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What was the outcome of reaction 'Circulatory collapse'? | Circulatory collapse during wound closure in spine surgery with an unknown cause: a possible adverse effect of topical application of vancomycin?
Vancomycin (VCM) is effective in fighting Gram-positive bacteria related severe infections, and topical application of VCM powder is widely used in orthopedic surgery to prevent wound infection. However, VCM could lead to infusion rate-dependent antibody-and complement-independent anaphylaxis reaction by inducing direct release of histamine.
We retrospectively analyzed seven cases of severe hypotension and shock during wound closure or immediately after orthopedic surgery with unidentifiable reasons. We found that these cases were all associated with local application of VCM powder during wound closure process. Two patients experienced sudden cardiac arrest. Most of the cases (6/7) with circulatory collapse were discharged without severe sequelae. While one case with application of 3 g VCM developed cardiac arrest and remained in a coma due to hypoxic-hypoxic encephalopathy. The clinical presentations and the time of the shock onset were considered to be related with a VCM induced anaphylaxis reaction. However, as this was a retrospective study, and there was no laboratory examination performed, the conclusion was made upon differential diagnosis based on clinical manifestations and the timing of the shock.
Local application of VCM may not be as safe as was once believed and may lead to a related anaphylaxis. As VCM induced infusion-rate dependent, non-IgE mediated anaphylaxis is characterized by delayed occurrence, severe hypotension and even circulatory collapse, surgeons and anesthesiologists should be extra vigilant during and after VCM application.
Background
Shock is defined as a state of insufficient perfusion and oxygen delivery to the tissues. The pathophysiology of shock could be simplified to three major components: cardiac function (the pump), intravascular volume (the tank), and systemic vascular resistance (the pipes) [1]. Whatever the causes of shock may be, if the impaired perfusion and oxygen delivery is not recognized and reversed, the circulatory collapse may progress into organ dysfunction and failure, tissue necrosis and even death. It is urgent to identify the causes of shock and take immediate measures. However, in critical situations, it is hard to rapidly distinguish the culprit during complex clinical situations. Here we present 7 cases (Table 1) of unidentifiable causes of shock during wound closure or shortly after spine surgery, and discuss the possible reasons.
Table 1 Summary of clinical presentations of seven patients with circulatory collapse and unknown etiologies during or shortly after wound closure in spine surgery
Case Demographic information Initial signs/symptoms of shock and management Hemoglobin value (g/L),
fluid resuscitation and blood product infusion VCM administration
and Postoperative sequelae
1 Female; 68-yr; 160 cm/60 kg
BMI: 23.4
Diagnosis:
Lumbar stenosis (L3-S1)
Surgery:
Posterior decompression, fixation and fusion of lumbar spine.
Medical and allergy history:
Hypertension
History of retina surgery
Time of occurrence:
Subcutaneous layer closure, 30 min after initiation of wound closure.
Signs and symptoms:
ABP: 30/20 mmHg
SpO2: undetectable
ECG: tarchycardia with elevated ST segment
Skin and airway symptoms: none.
Management:
Boluses and continuous infusion of noradrenaline (0.01–0.04 μg/kg/min) for 45 min. Fluid resuscitation and blood transfusion.
Preoperative HGB value: 124
Intraoperative minimum value of HGB: 73
Blood loss: 600 ml
Urine: 850 ml
Fluid and blood product infusion:
Crystalloid: 3450 ml
Colloid: 500 ml
PRBC infusion: 1200 ml
Infused autologous blood: 210 ml
VCM administration:
0.5 g mixed with bone debris into the cage and 0.5 g spraying on the dura mater and into the mascularis layer.
Postoperative sequelae:
Proceeded with surgery and the patient was extubated uneventfully.
2 Male; 74-yr; 171 cm/67 kg
BMI: 23.9
Diagnosis:
lumbar stenosis (L3–5)
Surgery:
Posterior decompression, fixation and fusion of lumbar spine.
Medical and allergy history:
nil relevant.
Time of occurrence:
Subcutaneous layer closure, 30 min after initiation of wound closure.
Signs and symptoms:
NBP: 45/15 mmHg
SpO2: undetectable
ECG: tachycardia with ST segment depression
Skin and airway symptoms: none.
Management:
Boluses and continuous infusion of noradrenaline (0.05–0.4 μg/kg/min) and adrenaline (0.5–0.15 μg/kg/min) for 4 h.
Preoperative HGB value:135
Intraoperative minimum value of HGB: 79
Blood loss: 600 ml
Urine: 1950 ml
Fluid and blood product infusion:
Crystalloid: 6300 ml
Colloid: 500 ml
PRBC infusion: 1200 ml
Plasma: 800 ml
Infused autologous blood: 254 ml
VCM administration:
0.5 g mixed with bone debris into the cage and 0.5 g spraying on the dura mater and into the mascularis layer.
Postoperative sequelae:
The patient was extubated and transferred to ICU due to neurological symptoms (unable to follow instructions).
Postoperative imaging: intracranial minor hemorrhage at subdural and subarachnoid space.
The patient was discharged from hospital without neurological deficit.
3 Male; 63-yr; 169 cm/70 kg
BMI: 24.5
Diagnosis:
Lumbar stenosis (L3–5)
Surgery:
Posterior decompression, fixation and fusion of lumbar spine.
Medical and allergy history:
Lacunar infarction;
Bilateral carotid atherosclerotic plaque formation
Time of occurrence:
50 min after initiation of wound closure and 20 min post-extubation in the PACU.
Signs and symptoms:
NBP: 60/25 mmHg
SpO2: 96%
HR:sudden elevation from 60 to 90 bpm
Postoperative agitation
Skin and airway symptoms: none.
Management:
Boluses of ephedrine, phenylephrine and fluid resuscitation.
Preoperative HGB value: 176
Intraoperative minimum value of HGB:123
Blood loss: 800 ml
Urine: 800 ml
Fluid and blood product infusion:
Crystalloid: 2350 ml
Colloid: 1000 ml
PRBC infusion: 400 ml
VCM administration:
Topical spraying of vancomycin (1 g) on the dura mater and into the mascularis.
Postoperative sequelae:
Uneventful.
4 Female; 70-yr; 160 cm/65 kg
BMI:25.4
Diagnosis:
Lumbar stenosis (L4-S1)
Surgery:
Posterior decompression, fixation and fusion of lumbar spine.
Hypertension
Diabetes Mellitus
Time of occurrence:
Subcutaneous layer closure, 30 min after initiation of wound closure.
Signs and symptoms:
NBP: 45/15 mmHg
SpO2: undetectable
Persistent tachycardia
Skin and airway symptoms: none.
Management:
Boluses of phenylephrine for treating severe hypotension and esmolol for tachycardia
Fluid resuscitation and blood transfusion.
Preoperative HGB value: 150
Intraoperative minimum value of HGB: 92
Blood loss: 1500 ml
Urine: 1800 ml
Fluid and blood product infusion:
Crystalloid: 3100 ml
Colloid: 1500 ml
PRBC infusion: 1200 ml
Infused autologous blood: 450 ml
VCM administration:
0.5 g mixed with bone debris into the cage and 0.5 g spraying on the dura mater and into the mascularis layer.
Postoperative sequelae:
The patient was extubated after surgery and transferred to ICU due to tachycardia after sufficient fluid resuscitation.
Recovered uneventfully.
5 Female;48-yr; 170 cm/75 kg
BMI: 26.0
Diagnosis:
Thoracic spinal canal stenosis (T6-T11)
Surgery:
Posterior decompression, fixation and fusion of thoracic spine.
Medical and allergy history:
nil relevant.
Time of occurrence:
Subcutaneous layer closure, 30 min after initiation of wound closure.
Signs and symptoms:
NBP: 40/30 mmHg to undetectable
HR: 120 bpm to 40 bpm
SpO2: undetectable
Cardiac arrest
Skin and airway symptoms: none.
Management:
Extracardiac compression
Boluses of noradrenaline (200 μg) and adrenaline (1 g)
Continuous infusion of noradrenaline (0.02–0.08 μg/kg/min) for 50 min
Fluid resuscitation and blood transfusion.
Preoperative HGB value: 132
Intraoperative minimum value of HGB: 74
Blood loss: 2500 ml
Urine: 1300 ml
Fluid and blood product infusion:
Crystalloid: 4000 ml
Colloid: 500 ml
PRBC infusion: 2400 ml
VCM administration:
Topical spraying of vancomycin (1 g) on the dura mater and into the mascularis layer.
Postoperative sequelae:
The patient was extubated after surgery, and discharged from hospital uneventfully.
6 Male; 66-yr; 175 cm/ 80 kg
BMI: 26.1
Diagnosis:
Lumbar stenosis (L3–5)
Surgery:
Posterior decompression, fixation and fusion of lumbar spine.
Medical and allergy history:
Carotid artery stenosis
Diabetes Mellitus
Time of occurrence:
Sudden cardiac arrest 10 min after extubation (approximately 45 min after initiation of wound closure) with full recovery from anesthesia and without any discomfort complaint.
Signs and symptoms:
Cardiac arrest and persistent VF
Skin and airway symptoms: none.
Management:
Continuous CPR
Persistent VF was treated with repeated defibrillation
Boluses of adrenaline (a total of 6 mg) and amiodarone.
Fluid resuscitation and blood transfusion.
Preoperative HGB value: 143
Intraoperative minimum value of HGB: 78
Blood loss: 1000 ml
Urine: 850 ml
Fluid and blood product infusion:
Crystalloid: 4400 ml
Colloid: 1000 ml
PRBC infusion: 1200 ml
Infused autologous blood: 600 ml
VCM administration:
Topical spraying of vancomycin (3 g) on the dura mater and into the mascularis.
Postoperative sequelae:
The patient was reintubated and transferred to ICU after ROSC. The patient was diagnosed as hypoxic encephalopathy and remained in a coma state. Tracheotomy was performed 2 weeks after surgery, and the patient was transferred to a nursing home for rehabilitation 1 month after orthopedic surgery.
7 Female; 43-yr; 155 cm / 54 kg
BMI: 22.4
Diagnosis:
Thoracic kyphosis (T7-T8)
Surgery:
Osteotomy for kyphosis of thoracic spine (T7-T8).
Medical and allergy history:
nil relevant.
Time of occurrence:
subcutaneous layer closure, 30 min after initiation of wound closure.
Signs and symptoms:
HR:tachycardia
NBP: 60/30 mmHg
SpO2 82%
Skin and airway symptoms: none.
Management:
Boluses of phenylephrine and ephedrine;
Continuous infusion of noradrenaline (0.05–0.1 μg/kg/min)
Fluid resuscitation and blood transfusion.
Preoperative HGB value: 138
Intraoperative minimum value of HGB: 95
Blood loss: 1200 ml
Urine: 1900 ml
Fluid and blood product infusion:
Crystalloid: 4700 ml
Colloid: 1000 ml
PRBC infusion: 1200 ml
Infused autologous blood: 470 ml
VCM administration:
Topical spraying of vancomycin (1 g) on the dura mater and into the mascularis layer.
Postoperative sequelae:
The patient was transferred to ICU for optimal monitoring and recovered uneventfully.
Abbreviations: NBP Non-invasive blood pressure; ABP Arterial blood pressure; (NBP is noted when ABP is not available.) VF Ventricular fibrillation; CPR Cardiopulmonary Resuscitation; HGB Hemoglobin; VCM Vancomycin; PRBC Packed red blood cell; ROSC Return of spontaneous circulation
Case presentation
The first case we encountered was a 68-yr female with past medical history of hypertension and surgical treated retina detachment, who underwent posterior decompression, fixation and fusion of lumbar spine due to lumbar stenosis (L3-S1). The operation was uneventful until sudden circulatory collapse occurred during the process of rinsing mascularis and superficial fascia layer whilst closing the wound. A sudden drop in arterial blood pressure (ABP) (130/60 mmHg to 30/20 mmHg), increased HR (60 bpm to 100 bpm) with elevated ST-segment and significant decrease of PetCO2 (31 mmHg to 16 mmHg) were noticed, with undetectable pulse oximetry read. The patient was turned to supine position immediately and managed with boluses (40–100 μg) and a continuous infusion of noradrenaline (0.01–0.04 μg/kg/min) for approximately 45 min. The circulation was gradually stabilized. No rash, erythema, or bronchospasm were noted. The bilateral breath sounds were equal and the airway pressure remained normal. We continued treatments of fluid resuscitation and blood transfusion with corticosteroid and ice cap to prevent hypoxic-ischemic encephalopathy. Intraoperative emergency consultations and immediate examinations of 12-lead ECG, point-of-care transthoracic echocardiography (TTE), and full panel laboratory tests were performed. However, these results did not support the causes of sudden cardiac dysfunction (the pump) including mechanical obstruction (pericardial tamponade and massive pulmonary embolus), acute myocardial infarction, acute valvular insufficiency, and arrhythmia. Vascular catastrophes were excluded and there were no signs of sepsis. We also examined the intravascular volume function (the tank) by performing the TTE, and ruled out intraperitoneal major hemorrhage which we once encountered (caused by inadvertent piercing of iliac artery when placing probe during lumbar surgery) by examination of abdominal ultrasound and hemoglobin level; Volume status was evaluated by measuring CVP, urine output, infused fluid volume; Surgical blood loss was reviewed to exclude hemorrhage shock and hypovolemia. As no special medications were given except anesthetic maintenance drugs, and no signs of mottled skin or bronchospasm were noticed, anaphylaxis was not considered at that time. After restoring circulatory stability, the surgery preceded uneventfully. The patient was discharged from hospital 7 days later.
It was intriguing that within 1 month, another case of circulatory collapse happened during wound closure in spine surgery performed by the same orthopedic surgeon. The intraoperative clinical manifestations were very similar to the previous one. Hemodynamic resuscitation were initiated immediately with repeated boluses and continuous infusion of noradrenaline (0.05–0.4 μg/kg/min) and adrenaline (0.5–0.15 μg/kg/min). After stabilizing the circulation 4 h later, the patient was extubated and transferred to ICU due to neurological symptoms (unable to follow instructions after full recovery from anesthesia). Postoperative imaging revealed intracranial micro hemorrhagic foci in the subdural and subarachnoid space. The patient was discharged from hospital without any neurological sequelae.
