superior displacement of the femoral head into the ilium consistent with protrusio fracture. This was further evaluated with a CT of the pelvis, which demonstrated comminution of anterior and posterior columns and 14 gapping of articular surface along anterosuperior acetabulum and medullary sclerosis of the surrounding ilium. Follow-up radiography seen in Figure 8 demonstrated increased displacement of anterior and posterior columns with medial acetabular wall displacement measuring 8 mm. Figure 8 was ultimately used for templating her implants. Iliac oblique and obturator oblique views at this time seen in Figure 9, Figure 10 better demonstrate involvement of the anterior and posterior column, medial protrusion of the acetabulum. She was no longer able to ambulate with a walker and was wheelchair bound. Her steroid dose then was 5 mg, 5 days per week, and 10 mg, 2 days per week. Treatment options discussed with patient included Girdlestone resection, THA, and THA with antiprotrusio cage or cup and cage construct. Reconstruction was preferred by patient over Girdlestone resection as she was hoping to resume ambulation and activities of daily living (ADLs). Surgery was pursued with posterior THA, with cage construct and posterior column plating. This fixation was used as the size of the pelvis was not large enough to facilitate a cup/cage construct. Medial acetabulum bony deficiency with both columns, or transverse-type insufficiency fracture or pelvic discontinuity variant, was encountered. After femoral neck cut was made, A 7-hole pelvic reconstruction plate was contoured, and a posterior column plated from ischium to ileum with good fixation using 4 small fragment screws. After the cage was placed, 10 mL of synthetic bone graft with 30 mL of allograft cancellous chips was placed posteriorly to cage. There were no intraoperative complications, and she was discharged home after 2 days. Two weeks postoperatively, she had a 2-day admission for viral gastroenteritis. She also underwent kyphoplasty for three (T9, T11, L1) vertebral compression fractures 2 months postoperatively. There were no readmissions or emergency department visits for postoperative complications.Figure 7 AP pelvic x-ray 6 months since onset of symptoms and 10 months preoperatively. Revealing displaced healing right acetabular fracture. Disruption of the right iliopubic line and sclerosis of the right supra-acetabular ilium. Sclerosis of the right femoral head was also observed.
Figure 8 AP pelvis x-ray 13 months since onset of symptoms and 1.5 months preoperatively. Showing comminuted displaced right acetabular transverse fracture also involving the posterior and medial acetabular walls. Right femoral head is also eroded and aspherical. This film was used for templating.
Figure 9 Right iliac oblique x-ray 13 months since onset of symptoms and 1.5 months preoperatively demonstrating transverse plus posterior acetabular wall fracture with 1.5 cm medial displacement of medial acetabular wall.
Figure 10 Right obturator oblique x-ray 13 months since onset of symptoms and 1.5 months preoperatively. Further demonstrating comminuted posterior acetabular wall insufficiency fracture, aspherical and eroded femoral head, and some bony callus.
One-month postoperatively, her pain was decreasing, and function with ADLs increased, although she required a walker because of back pain and deconditioning. Her gait was smooth, not antalgic, with the walker. Two views of AP pelvis performed at that time are seen in Figure 11. One-year postoperatively, her pain had resolved, she still required a walker, and she was noted to have Trendelenburg gait. AP pelvis 1 year postoperatively, seen in Figure 12, showed well-positioned THA with no lucencies or subsidence. Unfortunately, 3 years postoperatively, she died of causes related to her MDS and GVHD.Figure 11 Portable pelvis x-ray 1-month postoperatively. Intact cup and cage construct implants, near anatomic alignment of acetabular fracture.
Figure 12 AP pelvis x-rays 1-year postoperatively. Interval acetabular healing was seen. Diffuse osteopenia but no evidence of implant failure.
Discussion
Patients with hematologic malignancies are having increased remission and survivorship after autologous and allogenic hematopoietic stem cell transplantations [14,15]. Allogeneic stem cell transplantation is unique as opposed to autologous transplant as it can lead to GVHD. GVHD is a systemic immune reaction by donor cells against host cells [16]. Several studies have demonstrated the increased risk of osteonecrosis because of GVHD [5,9,11,17,18]. GVHD is thought to cause osteonecrosis because of an inflammatory process in the intraosseous vasculature. Sixou et al. [19] found histologic evidence of vasculitis attributed to GVHD. This vasculitis exacerbates risk factors associated with osteonecrosis inclusive to patients with hematologic malignancies including systemic glucocorticoids, chemotherapeutics, and irradiation [5].
Unique to the presented cases is osteonecrosis of the acetabulum and the timeline to develop osteonecrosis. Case 1 took 5 years for manifestation of acetabular osteonecrosis after initiation of steroids for GVHD. Case 2 took 13 months until acetabular osteonecrosis began after onset of GVHD. In 11 patients (19 hips, 8 patients with bilateral osteonecrosis) studied by Schulte and Beelen, onset of osteonecrosis after allogeneic stem cell transplant ranged from 5 to 57 months, with an average of 25 months [9,18]. However, all these cases were of the femoral head, and the hematologic malignancies were AML, MDS, CML, and ALL. It is unclear in the presented cases what circumstances led to osteonecrosis of the acetabulum. Location and timeline could be attributed to age. Bizot et al. [17] had 16 patients with osteonecrosis secondary to GVHD, although the oldest patient was 47 years old at the time of surgery (average age 13 ± 8 years). The patients presented were 60 and 52 years old at the time of surgery.
Several other studies have identified osteonecrosis risk factors in hematologic malignancies; Schulte and Beelen demonstrated that the most impactful risk factors were chronic GVHD and cumulative steroid intake, followed by female gender, younger age, and conditioning therapy before transplant. Advanced disease stages, bone mineral density, and body composition did not have a significant impact on osteonecrosis [9,18]. The disease process of lymphoma itself may contribute; Chalmers et al. showed that lymphoma was the underlying diagnosis in 33% of THAs in patients with a history of stem cell transplant. However, not all of these patients had a history of GVHD [13].
In these cases, owing to the insufficiency fractures of the acetabular with effective pelvic discontinuity (PD) and the tenuous vascular supply of surrounding bone, THA was conducted with cage construct and bridge plating of the posterior column. This construct has shown efficacy in cases with PD and severe acetabular bone loss in revision THA [[20], [21], [22], [23]]. Plating is primarily studied in revision arthroplasty cases with PD [24,25]. Plating was chosen to restore continuity, optimize contact of viable bone, and add stability to the reconstruction. This fixation technique of posterior column plating with antiprotrusion cage placement led to stability with improved ADLs, restoration of ambulation with full weightbearing, and resolution of pain at 1 year for both cases. Certainly, the perioperative risk of significant surgical or medical complications is high for patients with GVHD; therefore, this technique should be considered in situations with tenuous blood supply and insufficiency fractures in the setting of hematologic malignancy and GVHD.
Summary
These cases are unique reports of osteonecrosis focal to the acetabulum, in patients with history of stem cell transplant and subsequent GVHD. The impact of this disease process should not be overlooked in patients with hematologic malignances and GVHD. Surgical treatment with multifaceted construct, in these cases with an antiprotrusio cage bolstered by posterior column plating, can relieve pain and improve mobility.
Conflict of interest
Dr. Schabel obtains research support from Zimmer Biomet, unrelated to this work. She is also a board member for the Oregon Association of Orthopaedists.
Supplementary data
Conflict of Interest Statement for Nielsen
Conflict of Interest Statement for Schabel
Statements of informed consent were obtained from patients and family members of deceased patients. | Fatal | ReactionOutcome | CC BY-NC-ND | 33521198 | 18,921,114 | 2021-02 |
What was the outcome of reaction 'Graft versus host disease'? | Acetabular Insufficiency Fractures in the Setting of Graft vs Host Disease: A Report of Two Cases.