With further exploration and analysis of the similarities of these two cases, we found that local application of vancomycin (VCM) powder was used in these two patients to prevent postoperative surgical site infections (SSIs) during wound closure (0.5 g VCM loaded with bone debris into the cage and another 0.5 g sprayed on the dura mater and into the mascularis). Ramamani Mariappan reported a case of circulatory collapse after topical application of vancomycin powder during spine surgery, which exhibited almost the same clinical course as ours [2]. It was speculated that the rapid absorption of VCM applied to the surgical wound caused an anaphylaxis reaction and circulatory collapse. The reaction occurred approximately 30 min after the application and persisted for 6 h. The serum tryptase level was not elevated, suggesting that VCM caused a direct histamine release, which is in keeping with our current understanding. A similar case reported a 74-year-old woman who underwent a primary total knee replacement presented with red man syndrome in the PACU 45 min after release of tourniquet following the use of VCM-loaded bone cement. The patient remained fully conscious despite a sudden drop in blood pressure to 47/34 mmHg [3]. Therefore, local application of VCM may pose the risk of causing severe circulatory adverse effect.
Similar circulatory collapse cases in spine surgery without definitive causes during wound closure or shortly after surgery, though rare, were encountered in our institution. Therefore we retrospectively analyzed these cases for the past 2 years, and asked the anesthesiologists and orthopedic surgeons in charge for further information. A total of 7 cases were collected (Table 1). There were 3 males and 4 females, the median age was 66 y (43–74 y), and the averaged BMI was 24.39 ± 1.51 (22.3–26.1). It was interesting to note that these cases were all associated with topical application of VCM powder (Table 1). In these 7 cases, the onset time of severe circulatory fluctuation was 30 min in 5 cases, 50 min in one case (applied with 1 g of VCM), and approximately 45 min in another case (locally applied 3 g of VCM), respectively. Most of the cases (6/7) with severe circulatory fluctuation were corrected without severe sequelae. While in one case in which 3 g of VCM was applied on the dura mater and into the mascularis during wound closure, sudden cardiac arrest happened shortly after the patient had fully recovered from the anesthetic, following surgery and extubation in the OR. CPR was initiated immediately. The patient was reintubated and ventilated mechanically. The persistent VF was treated with continuous chest compressions and repeated defibrillation, with boluses of adrenaline (a total of 6 mg) and amiodarone. After 50 min of continuous CPR, with fluid resuscitation and blood transfusion, the patient was transferred to ICU following the return of spontaneous circulation and reverting into sinus rhythm. However, the patient remained in a comatose state due to hypoxic-hypoxic encephalopathy, and tracheotomy was performed 2 weeks later.
Discussion and conclusion
Vancomycin and anaphylaxis reaction
“International Consensus on (ICON) Anaphylaxis” define anaphylaxis as “a serious, generalized or systemic, allergic or hypersensitivity reaction that can be life threatening or fatal” [4]. It has been demonstrated that there exists IgE-dependent and three IgE-independent mechanisms in anaphylaxis pathophysiology [5]. VCM could directly activate mast cells to release histamine and other mediators through an IgE-independent mechanism that is calcium-, phospholipase C–, and phospholipase A2–dependent but otherwise unknown [5, 6]. Vancomycin-induced direct histamine release is also infusion rate dependent [7]. This IgE-independent anaphylaxis reaction generally disappears within 20 mins, but may linger for hours. The most common manifestation is a sudden drop in blood pressure, which is related to the negative inotropic effect and the vasodilator action stimulated by the histamine release. Alteration in vascular tone is also a common feature of anaphylactic shock [8]. Richter J and colleagues demonstrated in rats that VCM could directly influence the vascular tonus, affecting the microcirculation [9].
The VCM reactions studied in the pediatric population revealed that non-IgE mediated reaction accounts for the vast majority of reactions (92%; prevalence, 5.4–5.8%), whereas possible IgE-mediated vancomycin reactions were exceedingly rare (prevalence, 0.0–0.37%) [7]. For adults, the reported incidence of non-IgE mediated reaction varies between 3.7 and 47% in infected patients and 90% in healthy volunteers [2]. Elevated serum mast cell tryptase is a valuable indicator for diagnosing Ig-E mediated anaphylactic reaction. However, it is not useful in determining a non-IgE mediated anaphylactic reaction caused by histamine release [2]. Detection of histamine concentration in clinical blood specimens is difficult due to its extremely short half-life, and histamine is not a mast cell specific product [10]. As this study is retrospective in nature, and our hospital does not perform examination of serum tryptase and histamine concentration, we could not differentiate whether the adverse effects were caused by VCM induced IgE-mediated or non-IgE mediated reaction.
Topical application of vancomycin powder and surgical site infections
VCM is effective in fighting Gram-positive bacteria related severe infections [11]. While the actual utility of local application of VCM is controversial. After the first reported topical application of VCM by orthopedic surgeons to reduce postoperative surgical site infections (SSIs) rate [12], a large number of meta-analyses, retrospective cohort studies, and randomized controlled trials were published to assess the power of this method in preventing SSIs. Recent findings from large-scale propensity score matched analyses, meta analyses, RCTs studies, and observational studies of spine surgeries and knee arthroplasties all demonstrated that the intrawound VCM powder application may not decrease SSIs, but may increase postoperative complications [13–19].
VCM is an antibiotic that was considered safe in local application and has been widely used in hospitals. However, dose recommendations, dilutions, monitoring, infusion types and rates are still controversial [20]. There’s no defined time or situation during surgery when local VCM should be applied. Some may load VCM powder with bone debris into the cage, or apply VCM powder directly onto the dura mater or after closure of the fascia, whereas other studies reported that VCM powder was applied in the subfascial layer [2, 13]. However, intrawound absorption rate of VCM powder is uncontrollable as this depends on multiple factors, such as the extent and degree of tissue/muscle damaged by surgical manipulation, anatomic location where VCM powder is placed (mixed with bone debris, or between muscularis layers that are abundant with blood supply), and the surgeon’s suturing maneuvers (the flushing saline would leak from upper layer into the layer where VCM powder is deposited). These factors all pose potential risk of causing rapid drug dissolution and accelerated absorption into the circulatory system. Moreover, individual’s adverse reactions to VCM varied. These incidental events may be accidentally linked and lead to severe outcome. Since intravenous administration of VCM could lead to adverse effects, it is theoretically possible that local application of VCM powder may cause similar clinical manifestation.
Topical application of VCM was intended to achieve the effect of providing high local concentrations while avoiding high systemic levels and the risk of bacterial resistance. The serum concentration level peaks at 30 min and then declines to baseline at 6 h [2]. This may explain the delayed and unpredictable occurrence of anaphylaxis reactions after local application of VCM powder, due to the uncertainty of the drug absorption rate and individual reaction differences. The instructed therapeutic dosage of VCM is 30 mg/kg/day which should be fractioned in 2 or 3 doses. Moreover, the infusion rate should be within 10 mg/min, and last for more than 60 min. For elderly patients, this dosage should be reduced [21, 22]. Although the most commonly used dose of intrawound VCM is 1 g, some authors reported that they altered the dose according to the length of the incision [23]. VCM is not the first-choice antibiotic as its adverse effects are frequently reported including hypotension and tachycardia, phlebitis, nephrotoxicity, ototoxicity, hypersensitivity reactions, red man syndrome, neutropenia, chills, fever, interstitial nephritis, etc. [13]. As VCM induced adverse reactions are dose and infusion-rate dependent, doctors should be highly vigilant to over-dosing which might bring disastrous results.
Other issues related to shock
In this case series, the typical signs of erythema and redness (red man syndrome) have not appeared, which resemble the previous case reported by Mariappan R and colleagues [2]. The lack of skin flushing may be the result of reduced perfusion due to circulatory shock or the adverse effect of VCM mainly manifested as severe alteration of vascular tonus [8, 9]. In our experience, a rapid but low dose intravenous infusion of VCM induced anaphylaxis reaction was not necessarily associated with skin manifestations. Whether this is related to racial differences or rapid absorption of low dose VCM was not known. However, the clinical features of hypotension, tachycadia and low oxygenation were notable.
For this case series, as there is no definitive laboratory examination or gold standard to help reach a definitive diagnosis of VCM induced anaphylaxis reaction, the conclusions were made upon differential diagnosis based on clinical manifestations and the timing of the shock. Other possible causes or contributing factors for the development of severe hypotension and shock need to be considered. For example, restrictive fluid therapy during surgical procedure and restrictive blood transfusion strategy leading to hypovolemia and hypotension, complicated with unseen bleeding from surgical site and other compounding factors such as hypoproteinemia and unaltered anesthetic depth during wound closure.
Another issue needs to be addressed is that there’s a notable decrease in hemoglobin (HGB) concentration in all cases when severe hypotension occurred. However, the hemorrhagic shock induced by surgical blood loss was ruled out. We speculate that this might be due to the infusion of large amounts of fluid during resuscitation. It is reported that the administration of 500 ml of fluids may acutely decrease the HGB concentration by about 1 g/dl, or about 8%, by “dilutional anemia” [24]. In septic shock patients, approximately 30% decrease of hematocrit was commonly observed in patients receiving large amounts of fluids during resuscitation, which further indicates more blood transfusion [25]. In the current study, the HGB concentrations were all measured after the initiation of fluid resuscitation and this may at least partially explained the sharp decrease of the HGB level (Table 1). When severe hypotension with unknown causes occur, initial management is to infuse large amounts of fluid with vaso-constrictive drugs. The iatrogenic hemodilution related blood transfusion may result in dilutional coagulopathy and increase surgical bleeding. This then leads to a decreased HGB level below the acceptable transfusion threshold, leading to further blood transfusion in the absence of significant blood loss [26]. This is especially true when in the scenario of the existence of suspected hemorrhagic shock.
In conclusion, local application of VCM powder during wound closure could cause delayed occurrence of severe hypotension and shock in spine surgery. Hemodynamic changes may be under-emphasized and under-reported as in most cases, this hemodynamic reaction is easy to correct and normally wouldn’t cause serious consequences. However, the actual occurrence is not rare and this might be confused with hypovolemia or anesthetic induced hypotension. Surgeons and anesthesiologists should be highly aware of VCM induced IgE-independent anaphylaxis reactions. The differential diagnosis of anaphylactic shock must be taken into consideration in patients with acute hypotension during or immediately after wound closure. Prompt laboratory analysis of serum tryptase and histamine concentration could help differentiate the causes. Moreover, since controversies still exist in the actual effect of intrawound application of VCM powder to reduce SSIs in spine surgery, local application of this drug should be used with caution.
Abbreviations
VCMVancomycin
ABPArterial blood pressure
TTETransthoracic echocardiography
Publisher’s Note
Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
We sincerely thank our colleagues from anesthesia (Dr. XW, Dr. CW, Dr. WL, Dr. JY, Dr. YW, Dr. CN, Dr. CX, Dr. YT, Dr. HW, Dr. HT, Dr. WW, Dr. YT, Dr. XJ, HL, Dr. HW, Dr. HZ, Dr. YW, and Dr. BW) and surgical department (Dr. YD, Dr. YL, Dr. FZ, Dr. QQ, and Dr. ZC) for providing and verifying the cases.
The authors have completed the CARE reporting checklist.
Authors’ contributions
Guarantor of integrity of entire study: XZ, WZ, ML, XG. Literature research: XZ, WZ. Case study and follow-up: XZ, WZ. Manuscript preparation: XZ, WZ. Manuscript editing and revision: ML, XG. Manuscript final version approval: ML, XG. All authors have read and approved the manuscript.
Funding
This work was supported by the Clinical Key Project of Peking University Third Hospital, Grants No. BYSY2017001.
The role of the funder: study design, decision to submit the manuscript for publication.
Availability of data and materials
All data generated or analyzed during this study are included in this published article. More detailed information could be find in Table 1.
Ethics approval and consent to participate
This case was performed according to the ethical guidelines of the Helsinki Declaration and was approved by the Human Ethics Committee of Peking University Third Hospital. All the authors listed in the manuscript consent to participate the study. The consent for publication from patient or their relatives were collected retrospectively.
Consent for publication
As this is a retrospective case study, written informed consent to publish this manuscript were collected from patients or their relatives retrospectively. The proof of consent to publish from study participants can be requested at any time.
Competing interests
The author(s) declare no competing interests. | Recovered | ReactionOutcome | CC BY | 33407142 | 18,839,984 | 2021-01-06 |
What was the outcome of reaction 'Coma'? | Circulatory collapse during wound closure in spine surgery with an unknown cause: a possible adverse effect of topical application of vancomycin?
Vancomycin (VCM) is effective in fighting Gram-positive bacteria related severe infections, and topical application of VCM powder is widely used in orthopedic surgery to prevent wound infection. However, VCM could lead to infusion rate-dependent antibody-and complement-independent anaphylaxis reaction by inducing direct release of histamine.
We retrospectively analyzed seven cases of severe hypotension and shock during wound closure or immediately after orthopedic surgery with unidentifiable reasons. We found that these cases were all associated with local application of VCM powder during wound closure process. Two patients experienced sudden cardiac arrest. Most of the cases (6/7) with circulatory collapse were discharged without severe sequelae. While one case with application of 3 g VCM developed cardiac arrest and remained in a coma due to hypoxic-hypoxic encephalopathy. The clinical presentations and the time of the shock onset were considered to be related with a VCM induced anaphylaxis reaction. However, as this was a retrospective study, and there was no laboratory examination performed, the conclusion was made upon differential diagnosis based on clinical manifestations and the timing of the shock.
Local application of VCM may not be as safe as was once believed and may lead to a related anaphylaxis. As VCM induced infusion-rate dependent, non-IgE mediated anaphylaxis is characterized by delayed occurrence, severe hypotension and even circulatory collapse, surgeons and anesthesiologists should be extra vigilant during and after VCM application.
Background
Shock is defined as a state of insufficient perfusion and oxygen delivery to the tissues. The pathophysiology of shock could be simplified to three major components: cardiac function (the pump), intravascular volume (the tank), and systemic vascular resistance (the pipes) [1]. Whatever the causes of shock may be, if the impaired perfusion and oxygen delivery is not recognized and reversed, the circulatory collapse may progress into organ dysfunction and failure, tissue necrosis and even death. It is urgent to identify the causes of shock and take immediate measures. However, in critical situations, it is hard to rapidly distinguish the culprit during complex clinical situations. Here we present 7 cases (Table 1) of unidentifiable causes of shock during wound closure or shortly after spine surgery, and discuss the possible reasons.
Table 1 Summary of clinical presentations of seven patients with circulatory collapse and unknown etiologies during or shortly after wound closure in spine surgery
Case Demographic information Initial signs/symptoms of shock and management Hemoglobin value (g/L),
fluid resuscitation and blood product infusion VCM administration
and Postoperative sequelae
1 Female; 68-yr; 160 cm/60 kg
BMI: 23.4
Diagnosis:
Lumbar stenosis (L3-S1)
Surgery:
Posterior decompression, fixation and fusion of lumbar spine.
Medical and allergy history:
Hypertension
History of retina surgery
Time of occurrence:
Subcutaneous layer closure, 30 min after initiation of wound closure.
Signs and symptoms:
ABP: 30/20 mmHg
SpO2: undetectable
ECG: tarchycardia with elevated ST segment
Skin and airway symptoms: none.
Management:
Boluses and continuous infusion of noradrenaline (0.01–0.04 μg/kg/min) for 45 min. Fluid resuscitation and blood transfusion.
Preoperative HGB value: 124
Intraoperative minimum value of HGB: 73
Blood loss: 600 ml
Urine: 850 ml
Fluid and blood product infusion:
Crystalloid: 3450 ml
Colloid: 500 ml
PRBC infusion: 1200 ml
Infused autologous blood: 210 ml
VCM administration:
0.5 g mixed with bone debris into the cage and 0.5 g spraying on the dura mater and into the mascularis layer.
Postoperative sequelae:
Proceeded with surgery and the patient was extubated uneventfully.
2 Male; 74-yr; 171 cm/67 kg
BMI: 23.9
Diagnosis:
lumbar stenosis (L3–5)
Surgery:
Posterior decompression, fixation and fusion of lumbar spine.
Medical and allergy history:
nil relevant.
Time of occurrence:
Subcutaneous layer closure, 30 min after initiation of wound closure.
Signs and symptoms:
NBP: 45/15 mmHg
SpO2: undetectable
ECG: tachycardia with ST segment depression
Skin and airway symptoms: none.
Management:
Boluses and continuous infusion of noradrenaline (0.05–0.4 μg/kg/min) and adrenaline (0.5–0.15 μg/kg/min) for 4 h.
Preoperative HGB value:135
Intraoperative minimum value of HGB: 79
Blood loss: 600 ml
Urine: 1950 ml
Fluid and blood product infusion:
Crystalloid: 6300 ml
Colloid: 500 ml
PRBC infusion: 1200 ml
Plasma: 800 ml
Infused autologous blood: 254 ml
VCM administration:
0.5 g mixed with bone debris into the cage and 0.5 g spraying on the dura mater and into the mascularis layer.
Postoperative sequelae:
The patient was extubated and transferred to ICU due to neurological symptoms (unable to follow instructions).
Postoperative imaging: intracranial minor hemorrhage at subdural and subarachnoid space.
The patient was discharged from hospital without neurological deficit.
3 Male; 63-yr; 169 cm/70 kg
BMI: 24.5
Diagnosis:
Lumbar stenosis (L3–5)
Surgery:
Posterior decompression, fixation and fusion of lumbar spine.
Medical and allergy history:
Lacunar infarction;
Bilateral carotid atherosclerotic plaque formation
Time of occurrence:
50 min after initiation of wound closure and 20 min post-extubation in the PACU.
Signs and symptoms:
NBP: 60/25 mmHg
SpO2: 96%
HR:sudden elevation from 60 to 90 bpm
Postoperative agitation
Skin and airway symptoms: none.
Management:
Boluses of ephedrine, phenylephrine and fluid resuscitation.
Preoperative HGB value: 176
Intraoperative minimum value of HGB:123
Blood loss: 800 ml
Urine: 800 ml
Fluid and blood product infusion:
Crystalloid: 2350 ml
Colloid: 1000 ml
PRBC infusion: 400 ml
VCM administration:
Topical spraying of vancomycin (1 g) on the dura mater and into the mascularis.
Postoperative sequelae:
Uneventful.
4 Female; 70-yr; 160 cm/65 kg
BMI:25.4
Diagnosis:
Lumbar stenosis (L4-S1)
Surgery:
Posterior decompression, fixation and fusion of lumbar spine.
Hypertension
Diabetes Mellitus
Time of occurrence:
Subcutaneous layer closure, 30 min after initiation of wound closure.
Signs and symptoms:
NBP: 45/15 mmHg
SpO2: undetectable
Persistent tachycardia
Skin and airway symptoms: none.
Management:
Boluses of phenylephrine for treating severe hypotension and esmolol for tachycardia
Fluid resuscitation and blood transfusion.
Preoperative HGB value: 150
Intraoperative minimum value of HGB: 92
Blood loss: 1500 ml
Urine: 1800 ml
Fluid and blood product infusion:
Crystalloid: 3100 ml
Colloid: 1500 ml
PRBC infusion: 1200 ml
Infused autologous blood: 450 ml
VCM administration:
0.5 g mixed with bone debris into the cage and 0.5 g spraying on the dura mater and into the mascularis layer.
Postoperative sequelae:
The patient was extubated after surgery and transferred to ICU due to tachycardia after sufficient fluid resuscitation.
Recovered uneventfully.
5 Female;48-yr; 170 cm/75 kg
BMI: 26.0
Diagnosis:
Thoracic spinal canal stenosis (T6-T11)
Surgery:
Posterior decompression, fixation and fusion of thoracic spine.
Medical and allergy history:
nil relevant.
Time of occurrence:
Subcutaneous layer closure, 30 min after initiation of wound closure.
Signs and symptoms:
NBP: 40/30 mmHg to undetectable
HR: 120 bpm to 40 bpm
SpO2: undetectable
Cardiac arrest
Skin and airway symptoms: none.
Management:
Extracardiac compression
Boluses of noradrenaline (200 μg) and adrenaline (1 g)
Continuous infusion of noradrenaline (0.02–0.08 μg/kg/min) for 50 min
Fluid resuscitation and blood transfusion.
Preoperative HGB value: 132
Intraoperative minimum value of HGB: 74
Blood loss: 2500 ml
Urine: 1300 ml
Fluid and blood product infusion:
Crystalloid: 4000 ml
Colloid: 500 ml
PRBC infusion: 2400 ml
VCM administration:
Topical spraying of vancomycin (1 g) on the dura mater and into the mascularis layer.
Postoperative sequelae:
The patient was extubated after surgery, and discharged from hospital uneventfully.
6 Male; 66-yr; 175 cm/ 80 kg
BMI: 26.1
Diagnosis:
Lumbar stenosis (L3–5)
Surgery:
Posterior decompression, fixation and fusion of lumbar spine.
Medical and allergy history:
Carotid artery stenosis
Diabetes Mellitus
Time of occurrence:
Sudden cardiac arrest 10 min after extubation (approximately 45 min after initiation of wound closure) with full recovery from anesthesia and without any discomfort complaint.
Signs and symptoms:
Cardiac arrest and persistent VF
Skin and airway symptoms: none.
Management:
Continuous CPR
Persistent VF was treated with repeated defibrillation
Boluses of adrenaline (a total of 6 mg) and amiodarone.
Fluid resuscitation and blood transfusion.
Preoperative HGB value: 143
Intraoperative minimum value of HGB: 78
Blood loss: 1000 ml
Urine: 850 ml
Fluid and blood product infusion:
Crystalloid: 4400 ml
Colloid: 1000 ml
PRBC infusion: 1200 ml
Infused autologous blood: 600 ml
VCM administration:
Topical spraying of vancomycin (3 g) on the dura mater and into the mascularis.
Postoperative sequelae:
The patient was reintubated and transferred to ICU after ROSC. The patient was diagnosed as hypoxic encephalopathy and remained in a coma state. Tracheotomy was performed 2 weeks after surgery, and the patient was transferred to a nursing home for rehabilitation 1 month after orthopedic surgery.
7 Female; 43-yr; 155 cm / 54 kg
BMI: 22.4
Diagnosis:
Thoracic kyphosis (T7-T8)
Surgery:
Osteotomy for kyphosis of thoracic spine (T7-T8).
Medical and allergy history:
nil relevant.
Time of occurrence:
subcutaneous layer closure, 30 min after initiation of wound closure.
Signs and symptoms:
HR:tachycardia
NBP: 60/30 mmHg
SpO2 82%
Skin and airway symptoms: none.
Management:
Boluses of phenylephrine and ephedrine;
Continuous infusion of noradrenaline (0.05–0.1 μg/kg/min)
Fluid resuscitation and blood transfusion.
Preoperative HGB value: 138
Intraoperative minimum value of HGB: 95
Blood loss: 1200 ml
Urine: 1900 ml
Fluid and blood product infusion:
Crystalloid: 4700 ml
Colloid: 1000 ml
PRBC infusion: 1200 ml
Infused autologous blood: 470 ml
VCM administration:
Topical spraying of vancomycin (1 g) on the dura mater and into the mascularis layer.
Postoperative sequelae:
The patient was transferred to ICU for optimal monitoring and recovered uneventfully.
Abbreviations: NBP Non-invasive blood pressure; ABP Arterial blood pressure; (NBP is noted when ABP is not available.) VF Ventricular fibrillation; CPR Cardiopulmonary Resuscitation; HGB Hemoglobin; VCM Vancomycin; PRBC Packed red blood cell; ROSC Return of spontaneous circulation
Case presentation
The first case we encountered was a 68-yr female with past medical history of hypertension and surgical treated retina detachment, who underwent posterior decompression, fixation and fusion of lumbar spine due to lumbar stenosis (L3-S1). The operation was uneventful until sudden circulatory collapse occurred during the process of rinsing mascularis and superficial fascia layer whilst closing the wound. A sudden drop in arterial blood pressure (ABP) (130/60 mmHg to 30/20 mmHg), increased HR (60 bpm to 100 bpm) with elevated ST-segment and significant decrease of PetCO2 (31 mmHg to 16 mmHg) were noticed, with undetectable pulse oximetry read. The patient was turned to supine position immediately and managed with boluses (40–100 μg) and a continuous infusion of noradrenaline (0.01–0.04 μg/kg/min) for approximately 45 min. The circulation was gradually stabilized. No rash, erythema, or bronchospasm were noted. The bilateral breath sounds were equal and the airway pressure remained normal. We continued treatments of fluid resuscitation and blood transfusion with corticosteroid and ice cap to prevent hypoxic-ischemic encephalopathy. Intraoperative emergency consultations and immediate examinations of 12-lead ECG, point-of-care transthoracic echocardiography (TTE), and full panel laboratory tests were performed. However, these results did not support the causes of sudden cardiac dysfunction (the pump) including mechanical obstruction (pericardial tamponade and massive pulmonary embolus), acute myocardial infarction, acute valvular insufficiency, and arrhythmia. Vascular catastrophes were excluded and there were no signs of sepsis. We also examined the intravascular volume function (the tank) by performing the TTE, and ruled out intraperitoneal major hemorrhage which we once encountered (caused by inadvertent piercing of iliac artery when placing probe during lumbar surgery) by examination of abdominal ultrasound and hemoglobin level; Volume status was evaluated by measuring CVP, urine output, infused fluid volume; Surgical blood loss was reviewed to exclude hemorrhage shock and hypovolemia. As no special medications were given except anesthetic maintenance drugs, and no signs of mottled skin or bronchospasm were noticed, anaphylaxis was not considered at that time. After restoring circulatory stability, the surgery preceded uneventfully. The patient was discharged from hospital 7 days later.
It was intriguing that within 1 month, another case of circulatory collapse happened during wound closure in spine surgery performed by the same orthopedic surgeon. The intraoperative clinical manifestations were very similar to the previous one. Hemodynamic resuscitation were initiated immediately with repeated boluses and continuous infusion of noradrenaline (0.05–0.4 μg/kg/min) and adrenaline (0.5–0.15 μg/kg/min). After stabilizing the circulation 4 h later, the patient was extubated and transferred to ICU due to neurological symptoms (unable to follow instructions after full recovery from anesthesia). Postoperative imaging revealed intracranial micro hemorrhagic foci in the subdural and subarachnoid space. The patient was discharged from hospital without any neurological sequelae.
With further exploration and analysis of the similarities of these two cases, we found that local application of vancomycin (VCM) powder was used in these two patients to prevent postoperative surgical site infections (SSIs) during wound closure (0.5 g VCM loaded with bone debris into the cage and another 0.5 g sprayed on the dura mater and into the mascularis). Ramamani Mariappan reported a case of circulatory collapse after topical application of vancomycin powder during spine surgery, which exhibited almost the same clinical course as ours [2]. It was speculated that the rapid absorption of VCM applied to the surgical wound caused an anaphylaxis reaction and circulatory collapse. The reaction occurred approximately 30 min after the application and persisted for 6 h. The serum tryptase level was not elevated, suggesting that VCM caused a direct histamine release, which is in keeping with our current understanding. A similar case reported a 74-year-old woman who underwent a primary total knee replacement presented with red man syndrome in the PACU 45 min after release of tourniquet following the use of VCM-loaded bone cement. The patient remained fully conscious despite a sudden drop in blood pressure to 47/34 mmHg [3]. Therefore, local application of VCM may pose the risk of causing severe circulatory adverse effect.
Similar circulatory collapse cases in spine surgery without definitive causes during wound closure or shortly after surgery, though rare, were encountered in our institution. Therefore we retrospectively analyzed these cases for the past 2 years, and asked the anesthesiologists and orthopedic surgeons in charge for further information. A total of 7 cases were collected (Table 1). There were 3 males and 4 females, the median age was 66 y (43–74 y), and the averaged BMI was 24.39 ± 1.51 (22.3–26.1). It was interesting to note that these cases were all associated with topical application of VCM powder (Table 1). In these 7 cases, the onset time of severe circulatory fluctuation was 30 min in 5 cases, 50 min in one case (applied with 1 g of VCM), and approximately 45 min in another case (locally applied 3 g of VCM), respectively. Most of the cases (6/7) with severe circulatory fluctuation were corrected without severe sequelae. While in one case in which 3 g of VCM was applied on the dura mater and into the mascularis during wound closure, sudden cardiac arrest happened shortly after the patient had fully recovered from the anesthetic, following surgery and extubation in the OR. CPR was initiated immediately. The patient was reintubated and ventilated mechanically. The persistent VF was treated with continuous chest compressions and repeated defibrillation, with boluses of adrenaline (a total of 6 mg) and amiodarone. After 50 min of continuous CPR, with fluid resuscitation and blood transfusion, the patient was transferred to ICU following the return of spontaneous circulation and reverting into sinus rhythm. However, the patient remained in a comatose state due to hypoxic-hypoxic encephalopathy, and tracheotomy was performed 2 weeks later.