We report a case series of 2 patients with unilateral acetabular insufficiency fractures who received allogeneic peripheral blood stem cell transplantation for hematologic malignancies complicated by chronic graft vs host disease. These were managed with uncemented cup and cage total hip arthroplasty and stabilization of posterior column with plating. Osteonecrosis of the acetabulum is an uncommon musculoskeletal complication of chronic graft vs host disease. The orthopedic impact of this disease should not be overlooked. Surgical intervention with this construct can provide necessary stability to improve patient function.
Introduction
Graft vs host disease (GVHD) can manifest with multisystemic effects. GVHD can occur after allogeneic peripheral blood stem cell transplantation (PBSCT) and can have orthopedic implications such as osteonecrosis. The incidence of osteonecrosis after allogeneic stem cell transplantation is 4-19% [[1], [2], [3], [4]], and the risk is increased in patients with GVHD [5]. Most studies described involve the femoral head [[1], [2], [3], [4],[6], [7], [8], [9], [10], [11], [12]]. Osteonecrosis of the acetabulum, although rare, can lead to significant complications. These include interruption of the articular surface, insufficiency fracture, and protrusio acetabulum. Osteonecrosis of the acetabulum presents particular difficulty in fixation; poor bone quality can impact long-term patient outcomes and implant survivorship. Implant survivorship of THA in patients with allogeneic peripheral stem cell transplantation at 5 years is up to 93% [11], although it can be as low as 74.8% at 10 years [13]. Therefore, THA and fracture fixation in this setting require an approach that combines primary and revision arthroplasty skills to enable immediate weight bearing and pain relief. We present 2 cases of allogeneic PBSCT complicated by GVHD, with resultant acetabular osteonecrosis leading to acetabular insufficiency fracture and the surgical reconstruction that followed.
Case histories
Case 1
Case 1 is a 60-year-old woman with a history of diffuse large B-cell lymphoma who underwent 8 cycles of R-CHOP (rituximab, cyclophosphamide, hydroxydaunorubicin, oncovin [vincristine], and prednisolone). Her disease recurred and was treated with radiolabeled tositumomab with maintenance on rituximab. Relapse occurred once more, and she received salvage chemotherapy with R-ICE (rituximab, ifosfamide, etoposide, carboplatin) followed by autologous PBSCT. She underwent human leukocyte antigen (HLA)-matched allogeneic PBSCT after fludarabine-melphalan conditioning for relapse involving the central nervous system. This was complicated by GVHD, primarily affecting the gastrointestinal tract, that improved with 20-mg prednisone BID (0.5 mg/kg/day). After several dose escalations and relapses, she was tapered off prednisone three times, but after two severe episodes of pericarditis in the absence of steroids, she remained on 10-mg prednisone daily.
She presented to orthopedics with 1 month of acute, “aching” left-sided groin pain, global left hip weakness, difficulty ambulating (newly required a four-wheel walker), and ecchymosis in her inguinal crease. Physical examination revealed severe pain with hip internal and external rotation, as well as adduction and abduction. She could conduct passive hip flexion to 90 degrees but had pain with resisted hip flexion. Magnetic resonance imaging (MRI) of the pelvis and hip was obtained by her primary care provider before orthopedic referral, and AP of the pelvis was obtained as seen in Figure 1. Initial radiography in Figure 1 and MRI demonstrated comminuted minimally displaced fracture of the acetabulum involving the anterior and posterior columns with acetabular protrusio fracture and superior displacement of the femur of 3.5 cm. Interruption of the anterior and posterior columns is better visualized on iliac oblique and obturator oblique views seen in Figure 2, Figure 3.Figure 1 AP pelvis x-ray upon initial presentation showed displaced acetabular fracture and interruption of the femoroacetabular joint space.
Figure 2 Left obturator oblique better demonstrates insufficiency fracture of the posterior wall and anterior column.
Figure 3 Left iliac oblique further demonstrates osteonecrosis of the acetabulum and fracture extending through the posterior column.
Owing to severe disability and pain, and acetabular insufficiency (pathologic) fracture and joint collapse, posterior THA and posterior column stabilization was undertaken. Posterolateral approach was taken to optimize exposure of acetabular fracture and perform THA. Complex THA was performed using a cage construct. Pelvic size thwarted the use of a cup and cage construct. Findings include fragmentation of medial acetabulum with transverse-type insufficiency or pathologic fracture. Acetabular pathologic fracture was repaired, or stabilized, with 8-hole reconstruction plate bent for the left posterior column. Morselized femoral head autograft was placed at the base of the protruded acetabulum. Dome screws of antiprotrusio cage were placed before ilium cage screws, and 5 mL of synthetic bone graft and 30 mL of cancellous bone allograft was injected behind cage. Postoperative x-ray is demonstrated in Figure 4. Her postoperative activity restrictions included posterior hip precautions, and weightbearing as tolerated with an assistive device, with weaning as she was able.Figure 4 Day 0 postoperative AP pelvis x-ray. THA with cage construct and iliac plating.
At her 3-month follow-up visit, she was able to fully weight bear on her left lower extremity without pain or assistive device. Imaging obtained at that time is seen in Figure 5. At 5 months postoperatively, she underwent right total knee arthroplasty because of osteoarthritis present before the acetabular osteonecrosis and was progressing very well with physical therapy. Unfortunately, 16 months after complex left THA, she succumbed to complications of diffuse large B-cell lymphoma and GVHD.Figure 5 Three months postoperative AP pelvis. Revealed intact cage hardware, posterior column plating, and THA. Interval ileum healing was perceived.
Case 2
Case 2 is a 51-year-old woman with a history of acute myelogenous leukemia (AML), secondary myelodysplastic syndrome (MDS), GVHD, steroid-induced diabetes, and restrictive pulmonary disease. Autologous PBSCT was undertaken for AML 9 years before presentation. Matched unrelated donor PBSCT was conducted 1 year before presentation, after fludarabine-melphalan conditioning. GVHD characterized by gastrointestinal symptoms and florid skin rash complicated PBSCT 4 months before presentation. Steroid dosage during GVHD was started at 1 mg/kg/day (60 mg BID) with rapid resolution of symptoms leading to taper of steroids down to 0.5 mg/kg/day after 1 week. She developed recurrence of pulmonary symptoms and gastrointestinal symptoms with tapering and was restarted on 1 mg/kg/day.
She presented to orthopedics with 2 months of right hip pain, primarily in her deep inguinal crease. She required a walker for ambulation and was limited to very short distances because of pain. The examination was remarkable for BMI = 44, anasarca, and painful and limited right hip rotation with only 10 degrees of passive external and internal rotation. Radiographs taken at that time are seen in Figure 6. MRI performed at that time showed hypointensity of the supra-acetabular ilium with some T2 hyperintensity measuring 2.5 cm transverse × 2.4 cm AP suggestive of osteonecrosis, although without collapse. There was also osteonecrosis of the left femoral head, without collapse. Given significant comorbid conditions including bilateral lower extremity edema and severe open-leg ulcerations, surgery was not initially recommended.Figure 6 AP right hip obtained upon initial presentation to PCP with right hip pain. Revealing subchondral lucency of the right femoral head. No acetabular involvement noted.