Discussion and conclusion
Vancomycin and anaphylaxis reaction
“International Consensus on (ICON) Anaphylaxis” define anaphylaxis as “a serious, generalized or systemic, allergic or hypersensitivity reaction that can be life threatening or fatal” [4]. It has been demonstrated that there exists IgE-dependent and three IgE-independent mechanisms in anaphylaxis pathophysiology [5]. VCM could directly activate mast cells to release histamine and other mediators through an IgE-independent mechanism that is calcium-, phospholipase C–, and phospholipase A2–dependent but otherwise unknown [5, 6]. Vancomycin-induced direct histamine release is also infusion rate dependent [7]. This IgE-independent anaphylaxis reaction generally disappears within 20 mins, but may linger for hours. The most common manifestation is a sudden drop in blood pressure, which is related to the negative inotropic effect and the vasodilator action stimulated by the histamine release. Alteration in vascular tone is also a common feature of anaphylactic shock [8]. Richter J and colleagues demonstrated in rats that VCM could directly influence the vascular tonus, affecting the microcirculation [9].
The VCM reactions studied in the pediatric population revealed that non-IgE mediated reaction accounts for the vast majority of reactions (92%; prevalence, 5.4–5.8%), whereas possible IgE-mediated vancomycin reactions were exceedingly rare (prevalence, 0.0–0.37%) [7]. For adults, the reported incidence of non-IgE mediated reaction varies between 3.7 and 47% in infected patients and 90% in healthy volunteers [2]. Elevated serum mast cell tryptase is a valuable indicator for diagnosing Ig-E mediated anaphylactic reaction. However, it is not useful in determining a non-IgE mediated anaphylactic reaction caused by histamine release [2]. Detection of histamine concentration in clinical blood specimens is difficult due to its extremely short half-life, and histamine is not a mast cell specific product [10]. As this study is retrospective in nature, and our hospital does not perform examination of serum tryptase and histamine concentration, we could not differentiate whether the adverse effects were caused by VCM induced IgE-mediated or non-IgE mediated reaction.
Topical application of vancomycin powder and surgical site infections
VCM is effective in fighting Gram-positive bacteria related severe infections [11]. While the actual utility of local application of VCM is controversial. After the first reported topical application of VCM by orthopedic surgeons to reduce postoperative surgical site infections (SSIs) rate [12], a large number of meta-analyses, retrospective cohort studies, and randomized controlled trials were published to assess the power of this method in preventing SSIs. Recent findings from large-scale propensity score matched analyses, meta analyses, RCTs studies, and observational studies of spine surgeries and knee arthroplasties all demonstrated that the intrawound VCM powder application may not decrease SSIs, but may increase postoperative complications [13–19].
VCM is an antibiotic that was considered safe in local application and has been widely used in hospitals. However, dose recommendations, dilutions, monitoring, infusion types and rates are still controversial [20]. There’s no defined time or situation during surgery when local VCM should be applied. Some may load VCM powder with bone debris into the cage, or apply VCM powder directly onto the dura mater or after closure of the fascia, whereas other studies reported that VCM powder was applied in the subfascial layer [2, 13]. However, intrawound absorption rate of VCM powder is uncontrollable as this depends on multiple factors, such as the extent and degree of tissue/muscle damaged by surgical manipulation, anatomic location where VCM powder is placed (mixed with bone debris, or between muscularis layers that are abundant with blood supply), and the surgeon’s suturing maneuvers (the flushing saline would leak from upper layer into the layer where VCM powder is deposited). These factors all pose potential risk of causing rapid drug dissolution and accelerated absorption into the circulatory system. Moreover, individual’s adverse reactions to VCM varied. These incidental events may be accidentally linked and lead to severe outcome. Since intravenous administration of VCM could lead to adverse effects, it is theoretically possible that local application of VCM powder may cause similar clinical manifestation.
Topical application of VCM was intended to achieve the effect of providing high local concentrations while avoiding high systemic levels and the risk of bacterial resistance. The serum concentration level peaks at 30 min and then declines to baseline at 6 h [2]. This may explain the delayed and unpredictable occurrence of anaphylaxis reactions after local application of VCM powder, due to the uncertainty of the drug absorption rate and individual reaction differences. The instructed therapeutic dosage of VCM is 30 mg/kg/day which should be fractioned in 2 or 3 doses. Moreover, the infusion rate should be within 10 mg/min, and last for more than 60 min. For elderly patients, this dosage should be reduced [21, 22]. Although the most commonly used dose of intrawound VCM is 1 g, some authors reported that they altered the dose according to the length of the incision [23]. VCM is not the first-choice antibiotic as its adverse effects are frequently reported including hypotension and tachycardia, phlebitis, nephrotoxicity, ototoxicity, hypersensitivity reactions, red man syndrome, neutropenia, chills, fever, interstitial nephritis, etc. [13]. As VCM induced adverse reactions are dose and infusion-rate dependent, doctors should be highly vigilant to over-dosing which might bring disastrous results.
Other issues related to shock
In this case series, the typical signs of erythema and redness (red man syndrome) have not appeared, which resemble the previous case reported by Mariappan R and colleagues [2]. The lack of skin flushing may be the result of reduced perfusion due to circulatory shock or the adverse effect of VCM mainly manifested as severe alteration of vascular tonus [8, 9]. In our experience, a rapid but low dose intravenous infusion of VCM induced anaphylaxis reaction was not necessarily associated with skin manifestations. Whether this is related to racial differences or rapid absorption of low dose VCM was not known. However, the clinical features of hypotension, tachycadia and low oxygenation were notable.
For this case series, as there is no definitive laboratory examination or gold standard to help reach a definitive diagnosis of VCM induced anaphylaxis reaction, the conclusions were made upon differential diagnosis based on clinical manifestations and the timing of the shock. Other possible causes or contributing factors for the development of severe hypotension and shock need to be considered. For example, restrictive fluid therapy during surgical procedure and restrictive blood transfusion strategy leading to hypovolemia and hypotension, complicated with unseen bleeding from surgical site and other compounding factors such as hypoproteinemia and unaltered anesthetic depth during wound closure.
Another issue needs to be addressed is that there’s a notable decrease in hemoglobin (HGB) concentration in all cases when severe hypotension occurred. However, the hemorrhagic shock induced by surgical blood loss was ruled out. We speculate that this might be due to the infusion of large amounts of fluid during resuscitation. It is reported that the administration of 500 ml of fluids may acutely decrease the HGB concentration by about 1 g/dl, or about 8%, by “dilutional anemia” [24]. In septic shock patients, approximately 30% decrease of hematocrit was commonly observed in patients receiving large amounts of fluids during resuscitation, which further indicates more blood transfusion [25]. In the current study, the HGB concentrations were all measured after the initiation of fluid resuscitation and this may at least partially explained the sharp decrease of the HGB level (Table 1). When severe hypotension with unknown causes occur, initial management is to infuse large amounts of fluid with vaso-constrictive drugs. The iatrogenic hemodilution related blood transfusion may result in dilutional coagulopathy and increase surgical bleeding. This then leads to a decreased HGB level below the acceptable transfusion threshold, leading to further blood transfusion in the absence of significant blood loss [26]. This is especially true when in the scenario of the existence of suspected hemorrhagic shock.
In conclusion, local application of VCM powder during wound closure could cause delayed occurrence of severe hypotension and shock in spine surgery. Hemodynamic changes may be under-emphasized and under-reported as in most cases, this hemodynamic reaction is easy to correct and normally wouldn’t cause serious consequences. However, the actual occurrence is not rare and this might be confused with hypovolemia or anesthetic induced hypotension. Surgeons and anesthesiologists should be highly aware of VCM induced IgE-independent anaphylaxis reactions. The differential diagnosis of anaphylactic shock must be taken into consideration in patients with acute hypotension during or immediately after wound closure. Prompt laboratory analysis of serum tryptase and histamine concentration could help differentiate the causes. Moreover, since controversies still exist in the actual effect of intrawound application of VCM powder to reduce SSIs in spine surgery, local application of this drug should be used with caution.
Abbreviations
VCMVancomycin
ABPArterial blood pressure
TTETransthoracic echocardiography
Publisher’s Note
Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
We sincerely thank our colleagues from anesthesia (Dr. XW, Dr. CW, Dr. WL, Dr. JY, Dr. YW, Dr. CN, Dr. CX, Dr. YT, Dr. HW, Dr. HT, Dr. WW, Dr. YT, Dr. XJ, HL, Dr. HW, Dr. HZ, Dr. YW, and Dr. BW) and surgical department (Dr. YD, Dr. YL, Dr. FZ, Dr. QQ, and Dr. ZC) for providing and verifying the cases.
The authors have completed the CARE reporting checklist.
Authors’ contributions
Guarantor of integrity of entire study: XZ, WZ, ML, XG. Literature research: XZ, WZ. Case study and follow-up: XZ, WZ. Manuscript preparation: XZ, WZ. Manuscript editing and revision: ML, XG. Manuscript final version approval: ML, XG. All authors have read and approved the manuscript.
Funding
This work was supported by the Clinical Key Project of Peking University Third Hospital, Grants No. BYSY2017001.
The role of the funder: study design, decision to submit the manuscript for publication.
Availability of data and materials
All data generated or analyzed during this study are included in this published article. More detailed information could be find in Table 1.
Ethics approval and consent to participate
This case was performed according to the ethical guidelines of the Helsinki Declaration and was approved by the Human Ethics Committee of Peking University Third Hospital. All the authors listed in the manuscript consent to participate the study. The consent for publication from patient or their relatives were collected retrospectively.
Consent for publication
As this is a retrospective case study, written informed consent to publish this manuscript were collected from patients or their relatives retrospectively. The proof of consent to publish from study participants can be requested at any time.
Competing interests
The author(s) declare no competing interests. | Not recovered | ReactionOutcome | CC BY | 33407142 | 18,839,984 | 2021-01-06 |
What was the outcome of reaction 'Haemorrhage intracranial'? | Circulatory collapse during wound closure in spine surgery with an unknown cause: a possible adverse effect of topical application of vancomycin?
Vancomycin (VCM) is effective in fighting Gram-positive bacteria related severe infections, and topical application of VCM powder is widely used in orthopedic surgery to prevent wound infection. However, VCM could lead to infusion rate-dependent antibody-and complement-independent anaphylaxis reaction by inducing direct release of histamine.
We retrospectively analyzed seven cases of severe hypotension and shock during wound closure or immediately after orthopedic surgery with unidentifiable reasons. We found that these cases were all associated with local application of VCM powder during wound closure process. Two patients experienced sudden cardiac arrest. Most of the cases (6/7) with circulatory collapse were discharged without severe sequelae. While one case with application of 3 g VCM developed cardiac arrest and remained in a coma due to hypoxic-hypoxic encephalopathy. The clinical presentations and the time of the shock onset were considered to be related with a VCM induced anaphylaxis reaction. However, as this was a retrospective study, and there was no laboratory examination performed, the conclusion was made upon differential diagnosis based on clinical manifestations and the timing of the shock.
Local application of VCM may not be as safe as was once believed and may lead to a related anaphylaxis. As VCM induced infusion-rate dependent, non-IgE mediated anaphylaxis is characterized by delayed occurrence, severe hypotension and even circulatory collapse, surgeons and anesthesiologists should be extra vigilant during and after VCM application.
Background
Shock is defined as a state of insufficient perfusion and oxygen delivery to the tissues. The pathophysiology of shock could be simplified to three major components: cardiac function (the pump), intravascular volume (the tank), and systemic vascular resistance (the pipes) [1]. Whatever the causes of shock may be, if the impaired perfusion and oxygen delivery is not recognized and reversed, the circulatory collapse may progress into organ dysfunction and failure, tissue necrosis and even death. It is urgent to identify the causes of shock and take immediate measures. However, in critical situations, it is hard to rapidly distinguish the culprit during complex clinical situations. Here we present 7 cases (Table 1) of unidentifiable causes of shock during wound closure or shortly after spine surgery, and discuss the possible reasons.
Table 1 Summary of clinical presentations of seven patients with circulatory collapse and unknown etiologies during or shortly after wound closure in spine surgery
Case Demographic information Initial signs/symptoms of shock and management Hemoglobin value (g/L),
fluid resuscitation and blood product infusion VCM administration
and Postoperative sequelae
1 Female; 68-yr; 160 cm/60 kg
BMI: 23.4
Diagnosis:
Lumbar stenosis (L3-S1)
Surgery:
Posterior decompression, fixation and fusion of lumbar spine.
Medical and allergy history:
Hypertension
History of retina surgery
Time of occurrence:
Subcutaneous layer closure, 30 min after initiation of wound closure.
Signs and symptoms:
ABP: 30/20 mmHg
SpO2: undetectable
ECG: tarchycardia with elevated ST segment
Skin and airway symptoms: none.
Management:
Boluses and continuous infusion of noradrenaline (0.01–0.04 μg/kg/min) for 45 min. Fluid resuscitation and blood transfusion.
Preoperative HGB value: 124
Intraoperative minimum value of HGB: 73
Blood loss: 600 ml
Urine: 850 ml
Fluid and blood product infusion:
Crystalloid: 3450 ml
Colloid: 500 ml
PRBC infusion: 1200 ml
Infused autologous blood: 210 ml
VCM administration:
0.5 g mixed with bone debris into the cage and 0.5 g spraying on the dura mater and into the mascularis layer.
Postoperative sequelae:
Proceeded with surgery and the patient was extubated uneventfully.
2 Male; 74-yr; 171 cm/67 kg
BMI: 23.9
Diagnosis:
lumbar stenosis (L3–5)
Surgery:
Posterior decompression, fixation and fusion of lumbar spine.
Medical and allergy history:
nil relevant.
Time of occurrence:
Subcutaneous layer closure, 30 min after initiation of wound closure.
Signs and symptoms:
NBP: 45/15 mmHg
SpO2: undetectable
ECG: tachycardia with ST segment depression
Skin and airway symptoms: none.