Given ongoing severe pain and disability, she underwent medical optimization taking 13 months, although during that time, she developed progressive osteonecrosis of the acetabulum. The progression of this can be seen in Figure 7, Figure 8 obtained 1 month later. Her fracture initially demonstrated disruption of the right iliopubic line with sclerosis of the supraacetabular ilium with superior displacement of the femoral head into the ilium consistent with protrusio fracture. This was further evaluated with a CT of the pelvis, which demonstrated comminution of anterior and posterior columns and 14 gapping of articular surface along anterosuperior acetabulum and medullary sclerosis of the surrounding ilium. Follow-up radiography seen in Figure 8 demonstrated increased displacement of anterior and posterior columns with medial acetabular wall displacement measuring 8 mm. Figure 8 was ultimately used for templating her implants. Iliac oblique and obturator oblique views at this time seen in Figure 9, Figure 10 better demonstrate involvement of the anterior and posterior column, medial protrusion of the acetabulum. She was no longer able to ambulate with a walker and was wheelchair bound. Her steroid dose then was 5 mg, 5 days per week, and 10 mg, 2 days per week. Treatment options discussed with patient included Girdlestone resection, THA, and THA with antiprotrusio cage or cup and cage construct. Reconstruction was preferred by patient over Girdlestone resection as she was hoping to resume ambulation and activities of daily living (ADLs). Surgery was pursued with posterior THA, with cage construct and posterior column plating. This fixation was used as the size of the pelvis was not large enough to facilitate a cup/cage construct. Medial acetabulum bony deficiency with both columns, or transverse-type insufficiency fracture or pelvic discontinuity variant, was encountered. After femoral neck cut was made, A 7-hole pelvic reconstruction plate was contoured, and a posterior column plated from ischium to ileum with good fixation using 4 small fragment screws. After the cage was placed, 10 mL of synthetic bone graft with 30 mL of allograft cancellous chips was placed posteriorly to cage. There were no intraoperative complications, and she was discharged home after 2 days. Two weeks postoperatively, she had a 2-day admission for viral gastroenteritis. She also underwent kyphoplasty for three (T9, T11, L1) vertebral compression fractures 2 months postoperatively. There were no readmissions or emergency department visits for postoperative complications.Figure 7 AP pelvic x-ray 6 months since onset of symptoms and 10 months preoperatively. Revealing displaced healing right acetabular fracture. Disruption of the right iliopubic line and sclerosis of the right supra-acetabular ilium. Sclerosis of the right femoral head was also observed.
Figure 8 AP pelvis x-ray 13 months since onset of symptoms and 1.5 months preoperatively. Showing comminuted displaced right acetabular transverse fracture also involving the posterior and medial acetabular walls. Right femoral head is also eroded and aspherical. This film was used for templating.
Figure 9 Right iliac oblique x-ray 13 months since onset of symptoms and 1.5 months preoperatively demonstrating transverse plus posterior acetabular wall fracture with 1.5 cm medial displacement of medial acetabular wall.
Figure 10 Right obturator oblique x-ray 13 months since onset of symptoms and 1.5 months preoperatively. Further demonstrating comminuted posterior acetabular wall insufficiency fracture, aspherical and eroded femoral head, and some bony callus.
One-month postoperatively, her pain was decreasing, and function with ADLs increased, although she required a walker because of back pain and deconditioning. Her gait was smooth, not antalgic, with the walker. Two views of AP pelvis performed at that time are seen in Figure 11. One-year postoperatively, her pain had resolved, she still required a walker, and she was noted to have Trendelenburg gait. AP pelvis 1 year postoperatively, seen in Figure 12, showed well-positioned THA with no lucencies or subsidence. Unfortunately, 3 years postoperatively, she died of causes related to her MDS and GVHD.Figure 11 Portable pelvis x-ray 1-month postoperatively. Intact cup and cage construct implants, near anatomic alignment of acetabular fracture.
Figure 12 AP pelvis x-rays 1-year postoperatively. Interval acetabular healing was seen. Diffuse osteopenia but no evidence of implant failure.
Discussion
Patients with hematologic malignancies are having increased remission and survivorship after autologous and allogenic hematopoietic stem cell transplantations [14,15]. Allogeneic stem cell transplantation is unique as opposed to autologous transplant as it can lead to GVHD. GVHD is a systemic immune reaction by donor cells against host cells [16]. Several studies have demonstrated the increased risk of osteonecrosis because of GVHD [5,9,11,17,18]. GVHD is thought to cause osteonecrosis because of an inflammatory process in the intraosseous vasculature. Sixou et al. [19] found histologic evidence of vasculitis attributed to GVHD. This vasculitis exacerbates risk factors associated with osteonecrosis inclusive to patients with hematologic malignancies including systemic glucocorticoids, chemotherapeutics, and irradiation [5].
Unique to the presented cases is osteonecrosis of the acetabulum and the timeline to develop osteonecrosis. Case 1 took 5 years for manifestation of acetabular osteonecrosis after initiation of steroids for GVHD. Case 2 took 13 months until acetabular osteonecrosis began after onset of GVHD. In 11 patients (19 hips, 8 patients with bilateral osteonecrosis) studied by Schulte and Beelen, onset of osteonecrosis after allogeneic stem cell transplant ranged from 5 to 57 months, with an average of 25 months [9,18]. However, all these cases were of the femoral head, and the hematologic malignancies were AML, MDS, CML, and ALL. It is unclear in the presented cases what circumstances led to osteonecrosis of the acetabulum. Location and timeline could be attributed to age. Bizot et al. [17] had 16 patients with osteonecrosis secondary to GVHD, although the oldest patient was 47 years old at the time of surgery (average age 13 ± 8 years). The patients presented were 60 and 52 years old at the time of surgery.
Several other studies have identified osteonecrosis risk factors in hematologic malignancies; Schulte and Beelen demonstrated that the most impactful risk factors were chronic GVHD and cumulative steroid intake, followed by female gender, younger age, and conditioning therapy before transplant. Advanced disease stages, bone mineral density, and body composition did not have a significant impact on osteonecrosis [9,18]. The disease process of lymphoma itself may contribute; Chalmers et al. showed that lymphoma was the underlying diagnosis in 33% of THAs in patients with a history of stem cell transplant. However, not all of these patients had a history of GVHD [13].
In these cases, owing to the insufficiency fractures of the acetabular with effective pelvic discontinuity (PD) and the tenuous vascular supply of surrounding bone, THA was conducted with cage construct and bridge plating of the posterior column. This construct has shown efficacy in cases with PD and severe acetabular bone loss in revision THA [[20], [21], [22], [23]]. Plating is primarily studied in revision arthroplasty cases with PD [24,25]. Plating was chosen to restore continuity, optimize contact of viable bone, and add stability to the reconstruction. This fixation technique of posterior column plating with antiprotrusion cage placement led to stability with improved ADLs, restoration of ambulation with full weightbearing, and resolution of pain at 1 year for both cases. Certainly, the perioperative risk of significant surgical or medical complications is high for patients with GVHD; therefore, this technique should be considered in situations with tenuous blood supply and insufficiency fractures in the setting of hematologic malignancy and GVHD.
Summary
These cases are unique reports of osteonecrosis focal to the acetabulum, in patients with history of stem cell transplant and subsequent GVHD. The impact of this disease process should not be overlooked in patients with hematologic malignances and GVHD. Surgical treatment with multifaceted construct, in these cases with an antiprotrusio cage bolstered by posterior column plating, can relieve pain and improve mobility.
Conflict of interest
Dr. Schabel obtains research support from Zimmer Biomet, unrelated to this work. She is also a board member for the Oregon Association of Orthopaedists.
Supplementary data
Conflict of Interest Statement for Nielsen
Conflict of Interest Statement for Schabel
Statements of informed consent were obtained from patients and family members of deceased patients. | Fatal | ReactionOutcome | CC BY-NC-ND | 33521198 | 18,922,656 | 2021-02 |
What was the outcome of reaction 'Joint dislocation'? | Acetabular Insufficiency Fractures in the Setting of Graft vs Host Disease: A Report of Two Cases.
We report a case series of 2 patients with unilateral acetabular insufficiency fractures who received allogeneic peripheral blood stem cell transplantation for hematologic malignancies complicated by chronic graft vs host disease. These were managed with uncemented cup and cage total hip arthroplasty and stabilization of posterior column with plating. Osteonecrosis of the acetabulum is an uncommon musculoskeletal complication of chronic graft vs host disease. The orthopedic impact of this disease should not be overlooked. Surgical intervention with this construct can provide necessary stability to improve patient function.
Introduction
Graft vs host disease (GVHD) can manifest with multisystemic effects. GVHD can occur after allogeneic peripheral blood stem cell transplantation (PBSCT) and can have orthopedic implications such as osteonecrosis. The incidence of osteonecrosis after allogeneic stem cell transplantation is 4-19% [[1], [2], [3], [4]], and the risk is increased in patients with GVHD [5]. Most studies described involve the femoral head [[1], [2], [3], [4],[6], [7], [8], [9], [10], [11], [12]]. Osteonecrosis of the acetabulum, although rare, can lead to significant complications. These include interruption of the articular surface, insufficiency fracture, and protrusio acetabulum. Osteonecrosis of the acetabulum presents particular difficulty in fixation; poor bone quality can impact long-term patient outcomes and implant survivorship. Implant survivorship of THA in patients with allogeneic peripheral stem cell transplantation at 5 years is up to 93% [11], although it can be as low as 74.8% at 10 years [13]. Therefore, THA and fracture fixation in this setting require an approach that combines primary and revision arthroplasty skills to enable immediate weight bearing and pain relief. We present 2 cases of allogeneic PBSCT complicated by GVHD, with resultant acetabular osteonecrosis leading to acetabular insufficiency fracture and the surgical reconstruction that followed.
Case histories
Case 1
Case 1 is a 60-year-old woman with a history of diffuse large B-cell lymphoma who underwent 8 cycles of R-CHOP (rituximab, cyclophosphamide, hydroxydaunorubicin, oncovin [vincristine], and prednisolone). Her disease recurred and was treated with radiolabeled tositumomab with maintenance on rituximab. Relapse occurred once more, and she received salvage chemotherapy with R-ICE (rituximab, ifosfamide, etoposide, carboplatin) followed by autologous PBSCT. She underwent human leukocyte antigen (HLA)-matched allogeneic PBSCT after fludarabine-melphalan conditioning for relapse involving the central nervous system. This was complicated by GVHD, primarily affecting the gastrointestinal tract, that improved with 20-mg prednisone BID (0.5 mg/kg/day). After several dose escalations and relapses, she was tapered off prednisone three times, but after two severe episodes of pericarditis in the absence of steroids, she remained on 10-mg prednisone daily.
She presented to orthopedics with 1 month of acute, “aching” left-sided groin pain, global left hip weakness, difficulty ambulating (newly required a four-wheel walker), and ecchymosis in her inguinal crease. Physical examination revealed severe pain with hip internal and external rotation, as well as adduction and abduction. She could conduct passive hip flexion to 90 degrees but had pain with resisted hip flexion. Magnetic resonance imaging (MRI) of the pelvis and hip was obtained by her primary care provider before orthopedic referral, and AP of the pelvis was obtained as seen in Figure 1. Initial radiography in Figure 1 and MRI demonstrated comminuted minimally displaced fracture of the acetabulum involving the anterior and posterior columns with acetabular protrusio fracture and superior displacement of the femur of 3.5 cm. Interruption of the anterior and posterior columns is better visualized on iliac oblique and obturator oblique views seen in Figure 2, Figure 3.Figure 1 AP pelvis x-ray upon initial presentation showed displaced acetabular fracture and interruption of the femoroacetabular joint space.
Figure 2 Left obturator oblique better demonstrates insufficiency fracture of the posterior wall and anterior column.
Figure 3 Left iliac oblique further demonstrates osteonecrosis of the acetabulum and fracture extending through the posterior column.
Owing to severe disability and pain, and acetabular insufficiency (pathologic) fracture and joint collapse, posterior THA and posterior column stabilization was undertaken. Posterolateral approach was taken to optimize exposure of acetabular fracture and perform THA. Complex THA was performed using a cage construct. Pelvic size thwarted the use of a cup and cage construct. Findings include fragmentation of medial acetabulum with transverse-type insufficiency or pathologic fracture. Acetabular pathologic fracture was repaired, or stabilized, with 8-hole reconstruction plate bent for the left posterior column. Morselized femoral head autograft was placed at the base of the protruded acetabulum. Dome screws of antiprotrusio cage were placed before ilium cage screws, and 5 mL of synthetic bone graft and 30 mL of cancellous bone allograft was injected behind cage. Postoperative x-ray is demonstrated in Figure 4. Her postoperative activity restrictions included posterior hip precautions, and weightbearing as tolerated with an assistive device, with weaning as she was able.Figure 4 Day 0 postoperative AP pelvis x-ray. THA with cage construct and iliac plating.
At her 3-month follow-up visit, she was able to fully weight bear on her left lower extremity without pain or assistive device. Imaging obtained at that time is seen in Figure 5. At 5 months postoperatively, she underwent right total knee arthroplasty because of osteoarthritis present before the acetabular osteonecrosis and was progressing very well with physical therapy. Unfortunately, 16 months after complex left THA, she succumbed to complications of diffuse large B-cell lymphoma and GVHD.Figure 5 Three months postoperative AP pelvis. Revealed intact cage hardware, posterior column plating, and THA. Interval ileum healing was perceived.
Case 2
Case 2 is a 51-year-old woman with a history of acute myelogenous leukemia (AML), secondary myelodysplastic syndrome (MDS), GVHD, steroid-induced diabetes, and restrictive pulmonary disease. Autologous PBSCT was undertaken for AML 9 years before presentation. Matched unrelated donor PBSCT was conducted 1 year before presentation, after fludarabine-melphalan conditioning. GVHD characterized by gastrointestinal symptoms and florid skin rash complicated PBSCT 4 months before presentation. Steroid dosage during GVHD was started at 1 mg/kg/day (60 mg BID) with rapid resolution of symptoms leading to taper of steroids down to 0.5 mg/kg/day after 1 week. She developed recurrence of pulmonary symptoms and gastrointestinal symptoms with tapering and was restarted on 1 mg/kg/day.
She presented to orthopedics with 2 months of right hip pain, primarily in her deep inguinal crease. She required a walker for ambulation and was limited to very short distances because of pain. The examination was remarkable for BMI = 44, anasarca, and painful and limited right hip rotation with only 10 degrees of passive external and internal rotation. Radiographs taken at that time are seen in Figure 6. MRI performed at that time showed hypointensity of the supra-acetabular ilium with some T2 hyperintensity measuring 2.5 cm transverse × 2.4 cm AP suggestive of osteonecrosis, although without collapse. There was also osteonecrosis of the left femoral head, without collapse. Given significant comorbid conditions including bilateral lower extremity edema and severe open-leg ulcerations, surgery was not initially recommended.Figure 6 AP right hip obtained upon initial presentation to PCP with right hip pain. Revealing subchondral lucency of the right femoral head. No acetabular involvement noted.