Management:
Boluses and continuous infusion of noradrenaline (0.05–0.4 μg/kg/min) and adrenaline (0.5–0.15 μg/kg/min) for 4 h.
Preoperative HGB value:135
Intraoperative minimum value of HGB: 79
Blood loss: 600 ml
Urine: 1950 ml
Fluid and blood product infusion:
Crystalloid: 6300 ml
Colloid: 500 ml
PRBC infusion: 1200 ml
Plasma: 800 ml
Infused autologous blood: 254 ml
VCM administration:
0.5 g mixed with bone debris into the cage and 0.5 g spraying on the dura mater and into the mascularis layer.
Postoperative sequelae:
The patient was extubated and transferred to ICU due to neurological symptoms (unable to follow instructions).
Postoperative imaging: intracranial minor hemorrhage at subdural and subarachnoid space.
The patient was discharged from hospital without neurological deficit.
3 Male; 63-yr; 169 cm/70 kg
BMI: 24.5
Diagnosis:
Lumbar stenosis (L3–5)
Surgery:
Posterior decompression, fixation and fusion of lumbar spine.
Medical and allergy history:
Lacunar infarction;
Bilateral carotid atherosclerotic plaque formation
Time of occurrence:
50 min after initiation of wound closure and 20 min post-extubation in the PACU.
Signs and symptoms:
NBP: 60/25 mmHg
SpO2: 96%
HR:sudden elevation from 60 to 90 bpm
Postoperative agitation
Skin and airway symptoms: none.
Management:
Boluses of ephedrine, phenylephrine and fluid resuscitation.
Preoperative HGB value: 176
Intraoperative minimum value of HGB:123
Blood loss: 800 ml
Urine: 800 ml
Fluid and blood product infusion:
Crystalloid: 2350 ml
Colloid: 1000 ml
PRBC infusion: 400 ml
VCM administration:
Topical spraying of vancomycin (1 g) on the dura mater and into the mascularis.
Postoperative sequelae:
Uneventful.
4 Female; 70-yr; 160 cm/65 kg
BMI:25.4
Diagnosis:
Lumbar stenosis (L4-S1)
Surgery:
Posterior decompression, fixation and fusion of lumbar spine.
Hypertension
Diabetes Mellitus
Time of occurrence:
Subcutaneous layer closure, 30 min after initiation of wound closure.
Signs and symptoms:
NBP: 45/15 mmHg
SpO2: undetectable
Persistent tachycardia
Skin and airway symptoms: none.
Management:
Boluses of phenylephrine for treating severe hypotension and esmolol for tachycardia
Fluid resuscitation and blood transfusion.
Preoperative HGB value: 150
Intraoperative minimum value of HGB: 92
Blood loss: 1500 ml
Urine: 1800 ml
Fluid and blood product infusion:
Crystalloid: 3100 ml
Colloid: 1500 ml
PRBC infusion: 1200 ml
Infused autologous blood: 450 ml
VCM administration:
0.5 g mixed with bone debris into the cage and 0.5 g spraying on the dura mater and into the mascularis layer.
Postoperative sequelae:
The patient was extubated after surgery and transferred to ICU due to tachycardia after sufficient fluid resuscitation.
Recovered uneventfully.
5 Female;48-yr; 170 cm/75 kg
BMI: 26.0
Diagnosis:
Thoracic spinal canal stenosis (T6-T11)
Surgery:
Posterior decompression, fixation and fusion of thoracic spine.
Medical and allergy history:
nil relevant.
Time of occurrence:
Subcutaneous layer closure, 30 min after initiation of wound closure.
Signs and symptoms:
NBP: 40/30 mmHg to undetectable
HR: 120 bpm to 40 bpm
SpO2: undetectable
Cardiac arrest
Skin and airway symptoms: none.
Management:
Extracardiac compression
Boluses of noradrenaline (200 μg) and adrenaline (1 g)
Continuous infusion of noradrenaline (0.02–0.08 μg/kg/min) for 50 min
Fluid resuscitation and blood transfusion.
Preoperative HGB value: 132
Intraoperative minimum value of HGB: 74
Blood loss: 2500 ml
Urine: 1300 ml
Fluid and blood product infusion:
Crystalloid: 4000 ml
Colloid: 500 ml
PRBC infusion: 2400 ml
VCM administration:
Topical spraying of vancomycin (1 g) on the dura mater and into the mascularis layer.
Postoperative sequelae:
The patient was extubated after surgery, and discharged from hospital uneventfully.
6 Male; 66-yr; 175 cm/ 80 kg
BMI: 26.1
Diagnosis:
Lumbar stenosis (L3–5)
Surgery:
Posterior decompression, fixation and fusion of lumbar spine.
Medical and allergy history:
Carotid artery stenosis
Diabetes Mellitus
Time of occurrence:
Sudden cardiac arrest 10 min after extubation (approximately 45 min after initiation of wound closure) with full recovery from anesthesia and without any discomfort complaint.
Signs and symptoms:
Cardiac arrest and persistent VF
Skin and airway symptoms: none.
Management:
Continuous CPR
Persistent VF was treated with repeated defibrillation
Boluses of adrenaline (a total of 6 mg) and amiodarone.
Fluid resuscitation and blood transfusion.
Preoperative HGB value: 143
Intraoperative minimum value of HGB: 78
Blood loss: 1000 ml
Urine: 850 ml
Fluid and blood product infusion:
Crystalloid: 4400 ml
Colloid: 1000 ml
PRBC infusion: 1200 ml
Infused autologous blood: 600 ml
VCM administration:
Topical spraying of vancomycin (3 g) on the dura mater and into the mascularis.
Postoperative sequelae:
The patient was reintubated and transferred to ICU after ROSC. The patient was diagnosed as hypoxic encephalopathy and remained in a coma state. Tracheotomy was performed 2 weeks after surgery, and the patient was transferred to a nursing home for rehabilitation 1 month after orthopedic surgery.
7 Female; 43-yr; 155 cm / 54 kg
BMI: 22.4
Diagnosis:
Thoracic kyphosis (T7-T8)
Surgery:
Osteotomy for kyphosis of thoracic spine (T7-T8).
Medical and allergy history:
nil relevant.
Time of occurrence:
subcutaneous layer closure, 30 min after initiation of wound closure.
Signs and symptoms:
HR:tachycardia
NBP: 60/30 mmHg
SpO2 82%
Skin and airway symptoms: none.
Management:
Boluses of phenylephrine and ephedrine;
Continuous infusion of noradrenaline (0.05–0.1 μg/kg/min)
Fluid resuscitation and blood transfusion.
Preoperative HGB value: 138
Intraoperative minimum value of HGB: 95
Blood loss: 1200 ml
Urine: 1900 ml
Fluid and blood product infusion:
Crystalloid: 4700 ml
Colloid: 1000 ml
PRBC infusion: 1200 ml
Infused autologous blood: 470 ml
VCM administration:
Topical spraying of vancomycin (1 g) on the dura mater and into the mascularis layer.
Postoperative sequelae:
The patient was transferred to ICU for optimal monitoring and recovered uneventfully.
Abbreviations: NBP Non-invasive blood pressure; ABP Arterial blood pressure; (NBP is noted when ABP is not available.) VF Ventricular fibrillation; CPR Cardiopulmonary Resuscitation; HGB Hemoglobin; VCM Vancomycin; PRBC Packed red blood cell; ROSC Return of spontaneous circulation
Case presentation
The first case we encountered was a 68-yr female with past medical history of hypertension and surgical treated retina detachment, who underwent posterior decompression, fixation and fusion of lumbar spine due to lumbar stenosis (L3-S1). The operation was uneventful until sudden circulatory collapse occurred during the process of rinsing mascularis and superficial fascia layer whilst closing the wound. A sudden drop in arterial blood pressure (ABP) (130/60 mmHg to 30/20 mmHg), increased HR (60 bpm to 100 bpm) with elevated ST-segment and significant decrease of PetCO2 (31 mmHg to 16 mmHg) were noticed, with undetectable pulse oximetry read. The patient was turned to supine position immediately and managed with boluses (40–100 μg) and a continuous infusion of noradrenaline (0.01–0.04 μg/kg/min) for approximately 45 min. The circulation was gradually stabilized. No rash, erythema, or bronchospasm were noted. The bilateral breath sounds were equal and the airway pressure remained normal. We continued treatments of fluid resuscitation and blood transfusion with corticosteroid and ice cap to prevent hypoxic-ischemic encephalopathy. Intraoperative emergency consultations and immediate examinations of 12-lead ECG, point-of-care transthoracic echocardiography (TTE), and full panel laboratory tests were performed. However, these results did not support the causes of sudden cardiac dysfunction (the pump) including mechanical obstruction (pericardial tamponade and massive pulmonary embolus), acute myocardial infarction, acute valvular insufficiency, and arrhythmia. Vascular catastrophes were excluded and there were no signs of sepsis. We also examined the intravascular volume function (the tank) by performing the TTE, and ruled out intraperitoneal major hemorrhage which we once encountered (caused by inadvertent piercing of iliac artery when placing probe during lumbar surgery) by examination of abdominal ultrasound and hemoglobin level; Volume status was evaluated by measuring CVP, urine output, infused fluid volume; Surgical blood loss was reviewed to exclude hemorrhage shock and hypovolemia. As no special medications were given except anesthetic maintenance drugs, and no signs of mottled skin or bronchospasm were noticed, anaphylaxis was not considered at that time. After restoring circulatory stability, the surgery preceded uneventfully. The patient was discharged from hospital 7 days later.
It was intriguing that within 1 month, another case of circulatory collapse happened during wound closure in spine surgery performed by the same orthopedic surgeon. The intraoperative clinical manifestations were very similar to the previous one. Hemodynamic resuscitation were initiated immediately with repeated boluses and continuous infusion of noradrenaline (0.05–0.4 μg/kg/min) and adrenaline (0.5–0.15 μg/kg/min). After stabilizing the circulation 4 h later, the patient was extubated and transferred to ICU due to neurological symptoms (unable to follow instructions after full recovery from anesthesia). Postoperative imaging revealed intracranial micro hemorrhagic foci in the subdural and subarachnoid space. The patient was discharged from hospital without any neurological sequelae.
With further exploration and analysis of the similarities of these two cases, we found that local application of vancomycin (VCM) powder was used in these two patients to prevent postoperative surgical site infections (SSIs) during wound closure (0.5 g VCM loaded with bone debris into the cage and another 0.5 g sprayed on the dura mater and into the mascularis). Ramamani Mariappan reported a case of circulatory collapse after topical application of vancomycin powder during spine surgery, which exhibited almost the same clinical course as ours [2]. It was speculated that the rapid absorption of VCM applied to the surgical wound caused an anaphylaxis reaction and circulatory collapse. The reaction occurred approximately 30 min after the application and persisted for 6 h. The serum tryptase level was not elevated, suggesting that VCM caused a direct histamine release, which is in keeping with our current understanding. A similar case reported a 74-year-old woman who underwent a primary total knee replacement presented with red man syndrome in the PACU 45 min after release of tourniquet following the use of VCM-loaded bone cement. The patient remained fully conscious despite a sudden drop in blood pressure to 47/34 mmHg [3]. Therefore, local application of VCM may pose the risk of causing severe circulatory adverse effect.
Similar circulatory collapse cases in spine surgery without definitive causes during wound closure or shortly after surgery, though rare, were encountered in our institution. Therefore we retrospectively analyzed these cases for the past 2 years, and asked the anesthesiologists and orthopedic surgeons in charge for further information. A total of 7 cases were collected (Table 1). There were 3 males and 4 females, the median age was 66 y (43–74 y), and the averaged BMI was 24.39 ± 1.51 (22.3–26.1). It was interesting to note that these cases were all associated with topical application of VCM powder (Table 1). In these 7 cases, the onset time of severe circulatory fluctuation was 30 min in 5 cases, 50 min in one case (applied with 1 g of VCM), and approximately 45 min in another case (locally applied 3 g of VCM), respectively. Most of the cases (6/7) with severe circulatory fluctuation were corrected without severe sequelae. While in one case in which 3 g of VCM was applied on the dura mater and into the mascularis during wound closure, sudden cardiac arrest happened shortly after the patient had fully recovered from the anesthetic, following surgery and extubation in the OR. CPR was initiated immediately. The patient was reintubated and ventilated mechanically. The persistent VF was treated with continuous chest compressions and repeated defibrillation, with boluses of adrenaline (a total of 6 mg) and amiodarone. After 50 min of continuous CPR, with fluid resuscitation and blood transfusion, the patient was transferred to ICU following the return of spontaneous circulation and reverting into sinus rhythm. However, the patient remained in a comatose state due to hypoxic-hypoxic encephalopathy, and tracheotomy was performed 2 weeks later.
Discussion and conclusion
Vancomycin and anaphylaxis reaction
“International Consensus on (ICON) Anaphylaxis” define anaphylaxis as “a serious, generalized or systemic, allergic or hypersensitivity reaction that can be life threatening or fatal” [4]. It has been demonstrated that there exists IgE-dependent and three IgE-independent mechanisms in anaphylaxis pathophysiology [5]. VCM could directly activate mast cells to release histamine and other mediators through an IgE-independent mechanism that is calcium-, phospholipase C–, and phospholipase A2–dependent but otherwise unknown [5, 6]. Vancomycin-induced direct histamine release is also infusion rate dependent [7]. This IgE-independent anaphylaxis reaction generally disappears within 20 mins, but may linger for hours. The most common manifestation is a sudden drop in blood pressure, which is related to the negative inotropic effect and the vasodilator action stimulated by the histamine release. Alteration in vascular tone is also a common feature of anaphylactic shock [8]. Richter J and colleagues demonstrated in rats that VCM could directly influence the vascular tonus, affecting the microcirculation [9].
The VCM reactions studied in the pediatric population revealed that non-IgE mediated reaction accounts for the vast majority of reactions (92%; prevalence, 5.4–5.8%), whereas possible IgE-mediated vancomycin reactions were exceedingly rare (prevalence, 0.0–0.37%) [7]. For adults, the reported incidence of non-IgE mediated reaction varies between 3.7 and 47% in infected patients and 90% in healthy volunteers [2]. Elevated serum mast cell tryptase is a valuable indicator for diagnosing Ig-E mediated anaphylactic reaction. However, it is not useful in determining a non-IgE mediated anaphylactic reaction caused by histamine release [2]. Detection of histamine concentration in clinical blood specimens is difficult due to its extremely short half-life, and histamine is not a mast cell specific product [10]. As this study is retrospective in nature, and our hospital does not perform examination of serum tryptase and histamine concentration, we could not differentiate whether the adverse effects were caused by VCM induced IgE-mediated or non-IgE mediated reaction.