Given ongoing severe pain and disability, she underwent medical optimization taking 13 months, although during that time, she developed progressive osteonecrosis of the acetabulum. The progression of this can be seen in Figure 7, Figure 8 obtained 1 month later. Her fracture initially demonstrated disruption of the right iliopubic line with sclerosis of the supraacetabular ilium with superior displacement of the femoral head into the ilium consistent with protrusio fracture. This was further evaluated with a CT of the pelvis, which demonstrated comminution of anterior and posterior columns and 14 gapping of articular surface along anterosuperior acetabulum and medullary sclerosis of the surrounding ilium. Follow-up radiography seen in Figure 8 demonstrated increased displacement of anterior and posterior columns with medial acetabular wall displacement measuring 8 mm. Figure 8 was ultimately used for templating her implants. Iliac oblique and obturator oblique views at this time seen in Figure 9, Figure 10 better demonstrate involvement of the anterior and posterior column, medial protrusion of the acetabulum. She was no longer able to ambulate with a walker and was wheelchair bound. Her steroid dose then was 5 mg, 5 days per week, and 10 mg, 2 days per week. Treatment options discussed with patient included Girdlestone resection, THA, and THA with antiprotrusio cage or cup and cage construct. Reconstruction was preferred by patient over Girdlestone resection as she was hoping to resume ambulation and activities of daily living (ADLs). Surgery was pursued with posterior THA, with cage construct and posterior column plating. This fixation was used as the size of the pelvis was not large enough to facilitate a cup/cage construct. Medial acetabulum bony deficiency with both columns, or transverse-type insufficiency fracture or pelvic discontinuity variant, was encountered. After femoral neck cut was made, A 7-hole pelvic reconstruction plate was contoured, and a posterior column plated from ischium to ileum with good fixation using 4 small fragment screws. After the cage was placed, 10 mL of synthetic bone graft with 30 mL of allograft cancellous chips was placed posteriorly to cage. There were no intraoperative complications, and she was discharged home after 2 days. Two weeks postoperatively, she had a 2-day admission for viral gastroenteritis. She also underwent kyphoplasty for three (T9, T11, L1) vertebral compression fractures 2 months postoperatively. There were no readmissions or emergency department visits for postoperative complications.Figure 7 AP pelvic x-ray 6 months since onset of symptoms and 10 months preoperatively. Revealing displaced healing right acetabular fracture. Disruption of the right iliopubic line and sclerosis of the right supra-acetabular ilium. Sclerosis of the right femoral head was also observed.
Figure 8 AP pelvis x-ray 13 months since onset of symptoms and 1.5 months preoperatively. Showing comminuted displaced right acetabular transverse fracture also involving the posterior and medial acetabular walls. Right femoral head is also eroded and aspherical. This film was used for templating.
Figure 9 Right iliac oblique x-ray 13 months since onset of symptoms and 1.5 months preoperatively demonstrating transverse plus posterior acetabular wall fracture with 1.5 cm medial displacement of medial acetabular wall.
Figure 10 Right obturator oblique x-ray 13 months since onset of symptoms and 1.5 months preoperatively. Further demonstrating comminuted posterior acetabular wall insufficiency fracture, aspherical and eroded femoral head, and some bony callus.
One-month postoperatively, her pain was decreasing, and function with ADLs increased, although she required a walker because of back pain and deconditioning. Her gait was smooth, not antalgic, with the walker. Two views of AP pelvis performed at that time are seen in Figure 11. One-year postoperatively, her pain had resolved, she still required a walker, and she was noted to have Trendelenburg gait. AP pelvis 1 year postoperatively, seen in Figure 12, showed well-positioned THA with no lucencies or subsidence. Unfortunately, 3 years postoperatively, she died of causes related to her MDS and GVHD.Figure 11 Portable pelvis x-ray 1-month postoperatively. Intact cup and cage construct implants, near anatomic alignment of acetabular fracture.
Figure 12 AP pelvis x-rays 1-year postoperatively. Interval acetabular healing was seen. Diffuse osteopenia but no evidence of implant failure.
Discussion
Patients with hematologic malignancies are having increased remission and survivorship after autologous and allogenic hematopoietic stem cell transplantations [14,15]. Allogeneic stem cell transplantation is unique as opposed to autologous transplant as it can lead to GVHD. GVHD is a systemic immune reaction by donor cells against host cells [16]. Several studies have demonstrated the increased risk of osteonecrosis because of GVHD [5,9,11,17,18]. GVHD is thought to cause osteonecrosis because of an inflammatory process in the intraosseous vasculature. Sixou et al. [19] found histologic evidence of vasculitis attributed to GVHD. This vasculitis exacerbates risk factors associated with osteonecrosis inclusive to patients with hematologic malignancies including systemic glucocorticoids, chemotherapeutics, and irradiation [5].
Unique to the presented cases is osteonecrosis of the acetabulum and the timeline to develop osteonecrosis. Case 1 took 5 years for manifestation of acetabular osteonecrosis after initiation of steroids for GVHD. Case 2 took 13 months until acetabular osteonecrosis began after onset of GVHD. In 11 patients (19 hips, 8 patients with bilateral osteonecrosis) studied by Schulte and Beelen, onset of osteonecrosis after allogeneic stem cell transplant ranged from 5 to 57 months, with an average of 25 months [9,18]. However, all these cases were of the femoral head, and the hematologic malignancies were AML, MDS, CML, and ALL. It is unclear in the presented cases what circumstances led to osteonecrosis of the acetabulum. Location and timeline could be attributed to age. Bizot et al. [17] had 16 patients with osteonecrosis secondary to GVHD, although the oldest patient was 47 years old at the time of surgery (average age 13 ± 8 years). The patients presented were 60 and 52 years old at the time of surgery.
Several other studies have identified osteonecrosis risk factors in hematologic malignancies; Schulte and Beelen demonstrated that the most impactful risk factors were chronic GVHD and cumulative steroid intake, followed by female gender, younger age, and conditioning therapy before transplant. Advanced disease stages, bone mineral density, and body composition did not have a significant impact on osteonecrosis [9,18]. The disease process of lymphoma itself may contribute; Chalmers et al. showed that lymphoma was the underlying diagnosis in 33% of THAs in patients with a history of stem cell transplant. However, not all of these patients had a history of GVHD [13].
In these cases, owing to the insufficiency fractures of the acetabular with effective pelvic discontinuity (PD) and the tenuous vascular supply of surrounding bone, THA was conducted with cage construct and bridge plating of the posterior column. This construct has shown efficacy in cases with PD and severe acetabular bone loss in revision THA [[20], [21], [22], [23]]. Plating is primarily studied in revision arthroplasty cases with PD [24,25]. Plating was chosen to restore continuity, optimize contact of viable bone, and add stability to the reconstruction. This fixation technique of posterior column plating with antiprotrusion cage placement led to stability with improved ADLs, restoration of ambulation with full weightbearing, and resolution of pain at 1 year for both cases. Certainly, the perioperative risk of significant surgical or medical complications is high for patients with GVHD; therefore, this technique should be considered in situations with tenuous blood supply and insufficiency fractures in the setting of hematologic malignancy and GVHD.
Summary
These cases are unique reports of osteonecrosis focal to the acetabulum, in patients with history of stem cell transplant and subsequent GVHD. The impact of this disease process should not be overlooked in patients with hematologic malignances and GVHD. Surgical treatment with multifaceted construct, in these cases with an antiprotrusio cage bolstered by posterior column plating, can relieve pain and improve mobility.
Conflict of interest
Dr. Schabel obtains research support from Zimmer Biomet, unrelated to this work. She is also a board member for the Oregon Association of Orthopaedists.
Supplementary data
Conflict of Interest Statement for Nielsen
Conflict of Interest Statement for Schabel
Statements of informed consent were obtained from patients and family members of deceased patients. | Recovering | ReactionOutcome | CC BY-NC-ND | 33521198 | 18,981,647 | 2021-02 |
Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Acute respiratory failure'. | Amniotic membrane transplantation in a 2-month-old infant with toxic epidermal necrolysis.
To report a case of 2-month-old boy with Stevens-Johnson syndrome (SJS)/Toxic epidermal necrolysis (TEN) and ocular involvement that was successfully treated with cryopreserved amniotic membrane transplantation (AMT).
A 2-month-old otherwise healthy boy was referred to Boston Children's Hospital with extensive rash and desquamation concerning for SJS/TEN. A skin biopsy was performed which showed full-thickness epidermal necrosis. AMT was performed at the bedside under general anesthesia. A combination of tobramycin and dexamethasone ointment was prescribed four times per day. On reassessment two weeks following AMT, the entire ocular surface had healed with no signs of conjunctival and/or corneal inflammation or ulceration.
To the best of our knowledge, our case represents the youngest patient with SJS/TEN to be managed by AMT and one of very few cases where acetaminophen is suspected to be the offending agent. This case highlights the efficacy of AMT at such a young age and feasibility of performing the procedure at bedside in these patients It also highlights that SJS/TEN can develop at such young age.
1 Introduction
Stevens-Johnson syndrome (SJS) and its more severe variant toxic epidermal necrolysis (TEN) are serious life-threatening conditions that involve wide spread skin and mucous membrane destruction.1,2 We present a case of 2 month old boy with Stevens-Johnson syndrome/Toxic epidermal necrolysis and ocular involvement that was successfully treated with cryopreserved amniotic membrane transplantation (AMT).
2 Case report
A 2-month-old otherwise healthy boy was referred to Boston Children's Hospital with extensive rash and desquamation concerning for SJS/TEN. One week prior to presentation, he developed non-specific viral prodromal symptoms including fever to102.6 F (39.2 °C), decreased urine output, emesis and decreased appetite. There was no history of any allergies. Family history was only significant for Sjögren's syndrome for his mother and recent pneumonia actively treated with azithromycin for the patient's older sister. A full sepsis work-up at outside hospital was performed and was negative. The patient was empirically started on acyclovir, vancomycin, ceftriaxone and acetaminophen. One day later, he developed a diffuse maculopapular rash with vesicles and desquamation involving head, trunk, upper and lower extremities (Fig. 1). The patient developed acute respiratory failure for which he was sedated and nasally intubated. At that time, he was transferred to Boston Children's Hospital with skin detachment involving more than 40% of his total body surface area (TBSA). A skin biopsy was performed which showed full-thickness epidermal necrosis. The adjacent epidermis demonstrated basal layer vacuolization and scattered dyskeratotic cells (Fig. 2). Special stains were performed including periodic acid Schiff (PAS), gram stain and Grocott-Gomori's (or Gömöri) methenamine silver which were all negative. No immunoreactivity was detected with IgG, IgA, IgM, C3 and fibrin. These findings were consistent with diagnosis of SJS/TEN. Systemic intravenous immunoglobulin (IVIG) was initiated.Fig. 1 External photo showing diffuse maculopapular rash with skin desquamation and epidermal detachment involving head, trunk and upper extremities with bilateral macerated upper and lower eye lids.
Fig. 1Fig. 2 Histopathology showing A-full thickness epidermal necrosis and separation (black arrow). B- The adjacent epidermis demonstrated scattered dyskeratotic cells (a) and basal layer vacuolization (b).
Fig. 2
Ocular evaluation by a senior faculty member at the time of initial presentation to our institution showed bilateral desquamated upper and lower eye lids (Fig. 1), mild conjunctival injection and bilateral corneal epithelial defects. No conjunctival staining was detected at that time. The anterior chamber was quiet bilaterally, the pupils were equal, round, regular and reactive to light. Dilated fundus examination disclosed normal disc, vessels, macula, and periphery. Erythromycin ointment and artificial tears were prescribed for the corneal epithelial defects which healed in two days. Five days later, diffuse perilimbal conjunctival staining was noted with early mild symblepharon formation nasally and temporally. AMT was performed at the bedside under general anesthesia using our previously described technique.3 In summary, intravenous tubing was used to create bolsters and a symblepharon ring, the diameter of which was estimated based on the distance between the superior and inferior orbital rims. A 5 × 5cm AM piece was then placed as a continuous sheet over the ocular surface. The symblepharon ring was inserted to push the AM into the fornices. Finally, the AM was anchored to the skin with 6–0 polypropylene sutures over the bolsters. A combination of tobramycin and dexamethasone ointment was prescribed four times per day. On reassessment two weeks following AMT, the entire ocular surface had healed with no signs of conjunctival and/or corneal inflammation or ulceration. There was no evidence of limbal stem cell deficiency, and the tobramycin/dexamethasone drops were gradually tapered. The general condition of the patient continued to improve with signs of skin re-epithelization (Fig. 3). At the last follow-up, 2 months later, ocular examination showed normal anterior segment with no evidence of lid margin keratinization, entropion, trichiasis or any other complication (Fig. 4). Further follow-up visits have been scheduled for early detection of late complications.Fig. 3 External photo taken 2 weeks after initial presentation showing marked improvement in the patient's general condition with continued skin re-epithelization.
Fig. 3Fig. 4 External photo taken after discharge showing complete healing of lid desquamation and normal anterior segment.
Fig. 4
3 Discussion
Ocular involvement in SJS/TEN occurs in 84% of patients during the acute stage, especially those with epidermal detachment >10% of TBSA.4 Our patient had more than 40% of TBSA involved, therefore it is better classified as TEN rather than SJS. Atypical cases of SJS/TEN may initially present with ocular signs only.5 Prompt diagnosis of ocular surface inflammation and early intervention are essential to avoid cicatricial keratoconjunctivitis and limbal stem cell deficiency that may lead to vision threatening complications. AMT performed in the first week after ocular involvement has been reported to be an effective treatment modality due to anti-inflammatory and anti-scarring effects mediated by anti-inflammatory cytokines, including interleukin-10 and anti-inflammatory protease inhibitors such as alpha 1 antitrypsin inhibitor. This can subsequently facilitate rapid epithelial healing preventing long-term ocular morbidity during the chronic stage.3,6, 7, 8 We present a rare case of TEN in a very young patient (2 months) that was successfully managed with AMT. The triggering factor for SJS/TEN in our case remained unclear, however it may be multifactorial. It may be a viral infection based on the history of fever and sick contact with pneumonia (patient's older sister). Our patient received acetaminophen one day before development of maculopapular rash and desquamation which raise the possibility that it may be one of the factors that lead to TEN. It has been previously reported to be associated with SJS/TEN with few reports in the literature, however it was started together with vancomycin, ceftriaxone and acyclovir and any one of them may be the triggering agent.9,10 Neonatal lupus presenting as TEN-like syndrome was considered initially given mother's history of Sjögren's syndrome, however the skin biopsy and overall clinical picture was consistent with TEN. Long-term follow-up of these cases is essential for early detection of complications. Catt and colleagues retrospectively evaluated the ocular manifestations of pediatric SJS/TEN and reported that the median time for development of corneal opacification was 4 months, of limbal stem cell deficiency was 7 months and of corneal neovascularization was 10 months after admission.11
To the best of our knowledge our case represents the youngest patient with SJS/TEN to be managed by AMT and one of very few cases where acetaminophen is suspected to be the offending agent. This case highlights the efficacy of AMT at such a young age and feasibility of performing the procedure at bedside in these patients It also highlights that SJS/TEN can develop at such young age.
Patient consent
Written informed consent was obtained from the patient's legal guardian.
Authorship
All authors attest that they meet the current ICMJE criteria for authorship.
Funding
Children's Hospital Ophthalmology Foundation, Inc.
Declaration of competing interest
The following authors have no financial disclosures:
Abdelrahman M. Elhusseiny, Ryan Gise, Christina Scelfo, Iason Mantagos.
Acknowledgment
None. | ACETAMINOPHEN, ACYCLOVIR, CEFTRIAXONE, VANCOMYCIN | DrugsGivenReaction | CC BY-NC-ND | 33521381 | 18,930,561 | 2021-03 |
Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Conjunctival ulcer'. | Amniotic membrane transplantation in a 2-month-old infant with toxic epidermal necrolysis.
To report a case of 2-month-old boy with Stevens-Johnson syndrome (SJS)/Toxic epidermal necrolysis (TEN) and ocular involvement that was successfully treated with cryopreserved amniotic membrane transplantation (AMT).
A 2-month-old otherwise healthy boy was referred to Boston Children's Hospital with extensive rash and desquamation concerning for SJS/TEN. A skin biopsy was performed which showed full-thickness epidermal necrosis. AMT was performed at the bedside under general anesthesia. A combination of tobramycin and dexamethasone ointment was prescribed four times per day. On reassessment two weeks following AMT, the entire ocular surface had healed with no signs of conjunctival and/or corneal inflammation or ulceration.