Topical application of vancomycin powder and surgical site infections
VCM is effective in fighting Gram-positive bacteria related severe infections [11]. While the actual utility of local application of VCM is controversial. After the first reported topical application of VCM by orthopedic surgeons to reduce postoperative surgical site infections (SSIs) rate [12], a large number of meta-analyses, retrospective cohort studies, and randomized controlled trials were published to assess the power of this method in preventing SSIs. Recent findings from large-scale propensity score matched analyses, meta analyses, RCTs studies, and observational studies of spine surgeries and knee arthroplasties all demonstrated that the intrawound VCM powder application may not decrease SSIs, but may increase postoperative complications [13–19].
VCM is an antibiotic that was considered safe in local application and has been widely used in hospitals. However, dose recommendations, dilutions, monitoring, infusion types and rates are still controversial [20]. There’s no defined time or situation during surgery when local VCM should be applied. Some may load VCM powder with bone debris into the cage, or apply VCM powder directly onto the dura mater or after closure of the fascia, whereas other studies reported that VCM powder was applied in the subfascial layer [2, 13]. However, intrawound absorption rate of VCM powder is uncontrollable as this depends on multiple factors, such as the extent and degree of tissue/muscle damaged by surgical manipulation, anatomic location where VCM powder is placed (mixed with bone debris, or between muscularis layers that are abundant with blood supply), and the surgeon’s suturing maneuvers (the flushing saline would leak from upper layer into the layer where VCM powder is deposited). These factors all pose potential risk of causing rapid drug dissolution and accelerated absorption into the circulatory system. Moreover, individual’s adverse reactions to VCM varied. These incidental events may be accidentally linked and lead to severe outcome. Since intravenous administration of VCM could lead to adverse effects, it is theoretically possible that local application of VCM powder may cause similar clinical manifestation.
Topical application of VCM was intended to achieve the effect of providing high local concentrations while avoiding high systemic levels and the risk of bacterial resistance. The serum concentration level peaks at 30 min and then declines to baseline at 6 h [2]. This may explain the delayed and unpredictable occurrence of anaphylaxis reactions after local application of VCM powder, due to the uncertainty of the drug absorption rate and individual reaction differences. The instructed therapeutic dosage of VCM is 30 mg/kg/day which should be fractioned in 2 or 3 doses. Moreover, the infusion rate should be within 10 mg/min, and last for more than 60 min. For elderly patients, this dosage should be reduced [21, 22]. Although the most commonly used dose of intrawound VCM is 1 g, some authors reported that they altered the dose according to the length of the incision [23]. VCM is not the first-choice antibiotic as its adverse effects are frequently reported including hypotension and tachycardia, phlebitis, nephrotoxicity, ototoxicity, hypersensitivity reactions, red man syndrome, neutropenia, chills, fever, interstitial nephritis, etc. [13]. As VCM induced adverse reactions are dose and infusion-rate dependent, doctors should be highly vigilant to over-dosing which might bring disastrous results.
Other issues related to shock
In this case series, the typical signs of erythema and redness (red man syndrome) have not appeared, which resemble the previous case reported by Mariappan R and colleagues [2]. The lack of skin flushing may be the result of reduced perfusion due to circulatory shock or the adverse effect of VCM mainly manifested as severe alteration of vascular tonus [8, 9]. In our experience, a rapid but low dose intravenous infusion of VCM induced anaphylaxis reaction was not necessarily associated with skin manifestations. Whether this is related to racial differences or rapid absorption of low dose VCM was not known. However, the clinical features of hypotension, tachycadia and low oxygenation were notable.
For this case series, as there is no definitive laboratory examination or gold standard to help reach a definitive diagnosis of VCM induced anaphylaxis reaction, the conclusions were made upon differential diagnosis based on clinical manifestations and the timing of the shock. Other possible causes or contributing factors for the development of severe hypotension and shock need to be considered. For example, restrictive fluid therapy during surgical procedure and restrictive blood transfusion strategy leading to hypovolemia and hypotension, complicated with unseen bleeding from surgical site and other compounding factors such as hypoproteinemia and unaltered anesthetic depth during wound closure.
Another issue needs to be addressed is that there’s a notable decrease in hemoglobin (HGB) concentration in all cases when severe hypotension occurred. However, the hemorrhagic shock induced by surgical blood loss was ruled out. We speculate that this might be due to the infusion of large amounts of fluid during resuscitation. It is reported that the administration of 500 ml of fluids may acutely decrease the HGB concentration by about 1 g/dl, or about 8%, by “dilutional anemia” [24]. In septic shock patients, approximately 30% decrease of hematocrit was commonly observed in patients receiving large amounts of fluids during resuscitation, which further indicates more blood transfusion [25]. In the current study, the HGB concentrations were all measured after the initiation of fluid resuscitation and this may at least partially explained the sharp decrease of the HGB level (Table 1). When severe hypotension with unknown causes occur, initial management is to infuse large amounts of fluid with vaso-constrictive drugs. The iatrogenic hemodilution related blood transfusion may result in dilutional coagulopathy and increase surgical bleeding. This then leads to a decreased HGB level below the acceptable transfusion threshold, leading to further blood transfusion in the absence of significant blood loss [26]. This is especially true when in the scenario of the existence of suspected hemorrhagic shock.
In conclusion, local application of VCM powder during wound closure could cause delayed occurrence of severe hypotension and shock in spine surgery. Hemodynamic changes may be under-emphasized and under-reported as in most cases, this hemodynamic reaction is easy to correct and normally wouldn’t cause serious consequences. However, the actual occurrence is not rare and this might be confused with hypovolemia or anesthetic induced hypotension. Surgeons and anesthesiologists should be highly aware of VCM induced IgE-independent anaphylaxis reactions. The differential diagnosis of anaphylactic shock must be taken into consideration in patients with acute hypotension during or immediately after wound closure. Prompt laboratory analysis of serum tryptase and histamine concentration could help differentiate the causes. Moreover, since controversies still exist in the actual effect of intrawound application of VCM powder to reduce SSIs in spine surgery, local application of this drug should be used with caution.
Abbreviations
VCMVancomycin
ABPArterial blood pressure
TTETransthoracic echocardiography
Publisher’s Note
Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
We sincerely thank our colleagues from anesthesia (Dr. XW, Dr. CW, Dr. WL, Dr. JY, Dr. YW, Dr. CN, Dr. CX, Dr. YT, Dr. HW, Dr. HT, Dr. WW, Dr. YT, Dr. XJ, HL, Dr. HW, Dr. HZ, Dr. YW, and Dr. BW) and surgical department (Dr. YD, Dr. YL, Dr. FZ, Dr. QQ, and Dr. ZC) for providing and verifying the cases.
The authors have completed the CARE reporting checklist.
Authors’ contributions
Guarantor of integrity of entire study: XZ, WZ, ML, XG. Literature research: XZ, WZ. Case study and follow-up: XZ, WZ. Manuscript preparation: XZ, WZ. Manuscript editing and revision: ML, XG. Manuscript final version approval: ML, XG. All authors have read and approved the manuscript.
Funding
This work was supported by the Clinical Key Project of Peking University Third Hospital, Grants No. BYSY2017001.
The role of the funder: study design, decision to submit the manuscript for publication.
Availability of data and materials
All data generated or analyzed during this study are included in this published article. More detailed information could be find in Table 1.
Ethics approval and consent to participate
This case was performed according to the ethical guidelines of the Helsinki Declaration and was approved by the Human Ethics Committee of Peking University Third Hospital. All the authors listed in the manuscript consent to participate the study. The consent for publication from patient or their relatives were collected retrospectively.
Consent for publication
As this is a retrospective case study, written informed consent to publish this manuscript were collected from patients or their relatives retrospectively. The proof of consent to publish from study participants can be requested at any time.
Competing interests
The author(s) declare no competing interests. | Recovered | ReactionOutcome | CC BY | 33407142 | 18,822,543 | 2021-01-06 |
What was the outcome of reaction 'Hypoxic-ischaemic encephalopathy'? | Circulatory collapse during wound closure in spine surgery with an unknown cause: a possible adverse effect of topical application of vancomycin?
Vancomycin (VCM) is effective in fighting Gram-positive bacteria related severe infections, and topical application of VCM powder is widely used in orthopedic surgery to prevent wound infection. However, VCM could lead to infusion rate-dependent antibody-and complement-independent anaphylaxis reaction by inducing direct release of histamine.
We retrospectively analyzed seven cases of severe hypotension and shock during wound closure or immediately after orthopedic surgery with unidentifiable reasons. We found that these cases were all associated with local application of VCM powder during wound closure process. Two patients experienced sudden cardiac arrest. Most of the cases (6/7) with circulatory collapse were discharged without severe sequelae. While one case with application of 3 g VCM developed cardiac arrest and remained in a coma due to hypoxic-hypoxic encephalopathy. The clinical presentations and the time of the shock onset were considered to be related with a VCM induced anaphylaxis reaction. However, as this was a retrospective study, and there was no laboratory examination performed, the conclusion was made upon differential diagnosis based on clinical manifestations and the timing of the shock.
Local application of VCM may not be as safe as was once believed and may lead to a related anaphylaxis. As VCM induced infusion-rate dependent, non-IgE mediated anaphylaxis is characterized by delayed occurrence, severe hypotension and even circulatory collapse, surgeons and anesthesiologists should be extra vigilant during and after VCM application.
Background
Shock is defined as a state of insufficient perfusion and oxygen delivery to the tissues. The pathophysiology of shock could be simplified to three major components: cardiac function (the pump), intravascular volume (the tank), and systemic vascular resistance (the pipes) [1]. Whatever the causes of shock may be, if the impaired perfusion and oxygen delivery is not recognized and reversed, the circulatory collapse may progress into organ dysfunction and failure, tissue necrosis and even death. It is urgent to identify the causes of shock and take immediate measures. However, in critical situations, it is hard to rapidly distinguish the culprit during complex clinical situations. Here we present 7 cases (Table 1) of unidentifiable causes of shock during wound closure or shortly after spine surgery, and discuss the possible reasons.
Table 1 Summary of clinical presentations of seven patients with circulatory collapse and unknown etiologies during or shortly after wound closure in spine surgery
Case Demographic information Initial signs/symptoms of shock and management Hemoglobin value (g/L),
fluid resuscitation and blood product infusion VCM administration
and Postoperative sequelae
1 Female; 68-yr; 160 cm/60 kg
BMI: 23.4
Diagnosis:
Lumbar stenosis (L3-S1)
Surgery:
Posterior decompression, fixation and fusion of lumbar spine.
Medical and allergy history:
Hypertension
History of retina surgery
Time of occurrence:
Subcutaneous layer closure, 30 min after initiation of wound closure.
Signs and symptoms:
ABP: 30/20 mmHg
SpO2: undetectable
ECG: tarchycardia with elevated ST segment
Skin and airway symptoms: none.
Management:
Boluses and continuous infusion of noradrenaline (0.01–0.04 μg/kg/min) for 45 min. Fluid resuscitation and blood transfusion.
Preoperative HGB value: 124
Intraoperative minimum value of HGB: 73
Blood loss: 600 ml
Urine: 850 ml
Fluid and blood product infusion:
Crystalloid: 3450 ml
Colloid: 500 ml
PRBC infusion: 1200 ml
Infused autologous blood: 210 ml
VCM administration:
0.5 g mixed with bone debris into the cage and 0.5 g spraying on the dura mater and into the mascularis layer.
Postoperative sequelae:
Proceeded with surgery and the patient was extubated uneventfully.
2 Male; 74-yr; 171 cm/67 kg
BMI: 23.9
Diagnosis:
lumbar stenosis (L3–5)
Surgery:
Posterior decompression, fixation and fusion of lumbar spine.
Medical and allergy history:
nil relevant.
Time of occurrence:
Subcutaneous layer closure, 30 min after initiation of wound closure.
Signs and symptoms:
NBP: 45/15 mmHg
SpO2: undetectable
ECG: tachycardia with ST segment depression
Skin and airway symptoms: none.
Management:
Boluses and continuous infusion of noradrenaline (0.05–0.4 μg/kg/min) and adrenaline (0.5–0.15 μg/kg/min) for 4 h.
Preoperative HGB value:135
Intraoperative minimum value of HGB: 79
Blood loss: 600 ml
Urine: 1950 ml
Fluid and blood product infusion:
Crystalloid: 6300 ml
Colloid: 500 ml
PRBC infusion: 1200 ml
Plasma: 800 ml
Infused autologous blood: 254 ml
VCM administration:
0.5 g mixed with bone debris into the cage and 0.5 g spraying on the dura mater and into the mascularis layer.
Postoperative sequelae:
The patient was extubated and transferred to ICU due to neurological symptoms (unable to follow instructions).
Postoperative imaging: intracranial minor hemorrhage at subdural and subarachnoid space.
The patient was discharged from hospital without neurological deficit.
3 Male; 63-yr; 169 cm/70 kg
BMI: 24.5
Diagnosis:
Lumbar stenosis (L3–5)
Surgery:
Posterior decompression, fixation and fusion of lumbar spine.
Medical and allergy history:
Lacunar infarction;
Bilateral carotid atherosclerotic plaque formation
Time of occurrence:
50 min after initiation of wound closure and 20 min post-extubation in the PACU.
Signs and symptoms:
NBP: 60/25 mmHg
SpO2: 96%
HR:sudden elevation from 60 to 90 bpm
Postoperative agitation
Skin and airway symptoms: none.
Management:
Boluses of ephedrine, phenylephrine and fluid resuscitation.
Preoperative HGB value: 176
Intraoperative minimum value of HGB:123
Blood loss: 800 ml
Urine: 800 ml
Fluid and blood product infusion:
Crystalloid: 2350 ml
Colloid: 1000 ml
PRBC infusion: 400 ml
VCM administration:
Topical spraying of vancomycin (1 g) on the dura mater and into the mascularis.
Postoperative sequelae:
Uneventful.
4 Female; 70-yr; 160 cm/65 kg
BMI:25.4
Diagnosis:
Lumbar stenosis (L4-S1)
Surgery:
Posterior decompression, fixation and fusion of lumbar spine.