To the best of our knowledge, our case represents the youngest patient with SJS/TEN to be managed by AMT and one of very few cases where acetaminophen is suspected to be the offending agent. This case highlights the efficacy of AMT at such a young age and feasibility of performing the procedure at bedside in these patients It also highlights that SJS/TEN can develop at such young age.
1 Introduction
Stevens-Johnson syndrome (SJS) and its more severe variant toxic epidermal necrolysis (TEN) are serious life-threatening conditions that involve wide spread skin and mucous membrane destruction.1,2 We present a case of 2 month old boy with Stevens-Johnson syndrome/Toxic epidermal necrolysis and ocular involvement that was successfully treated with cryopreserved amniotic membrane transplantation (AMT).
2 Case report
A 2-month-old otherwise healthy boy was referred to Boston Children's Hospital with extensive rash and desquamation concerning for SJS/TEN. One week prior to presentation, he developed non-specific viral prodromal symptoms including fever to102.6 F (39.2 °C), decreased urine output, emesis and decreased appetite. There was no history of any allergies. Family history was only significant for Sjögren's syndrome for his mother and recent pneumonia actively treated with azithromycin for the patient's older sister. A full sepsis work-up at outside hospital was performed and was negative. The patient was empirically started on acyclovir, vancomycin, ceftriaxone and acetaminophen. One day later, he developed a diffuse maculopapular rash with vesicles and desquamation involving head, trunk, upper and lower extremities (Fig. 1). The patient developed acute respiratory failure for which he was sedated and nasally intubated. At that time, he was transferred to Boston Children's Hospital with skin detachment involving more than 40% of his total body surface area (TBSA). A skin biopsy was performed which showed full-thickness epidermal necrosis. The adjacent epidermis demonstrated basal layer vacuolization and scattered dyskeratotic cells (Fig. 2). Special stains were performed including periodic acid Schiff (PAS), gram stain and Grocott-Gomori's (or Gömöri) methenamine silver which were all negative. No immunoreactivity was detected with IgG, IgA, IgM, C3 and fibrin. These findings were consistent with diagnosis of SJS/TEN. Systemic intravenous immunoglobulin (IVIG) was initiated.Fig. 1 External photo showing diffuse maculopapular rash with skin desquamation and epidermal detachment involving head, trunk and upper extremities with bilateral macerated upper and lower eye lids.
Fig. 1Fig. 2 Histopathology showing A-full thickness epidermal necrosis and separation (black arrow). B- The adjacent epidermis demonstrated scattered dyskeratotic cells (a) and basal layer vacuolization (b).
Fig. 2
Ocular evaluation by a senior faculty member at the time of initial presentation to our institution showed bilateral desquamated upper and lower eye lids (Fig. 1), mild conjunctival injection and bilateral corneal epithelial defects. No conjunctival staining was detected at that time. The anterior chamber was quiet bilaterally, the pupils were equal, round, regular and reactive to light. Dilated fundus examination disclosed normal disc, vessels, macula, and periphery. Erythromycin ointment and artificial tears were prescribed for the corneal epithelial defects which healed in two days. Five days later, diffuse perilimbal conjunctival staining was noted with early mild symblepharon formation nasally and temporally. AMT was performed at the bedside under general anesthesia using our previously described technique.3 In summary, intravenous tubing was used to create bolsters and a symblepharon ring, the diameter of which was estimated based on the distance between the superior and inferior orbital rims. A 5 × 5cm AM piece was then placed as a continuous sheet over the ocular surface. The symblepharon ring was inserted to push the AM into the fornices. Finally, the AM was anchored to the skin with 6–0 polypropylene sutures over the bolsters. A combination of tobramycin and dexamethasone ointment was prescribed four times per day. On reassessment two weeks following AMT, the entire ocular surface had healed with no signs of conjunctival and/or corneal inflammation or ulceration. There was no evidence of limbal stem cell deficiency, and the tobramycin/dexamethasone drops were gradually tapered. The general condition of the patient continued to improve with signs of skin re-epithelization (Fig. 3). At the last follow-up, 2 months later, ocular examination showed normal anterior segment with no evidence of lid margin keratinization, entropion, trichiasis or any other complication (Fig. 4). Further follow-up visits have been scheduled for early detection of late complications.Fig. 3 External photo taken 2 weeks after initial presentation showing marked improvement in the patient's general condition with continued skin re-epithelization.
Fig. 3Fig. 4 External photo taken after discharge showing complete healing of lid desquamation and normal anterior segment.
Fig. 4
3 Discussion
Ocular involvement in SJS/TEN occurs in 84% of patients during the acute stage, especially those with epidermal detachment >10% of TBSA.4 Our patient had more than 40% of TBSA involved, therefore it is better classified as TEN rather than SJS. Atypical cases of SJS/TEN may initially present with ocular signs only.5 Prompt diagnosis of ocular surface inflammation and early intervention are essential to avoid cicatricial keratoconjunctivitis and limbal stem cell deficiency that may lead to vision threatening complications. AMT performed in the first week after ocular involvement has been reported to be an effective treatment modality due to anti-inflammatory and anti-scarring effects mediated by anti-inflammatory cytokines, including interleukin-10 and anti-inflammatory protease inhibitors such as alpha 1 antitrypsin inhibitor. This can subsequently facilitate rapid epithelial healing preventing long-term ocular morbidity during the chronic stage.3,6, 7, 8 We present a rare case of TEN in a very young patient (2 months) that was successfully managed with AMT. The triggering factor for SJS/TEN in our case remained unclear, however it may be multifactorial. It may be a viral infection based on the history of fever and sick contact with pneumonia (patient's older sister). Our patient received acetaminophen one day before development of maculopapular rash and desquamation which raise the possibility that it may be one of the factors that lead to TEN. It has been previously reported to be associated with SJS/TEN with few reports in the literature, however it was started together with vancomycin, ceftriaxone and acyclovir and any one of them may be the triggering agent.9,10 Neonatal lupus presenting as TEN-like syndrome was considered initially given mother's history of Sjögren's syndrome, however the skin biopsy and overall clinical picture was consistent with TEN. Long-term follow-up of these cases is essential for early detection of complications. Catt and colleagues retrospectively evaluated the ocular manifestations of pediatric SJS/TEN and reported that the median time for development of corneal opacification was 4 months, of limbal stem cell deficiency was 7 months and of corneal neovascularization was 10 months after admission.11
To the best of our knowledge our case represents the youngest patient with SJS/TEN to be managed by AMT and one of very few cases where acetaminophen is suspected to be the offending agent. This case highlights the efficacy of AMT at such a young age and feasibility of performing the procedure at bedside in these patients It also highlights that SJS/TEN can develop at such young age.
Patient consent
Written informed consent was obtained from the patient's legal guardian.
Authorship
All authors attest that they meet the current ICMJE criteria for authorship.
Funding
Children's Hospital Ophthalmology Foundation, Inc.
Declaration of competing interest
The following authors have no financial disclosures:
Abdelrahman M. Elhusseiny, Ryan Gise, Christina Scelfo, Iason Mantagos.
Acknowledgment
None. | ACETAMINOPHEN\HYDROCODONE, ACYCLOVIR, CEFTRIAXONE, VANCOMYCIN | DrugsGivenReaction | CC BY-NC-ND | 33521381 | 18,940,084 | 2021-03 |
Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Ulcerative keratitis'. | Amniotic membrane transplantation in a 2-month-old infant with toxic epidermal necrolysis.
To report a case of 2-month-old boy with Stevens-Johnson syndrome (SJS)/Toxic epidermal necrolysis (TEN) and ocular involvement that was successfully treated with cryopreserved amniotic membrane transplantation (AMT).
A 2-month-old otherwise healthy boy was referred to Boston Children's Hospital with extensive rash and desquamation concerning for SJS/TEN. A skin biopsy was performed which showed full-thickness epidermal necrosis. AMT was performed at the bedside under general anesthesia. A combination of tobramycin and dexamethasone ointment was prescribed four times per day. On reassessment two weeks following AMT, the entire ocular surface had healed with no signs of conjunctival and/or corneal inflammation or ulceration.
To the best of our knowledge, our case represents the youngest patient with SJS/TEN to be managed by AMT and one of very few cases where acetaminophen is suspected to be the offending agent. This case highlights the efficacy of AMT at such a young age and feasibility of performing the procedure at bedside in these patients It also highlights that SJS/TEN can develop at such young age.
1 Introduction
Stevens-Johnson syndrome (SJS) and its more severe variant toxic epidermal necrolysis (TEN) are serious life-threatening conditions that involve wide spread skin and mucous membrane destruction.1,2 We present a case of 2 month old boy with Stevens-Johnson syndrome/Toxic epidermal necrolysis and ocular involvement that was successfully treated with cryopreserved amniotic membrane transplantation (AMT).
2 Case report
A 2-month-old otherwise healthy boy was referred to Boston Children's Hospital with extensive rash and desquamation concerning for SJS/TEN. One week prior to presentation, he developed non-specific viral prodromal symptoms including fever to102.6 F (39.2 °C), decreased urine output, emesis and decreased appetite. There was no history of any allergies. Family history was only significant for Sjögren's syndrome for his mother and recent pneumonia actively treated with azithromycin for the patient's older sister. A full sepsis work-up at outside hospital was performed and was negative. The patient was empirically started on acyclovir, vancomycin, ceftriaxone and acetaminophen. One day later, he developed a diffuse maculopapular rash with vesicles and desquamation involving head, trunk, upper and lower extremities (Fig. 1). The patient developed acute respiratory failure for which he was sedated and nasally intubated. At that time, he was transferred to Boston Children's Hospital with skin detachment involving more than 40% of his total body surface area (TBSA). A skin biopsy was performed which showed full-thickness epidermal necrosis. The adjacent epidermis demonstrated basal layer vacuolization and scattered dyskeratotic cells (Fig. 2). Special stains were performed including periodic acid Schiff (PAS), gram stain and Grocott-Gomori's (or Gömöri) methenamine silver which were all negative. No immunoreactivity was detected with IgG, IgA, IgM, C3 and fibrin. These findings were consistent with diagnosis of SJS/TEN. Systemic intravenous immunoglobulin (IVIG) was initiated.Fig. 1 External photo showing diffuse maculopapular rash with skin desquamation and epidermal detachment involving head, trunk and upper extremities with bilateral macerated upper and lower eye lids.
Fig. 1Fig. 2 Histopathology showing A-full thickness epidermal necrosis and separation (black arrow). B- The adjacent epidermis demonstrated scattered dyskeratotic cells (a) and basal layer vacuolization (b).
Fig. 2
Ocular evaluation by a senior faculty member at the time of initial presentation to our institution showed bilateral desquamated upper and lower eye lids (Fig. 1), mild conjunctival injection and bilateral corneal epithelial defects. No conjunctival staining was detected at that time. The anterior chamber was quiet bilaterally, the pupils were equal, round, regular and reactive to light. Dilated fundus examination disclosed normal disc, vessels, macula, and periphery. Erythromycin ointment and artificial tears were prescribed for the corneal epithelial defects which healed in two days. Five days later, diffuse perilimbal conjunctival staining was noted with early mild symblepharon formation nasally and temporally. AMT was performed at the bedside under general anesthesia using our previously described technique.3 In summary, intravenous tubing was used to create bolsters and a symblepharon ring, the diameter of which was estimated based on the distance between the superior and inferior orbital rims. A 5 × 5cm AM piece was then placed as a continuous sheet over the ocular surface. The symblepharon ring was inserted to push the AM into the fornices. Finally, the AM was anchored to the skin with 6–0 polypropylene sutures over the bolsters. A combination of tobramycin and dexamethasone ointment was prescribed four times per day. On reassessment two weeks following AMT, the entire ocular surface had healed with no signs of conjunctival and/or corneal inflammation or ulceration. There was no evidence of limbal stem cell deficiency, and the tobramycin/dexamethasone drops were gradually tapered. The general condition of the patient continued to improve with signs of skin re-epithelization (Fig. 3). At the last follow-up, 2 months later, ocular examination showed normal anterior segment with no evidence of lid margin keratinization, entropion, trichiasis or any other complication (Fig. 4). Further follow-up visits have been scheduled for early detection of late complications.Fig. 3 External photo taken 2 weeks after initial presentation showing marked improvement in the patient's general condition with continued skin re-epithelization.
Fig. 3Fig. 4 External photo taken after discharge showing complete healing of lid desquamation and normal anterior segment.
Fig. 4
3 Discussion
Ocular involvement in SJS/TEN occurs in 84% of patients during the acute stage, especially those with epidermal detachment >10% of TBSA.4 Our patient had more than 40% of TBSA involved, therefore it is better classified as TEN rather than SJS. Atypical cases of SJS/TEN may initially present with ocular signs only.5 Prompt diagnosis of ocular surface inflammation and early intervention are essential to avoid cicatricial keratoconjunctivitis and limbal stem cell deficiency that may lead to vision threatening complications. AMT performed in the first week after ocular involvement has been reported to be an effective treatment modality due to anti-inflammatory and anti-scarring effects mediated by anti-inflammatory cytokines, including interleukin-10 and anti-inflammatory protease inhibitors such as alpha 1 antitrypsin inhibitor. This can subsequently facilitate rapid epithelial healing preventing long-term ocular morbidity during the chronic stage.3,6, 7, 8 We present a rare case of TEN in a very young patient (2 months) that was successfully managed with AMT. The triggering factor for SJS/TEN in our case remained unclear, however it may be multifactorial. It may be a viral infection based on the history of fever and sick contact with pneumonia (patient's older sister). Our patient received acetaminophen one day before development of maculopapular rash and desquamation which raise the possibility that it may be one of the factors that lead to TEN. It has been previously reported to be associated with SJS/TEN with few reports in the literature, however it was started together with vancomycin, ceftriaxone and acyclovir and any one of them may be the triggering agent.9,10 Neonatal lupus presenting as TEN-like syndrome was considered initially given mother's history of Sjögren's syndrome, however the skin biopsy and overall clinical picture was consistent with TEN. Long-term follow-up of these cases is essential for early detection of complications. Catt and colleagues retrospectively evaluated the ocular manifestations of pediatric SJS/TEN and reported that the median time for development of corneal opacification was 4 months, of limbal stem cell deficiency was 7 months and of corneal neovascularization was 10 months after admission.11
To the best of our knowledge our case represents the youngest patient with SJS/TEN to be managed by AMT and one of very few cases where acetaminophen is suspected to be the offending agent. This case highlights the efficacy of AMT at such a young age and feasibility of performing the procedure at bedside in these patients It also highlights that SJS/TEN can develop at such young age.
Patient consent
Written informed consent was obtained from the patient's legal guardian.
Authorship
All authors attest that they meet the current ICMJE criteria for authorship.
Funding
Children's Hospital Ophthalmology Foundation, Inc.
Declaration of competing interest
The following authors have no financial disclosures:
Abdelrahman M. Elhusseiny, Ryan Gise, Christina Scelfo, Iason Mantagos.
Acknowledgment
None. | ACETAMINOPHEN\HYDROCODONE, ACYCLOVIR, CEFTRIAXONE, VANCOMYCIN | DrugsGivenReaction | CC BY-NC-ND | 33521381 | 18,940,084 | 2021-03 |
Subsets and Splits
No community queries yet
The top public SQL queries from the community will appear here once available.