Hypertension
Diabetes Mellitus
Time of occurrence:
Subcutaneous layer closure, 30 min after initiation of wound closure.
Signs and symptoms:
NBP: 45/15 mmHg
SpO2: undetectable
Persistent tachycardia
Skin and airway symptoms: none.
Management:
Boluses of phenylephrine for treating severe hypotension and esmolol for tachycardia
Fluid resuscitation and blood transfusion.
Preoperative HGB value: 150
Intraoperative minimum value of HGB: 92
Blood loss: 1500 ml
Urine: 1800 ml
Fluid and blood product infusion:
Crystalloid: 3100 ml
Colloid: 1500 ml
PRBC infusion: 1200 ml
Infused autologous blood: 450 ml
VCM administration:
0.5 g mixed with bone debris into the cage and 0.5 g spraying on the dura mater and into the mascularis layer.
Postoperative sequelae:
The patient was extubated after surgery and transferred to ICU due to tachycardia after sufficient fluid resuscitation.
Recovered uneventfully.
5 Female;48-yr; 170 cm/75 kg
BMI: 26.0
Diagnosis:
Thoracic spinal canal stenosis (T6-T11)
Surgery:
Posterior decompression, fixation and fusion of thoracic spine.
Medical and allergy history:
nil relevant.
Time of occurrence:
Subcutaneous layer closure, 30 min after initiation of wound closure.
Signs and symptoms:
NBP: 40/30 mmHg to undetectable
HR: 120 bpm to 40 bpm
SpO2: undetectable
Cardiac arrest
Skin and airway symptoms: none.
Management:
Extracardiac compression
Boluses of noradrenaline (200 μg) and adrenaline (1 g)
Continuous infusion of noradrenaline (0.02–0.08 μg/kg/min) for 50 min
Fluid resuscitation and blood transfusion.
Preoperative HGB value: 132
Intraoperative minimum value of HGB: 74
Blood loss: 2500 ml
Urine: 1300 ml
Fluid and blood product infusion:
Crystalloid: 4000 ml
Colloid: 500 ml
PRBC infusion: 2400 ml
VCM administration:
Topical spraying of vancomycin (1 g) on the dura mater and into the mascularis layer.
Postoperative sequelae:
The patient was extubated after surgery, and discharged from hospital uneventfully.
6 Male; 66-yr; 175 cm/ 80 kg
BMI: 26.1
Diagnosis:
Lumbar stenosis (L3–5)
Surgery:
Posterior decompression, fixation and fusion of lumbar spine.
Medical and allergy history:
Carotid artery stenosis
Diabetes Mellitus
Time of occurrence:
Sudden cardiac arrest 10 min after extubation (approximately 45 min after initiation of wound closure) with full recovery from anesthesia and without any discomfort complaint.
Signs and symptoms:
Cardiac arrest and persistent VF
Skin and airway symptoms: none.
Management:
Continuous CPR
Persistent VF was treated with repeated defibrillation
Boluses of adrenaline (a total of 6 mg) and amiodarone.
Fluid resuscitation and blood transfusion.
Preoperative HGB value: 143
Intraoperative minimum value of HGB: 78
Blood loss: 1000 ml
Urine: 850 ml
Fluid and blood product infusion:
Crystalloid: 4400 ml
Colloid: 1000 ml
PRBC infusion: 1200 ml
Infused autologous blood: 600 ml
VCM administration:
Topical spraying of vancomycin (3 g) on the dura mater and into the mascularis.
Postoperative sequelae:
The patient was reintubated and transferred to ICU after ROSC. The patient was diagnosed as hypoxic encephalopathy and remained in a coma state. Tracheotomy was performed 2 weeks after surgery, and the patient was transferred to a nursing home for rehabilitation 1 month after orthopedic surgery.
7 Female; 43-yr; 155 cm / 54 kg
BMI: 22.4
Diagnosis:
Thoracic kyphosis (T7-T8)
Surgery:
Osteotomy for kyphosis of thoracic spine (T7-T8).
Medical and allergy history:
nil relevant.
Time of occurrence:
subcutaneous layer closure, 30 min after initiation of wound closure.
Signs and symptoms:
HR:tachycardia
NBP: 60/30 mmHg
SpO2 82%
Skin and airway symptoms: none.
Management:
Boluses of phenylephrine and ephedrine;
Continuous infusion of noradrenaline (0.05–0.1 μg/kg/min)
Fluid resuscitation and blood transfusion.
Preoperative HGB value: 138
Intraoperative minimum value of HGB: 95
Blood loss: 1200 ml
Urine: 1900 ml
Fluid and blood product infusion:
Crystalloid: 4700 ml
Colloid: 1000 ml
PRBC infusion: 1200 ml
Infused autologous blood: 470 ml
VCM administration:
Topical spraying of vancomycin (1 g) on the dura mater and into the mascularis layer.
Postoperative sequelae:
The patient was transferred to ICU for optimal monitoring and recovered uneventfully.
Abbreviations: NBP Non-invasive blood pressure; ABP Arterial blood pressure; (NBP is noted when ABP is not available.) VF Ventricular fibrillation; CPR Cardiopulmonary Resuscitation; HGB Hemoglobin; VCM Vancomycin; PRBC Packed red blood cell; ROSC Return of spontaneous circulation
Case presentation
The first case we encountered was a 68-yr female with past medical history of hypertension and surgical treated retina detachment, who underwent posterior decompression, fixation and fusion of lumbar spine due to lumbar stenosis (L3-S1). The operation was uneventful until sudden circulatory collapse occurred during the process of rinsing mascularis and superficial fascia layer whilst closing the wound. A sudden drop in arterial blood pressure (ABP) (130/60 mmHg to 30/20 mmHg), increased HR (60 bpm to 100 bpm) with elevated ST-segment and significant decrease of PetCO2 (31 mmHg to 16 mmHg) were noticed, with undetectable pulse oximetry read. The patient was turned to supine position immediately and managed with boluses (40–100 μg) and a continuous infusion of noradrenaline (0.01–0.04 μg/kg/min) for approximately 45 min. The circulation was gradually stabilized. No rash, erythema, or bronchospasm were noted. The bilateral breath sounds were equal and the airway pressure remained normal. We continued treatments of fluid resuscitation and blood transfusion with corticosteroid and ice cap to prevent hypoxic-ischemic encephalopathy. Intraoperative emergency consultations and immediate examinations of 12-lead ECG, point-of-care transthoracic echocardiography (TTE), and full panel laboratory tests were performed. However, these results did not support the causes of sudden cardiac dysfunction (the pump) including mechanical obstruction (pericardial tamponade and massive pulmonary embolus), acute myocardial infarction, acute valvular insufficiency, and arrhythmia. Vascular catastrophes were excluded and there were no signs of sepsis. We also examined the intravascular volume function (the tank) by performing the TTE, and ruled out intraperitoneal major hemorrhage which we once encountered (caused by inadvertent piercing of iliac artery when placing probe during lumbar surgery) by examination of abdominal ultrasound and hemoglobin level; Volume status was evaluated by measuring CVP, urine output, infused fluid volume; Surgical blood loss was reviewed to exclude hemorrhage shock and hypovolemia. As no special medications were given except anesthetic maintenance drugs, and no signs of mottled skin or bronchospasm were noticed, anaphylaxis was not considered at that time. After restoring circulatory stability, the surgery preceded uneventfully. The patient was discharged from hospital 7 days later.
It was intriguing that within 1 month, another case of circulatory collapse happened during wound closure in spine surgery performed by the same orthopedic surgeon. The intraoperative clinical manifestations were very similar to the previous one. Hemodynamic resuscitation were initiated immediately with repeated boluses and continuous infusion of noradrenaline (0.05–0.4 μg/kg/min) and adrenaline (0.5–0.15 μg/kg/min). After stabilizing the circulation 4 h later, the patient was extubated and transferred to ICU due to neurological symptoms (unable to follow instructions after full recovery from anesthesia). Postoperative imaging revealed intracranial micro hemorrhagic foci in the subdural and subarachnoid space. The patient was discharged from hospital without any neurological sequelae.
With further exploration and analysis of the similarities of these two cases, we found that local application of vancomycin (VCM) powder was used in these two patients to prevent postoperative surgical site infections (SSIs) during wound closure (0.5 g VCM loaded with bone debris into the cage and another 0.5 g sprayed on the dura mater and into the mascularis). Ramamani Mariappan reported a case of circulatory collapse after topical application of vancomycin powder during spine surgery, which exhibited almost the same clinical course as ours [2]. It was speculated that the rapid absorption of VCM applied to the surgical wound caused an anaphylaxis reaction and circulatory collapse. The reaction occurred approximately 30 min after the application and persisted for 6 h. The serum tryptase level was not elevated, suggesting that VCM caused a direct histamine release, which is in keeping with our current understanding. A similar case reported a 74-year-old woman who underwent a primary total knee replacement presented with red man syndrome in the PACU 45 min after release of tourniquet following the use of VCM-loaded bone cement. The patient remained fully conscious despite a sudden drop in blood pressure to 47/34 mmHg [3]. Therefore, local application of VCM may pose the risk of causing severe circulatory adverse effect.
Similar circulatory collapse cases in spine surgery without definitive causes during wound closure or shortly after surgery, though rare, were encountered in our institution. Therefore we retrospectively analyzed these cases for the past 2 years, and asked the anesthesiologists and orthopedic surgeons in charge for further information. A total of 7 cases were collected (Table 1). There were 3 males and 4 females, the median age was 66 y (43–74 y), and the averaged BMI was 24.39 ± 1.51 (22.3–26.1). It was interesting to note that these cases were all associated with topical application of VCM powder (Table 1). In these 7 cases, the onset time of severe circulatory fluctuation was 30 min in 5 cases, 50 min in one case (applied with 1 g of VCM), and approximately 45 min in another case (locally applied 3 g of VCM), respectively. Most of the cases (6/7) with severe circulatory fluctuation were corrected without severe sequelae. While in one case in which 3 g of VCM was applied on the dura mater and into the mascularis during wound closure, sudden cardiac arrest happened shortly after the patient had fully recovered from the anesthetic, following surgery and extubation in the OR. CPR was initiated immediately. The patient was reintubated and ventilated mechanically. The persistent VF was treated with continuous chest compressions and repeated defibrillation, with boluses of adrenaline (a total of 6 mg) and amiodarone. After 50 min of continuous CPR, with fluid resuscitation and blood transfusion, the patient was transferred to ICU following the return of spontaneous circulation and reverting into sinus rhythm. However, the patient remained in a comatose state due to hypoxic-hypoxic encephalopathy, and tracheotomy was performed 2 weeks later.
Discussion and conclusion
Vancomycin and anaphylaxis reaction
“International Consensus on (ICON) Anaphylaxis” define anaphylaxis as “a serious, generalized or systemic, allergic or hypersensitivity reaction that can be life threatening or fatal” [4]. It has been demonstrated that there exists IgE-dependent and three IgE-independent mechanisms in anaphylaxis pathophysiology [5]. VCM could directly activate mast cells to release histamine and other mediators through an IgE-independent mechanism that is calcium-, phospholipase C–, and phospholipase A2–dependent but otherwise unknown [5, 6]. Vancomycin-induced direct histamine release is also infusion rate dependent [7]. This IgE-independent anaphylaxis reaction generally disappears within 20 mins, but may linger for hours. The most common manifestation is a sudden drop in blood pressure, which is related to the negative inotropic effect and the vasodilator action stimulated by the histamine release. Alteration in vascular tone is also a common feature of anaphylactic shock [8]. Richter J and colleagues demonstrated in rats that VCM could directly influence the vascular tonus, affecting the microcirculation [9].
The VCM reactions studied in the pediatric population revealed that non-IgE mediated reaction accounts for the vast majority of reactions (92%; prevalence, 5.4–5.8%), whereas possible IgE-mediated vancomycin reactions were exceedingly rare (prevalence, 0.0–0.37%) [7]. For adults, the reported incidence of non-IgE mediated reaction varies between 3.7 and 47% in infected patients and 90% in healthy volunteers [2]. Elevated serum mast cell tryptase is a valuable indicator for diagnosing Ig-E mediated anaphylactic reaction. However, it is not useful in determining a non-IgE mediated anaphylactic reaction caused by histamine release [2]. Detection of histamine concentration in clinical blood specimens is difficult due to its extremely short half-life, and histamine is not a mast cell specific product [10]. As this study is retrospective in nature, and our hospital does not perform examination of serum tryptase and histamine concentration, we could not differentiate whether the adverse effects were caused by VCM induced IgE-mediated or non-IgE mediated reaction.
Topical application of vancomycin powder and surgical site infections
VCM is effective in fighting Gram-positive bacteria related severe infections [11]. While the actual utility of local application of VCM is controversial. After the first reported topical application of VCM by orthopedic surgeons to reduce postoperative surgical site infections (SSIs) rate [12], a large number of meta-analyses, retrospective cohort studies, and randomized controlled trials were published to assess the power of this method in preventing SSIs. Recent findings from large-scale propensity score matched analyses, meta analyses, RCTs studies, and observational studies of spine surgeries and knee arthroplasties all demonstrated that the intrawound VCM powder application may not decrease SSIs, but may increase postoperative complications [13–19].
VCM is an antibiotic that was considered safe in local application and has been widely used in hospitals. However, dose recommendations, dilutions, monitoring, infusion types and rates are still controversial [20]. There’s no defined time or situation during surgery when local VCM should be applied. Some may load VCM powder with bone debris into the cage, or apply VCM powder directly onto the dura mater or after closure of the fascia, whereas other studies reported that VCM powder was applied in the subfascial layer [2, 13]. However, intrawound absorption rate of VCM powder is uncontrollable as this depends on multiple factors, such as the extent and degree of tissue/muscle damaged by surgical manipulation, anatomic location where VCM powder is placed (mixed with bone debris, or between muscularis layers that are abundant with blood supply), and the surgeon’s suturing maneuvers (the flushing saline would leak from upper layer into the layer where VCM powder is deposited). These factors all pose potential risk of causing rapid drug dissolution and accelerated absorption into the circulatory system. Moreover, individual’s adverse reactions to VCM varied. These incidental events may be accidentally linked and lead to severe outcome. Since intravenous administration of VCM could lead to adverse effects, it is theoretically possible that local application of VCM powder may cause similar clinical manifestation.
Topical application of VCM was intended to achieve the effect of providing high local concentrations while avoiding high systemic levels and the risk of bacterial resistance. The serum concentration level peaks at 30 min and then declines to baseline at 6 h [2]. This may explain the delayed and unpredictable occurrence of anaphylaxis reactions after local application of VCM powder, due to the uncertainty of the drug absorption rate and individual reaction differences. The instructed therapeutic dosage of VCM is 30 mg/kg/day which should be fractioned in 2 or 3 doses. Moreover, the infusion rate should be within 10 mg/min, and last for more than 60 min. For elderly patients, this dosage should be reduced [21, 22]. Although the most commonly used dose of intrawound VCM is 1 g, some authors reported that they altered the dose according to the length of the incision [23]. VCM is not the first-choice antibiotic as its adverse effects are frequently reported including hypotension and tachycardia, phlebitis, nephrotoxicity, ototoxicity, hypersensitivity reactions, red man syndrome, neutropenia, chills, fever, interstitial nephritis, etc. [13]. As VCM induced adverse reactions are dose and infusion-rate dependent, doctors should be highly vigilant to over-dosing which might bring disastrous results.
Other issues related to shock
In this case series, the typical signs of erythema and redness (red man syndrome) have not appeared, which resemble the previous case reported by Mariappan R and colleagues [2]. The lack of skin flushing may be the result of reduced perfusion due to circulatory shock or the adverse effect of VCM mainly manifested as severe alteration of vascular tonus [8, 9]. In our experience, a rapid but low dose intravenous infusion of VCM induced anaphylaxis reaction was not necessarily associated with skin manifestations. Whether this is related to racial differences or rapid absorption of low dose VCM was not known. However, the clinical features of hypotension, tachycadia and low oxygenation were notable.
For this case series, as there is no definitive laboratory examination or gold standard to help reach a definitive diagnosis of VCM induced anaphylaxis reaction, the conclusions were made upon differential diagnosis based on clinical manifestations and the timing of the shock. Other possible causes or contributing factors for the development of severe hypotension and shock need to be considered. For example, restrictive fluid therapy during surgical procedure and restrictive blood transfusion strategy leading to hypovolemia and hypotension, complicated with unseen bleeding from surgical site and other compounding factors such as hypoproteinemia and unaltered anesthetic depth during wound closure.
Another issue needs to be addressed is that there’s a notable decrease in hemoglobin (HGB) concentration in all cases when severe hypotension occurred. However, the hemorrhagic shock induced by surgical blood loss was ruled out. We speculate that this might be due to the infusion of large amounts of fluid during resuscitation. It is reported that the administration of 500 ml of fluids may acutely decrease the HGB concentration by about 1 g/dl, or about 8%, by “dilutional anemia” [24]. In septic shock patients, approximately 30% decrease of hematocrit was commonly observed in patients receiving large amounts of fluids during resuscitation, which further indicates more blood transfusion [25]. In the current study, the HGB concentrations were all measured after the initiation of fluid resuscitation and this may at least partially explained the sharp decrease of the HGB level (Table 1). When severe hypotension with unknown causes occur, initial management is to infuse large amounts of fluid with vaso-constrictive drugs. The iatrogenic hemodilution related blood transfusion may result in dilutional coagulopathy and increase surgical bleeding. This then leads to a decreased HGB level below the acceptable transfusion threshold, leading to further blood transfusion in the absence of significant blood loss [26]. This is especially true when in the scenario of the existence of suspected hemorrhagic shock.
In conclusion, local application of VCM powder during wound closure could cause delayed occurrence of severe hypotension and shock in spine surgery. Hemodynamic changes may be under-emphasized and under-reported as in most cases, this hemodynamic reaction is easy to correct and normally wouldn’t cause serious consequences. However, the actual occurrence is not rare and this might be confused with hypovolemia or anesthetic induced hypotension. Surgeons and anesthesiologists should be highly aware of VCM induced IgE-independent anaphylaxis reactions. The differential diagnosis of anaphylactic shock must be taken into consideration in patients with acute hypotension during or immediately after wound closure. Prompt laboratory analysis of serum tryptase and histamine concentration could help differentiate the causes. Moreover, since controversies still exist in the actual effect of intrawound application of VCM powder to reduce SSIs in spine surgery, local application of this drug should be used with caution.
Abbreviations
VCMVancomycin
ABPArterial blood pressure
TTETransthoracic echocardiography
Publisher’s Note
Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
We sincerely thank our colleagues from anesthesia (Dr. XW, Dr. CW, Dr. WL, Dr. JY, Dr. YW, Dr. CN, Dr. CX, Dr. YT, Dr. HW, Dr. HT, Dr. WW, Dr. YT, Dr. XJ, HL, Dr. HW, Dr. HZ, Dr. YW, and Dr. BW) and surgical department (Dr. YD, Dr. YL, Dr. FZ, Dr. QQ, and Dr. ZC) for providing and verifying the cases.
The authors have completed the CARE reporting checklist.
Authors’ contributions
Guarantor of integrity of entire study: XZ, WZ, ML, XG. Literature research: XZ, WZ. Case study and follow-up: XZ, WZ. Manuscript preparation: XZ, WZ. Manuscript editing and revision: ML, XG. Manuscript final version approval: ML, XG. All authors have read and approved the manuscript.
Funding
This work was supported by the Clinical Key Project of Peking University Third Hospital, Grants No. BYSY2017001.
The role of the funder: study design, decision to submit the manuscript for publication.
Availability of data and materials
All data generated or analyzed during this study are included in this published article. More detailed information could be find in Table 1.
Ethics approval and consent to participate
This case was performed according to the ethical guidelines of the Helsinki Declaration and was approved by the Human Ethics Committee of Peking University Third Hospital. All the authors listed in the manuscript consent to participate the study. The consent for publication from patient or their relatives were collected retrospectively.
Consent for publication
As this is a retrospective case study, written informed consent to publish this manuscript were collected from patients or their relatives retrospectively. The proof of consent to publish from study participants can be requested at any time.
Competing interests
The author(s) declare no competing interests. | Not recovered | ReactionOutcome | CC BY | 33407142 | 18,839,984 | 2021-01-06 |
What was the outcome of reaction 'Ventricular fibrillation'? | Circulatory collapse during wound closure in spine surgery with an unknown cause: a possible adverse effect of topical application of vancomycin?
Vancomycin (VCM) is effective in fighting Gram-positive bacteria related severe infections, and topical application of VCM powder is widely used in orthopedic surgery to prevent wound infection. However, VCM could lead to infusion rate-dependent antibody-and complement-independent anaphylaxis reaction by inducing direct release of histamine.
We retrospectively analyzed seven cases of severe hypotension and shock during wound closure or immediately after orthopedic surgery with unidentifiable reasons. We found that these cases were all associated with local application of VCM powder during wound closure process. Two patients experienced sudden cardiac arrest. Most of the cases (6/7) with circulatory collapse were discharged without severe sequelae. While one case with application of 3 g VCM developed cardiac arrest and remained in a coma due to hypoxic-hypoxic encephalopathy. The clinical presentations and the time of the shock onset were considered to be related with a VCM induced anaphylaxis reaction. However, as this was a retrospective study, and there was no laboratory examination performed, the conclusion was made upon differential diagnosis based on clinical manifestations and the timing of the shock.
Local application of VCM may not be as safe as was once believed and may lead to a related anaphylaxis. As VCM induced infusion-rate dependent, non-IgE mediated anaphylaxis is characterized by delayed occurrence, severe hypotension and even circulatory collapse, surgeons and anesthesiologists should be extra vigilant during and after VCM application.
Background
Shock is defined as a state of insufficient perfusion and oxygen delivery to the tissues. The pathophysiology of shock could be simplified to three major components: cardiac function (the pump), intravascular volume (the tank), and systemic vascular resistance (the pipes) [1]. Whatever the causes of shock may be, if the impaired perfusion and oxygen delivery is not recognized and reversed, the circulatory collapse may progress into organ dysfunction and failure, tissue necrosis and even death. It is urgent to identify the causes of shock and take immediate measures. However, in critical situations, it is hard to rapidly distinguish the culprit during complex clinical situations. Here we present 7 cases (Table 1) of unidentifiable causes of shock during wound closure or shortly after spine surgery, and discuss the possible reasons.
Table 1 Summary of clinical presentations of seven patients with circulatory collapse and unknown etiologies during or shortly after wound closure in spine surgery
Case Demographic information Initial signs/symptoms of shock and management Hemoglobin value (g/L),
fluid resuscitation and blood product infusion VCM administration
and Postoperative sequelae
1 Female; 68-yr; 160 cm/60 kg
BMI: 23.4
Diagnosis:
Lumbar stenosis (L3-S1)
Surgery:
Posterior decompression, fixation and fusion of lumbar spine.
Medical and allergy history:
Hypertension
History of retina surgery
Time of occurrence:
Subcutaneous layer closure, 30 min after initiation of wound closure.
Signs and symptoms:
ABP: 30/20 mmHg
SpO2: undetectable
ECG: tarchycardia with elevated ST segment
Skin and airway symptoms: none.
Management:
Boluses and continuous infusion of noradrenaline (0.01–0.04 μg/kg/min) for 45 min. Fluid resuscitation and blood transfusion.
Preoperative HGB value: 124
Intraoperative minimum value of HGB: 73
Blood loss: 600 ml
Urine: 850 ml
Fluid and blood product infusion:
Crystalloid: 3450 ml
Colloid: 500 ml
PRBC infusion: 1200 ml
Infused autologous blood: 210 ml
VCM administration:
0.5 g mixed with bone debris into the cage and 0.5 g spraying on the dura mater and into the mascularis layer.
Postoperative sequelae:
Proceeded with surgery and the patient was extubated uneventfully.
2 Male; 74-yr; 171 cm/67 kg
BMI: 23.9
Diagnosis:
lumbar stenosis (L3–5)
Surgery:
Posterior decompression, fixation and fusion of lumbar spine.
Medical and allergy history:
nil relevant.
Time of occurrence:
Subcutaneous layer closure, 30 min after initiation of wound closure.
Signs and symptoms:
NBP: 45/15 mmHg
SpO2: undetectable
ECG: tachycardia with ST segment depression
Skin and airway symptoms: none.
Management:
Boluses and continuous infusion of noradrenaline (0.05–0.4 μg/kg/min) and adrenaline (0.5–0.15 μg/kg/min) for 4 h.
Preoperative HGB value:135
Intraoperative minimum value of HGB: 79
Blood loss: 600 ml
Urine: 1950 ml
Fluid and blood product infusion:
Crystalloid: 6300 ml
Colloid: 500 ml
PRBC infusion: 1200 ml
Plasma: 800 ml
Infused autologous blood: 254 ml
VCM administration:
0.5 g mixed with bone debris into the cage and 0.5 g spraying on the dura mater and into the mascularis layer.
Postoperative sequelae:
The patient was extubated and transferred to ICU due to neurological symptoms (unable to follow instructions).
Postoperative imaging: intracranial minor hemorrhage at subdural and subarachnoid space.
The patient was discharged from hospital without neurological deficit.
3 Male; 63-yr; 169 cm/70 kg
BMI: 24.5
Diagnosis:
Lumbar stenosis (L3–5)
Surgery:
Posterior decompression, fixation and fusion of lumbar spine.
Medical and allergy history:
Lacunar infarction;
Bilateral carotid atherosclerotic plaque formation
Time of occurrence:
50 min after initiation of wound closure and 20 min post-extubation in the PACU.
Signs and symptoms:
NBP: 60/25 mmHg
SpO2: 96%
HR:sudden elevation from 60 to 90 bpm
Postoperative agitation
Skin and airway symptoms: none.
Management:
Boluses of ephedrine, phenylephrine and fluid resuscitation.
Preoperative HGB value: 176
Intraoperative minimum value of HGB:123
Blood loss: 800 ml
Urine: 800 ml
Fluid and blood product infusion:
Crystalloid: 2350 ml
Colloid: 1000 ml
PRBC infusion: 400 ml
VCM administration:
Topical spraying of vancomycin (1 g) on the dura mater and into the mascularis.
Postoperative sequelae:
Uneventful.
4 Female; 70-yr; 160 cm/65 kg
BMI:25.4
Diagnosis:
Lumbar stenosis (L4-S1)
Surgery:
Posterior decompression, fixation and fusion of lumbar spine.
Hypertension
Diabetes Mellitus
Time of occurrence:
Subcutaneous layer closure, 30 min after initiation of wound closure.
Signs and symptoms:
NBP: 45/15 mmHg
SpO2: undetectable
Persistent tachycardia
Skin and airway symptoms: none.
Management:
Boluses of phenylephrine for treating severe hypotension and esmolol for tachycardia
Fluid resuscitation and blood transfusion.
Preoperative HGB value: 150
Intraoperative minimum value of HGB: 92
Blood loss: 1500 ml
Urine: 1800 ml
Fluid and blood product infusion:
Crystalloid: 3100 ml
Colloid: 1500 ml
PRBC infusion: 1200 ml
Infused autologous blood: 450 ml
VCM administration:
0.5 g mixed with bone debris into the cage and 0.5 g spraying on the dura mater and into the mascularis layer.
Postoperative sequelae:
The patient was extubated after surgery and transferred to ICU due to tachycardia after sufficient fluid resuscitation.
Recovered uneventfully.
5 Female;48-yr; 170 cm/75 kg
BMI: 26.0
Diagnosis:
Thoracic spinal canal stenosis (T6-T11)
Surgery:
Posterior decompression, fixation and fusion of thoracic spine.
Medical and allergy history:
nil relevant.
Time of occurrence:
Subcutaneous layer closure, 30 min after initiation of wound closure.
Signs and symptoms:
NBP: 40/30 mmHg to undetectable
HR: 120 bpm to 40 bpm
SpO2: undetectable
Cardiac arrest
Skin and airway symptoms: none.
Management:
Extracardiac compression
Boluses of noradrenaline (200 μg) and adrenaline (1 g)
Continuous infusion of noradrenaline (0.02–0.08 μg/kg/min) for 50 min
Fluid resuscitation and blood transfusion.
Preoperative HGB value: 132
Intraoperative minimum value of HGB: 74
Blood loss: 2500 ml
Urine: 1300 ml
Fluid and blood product infusion:
Crystalloid: 4000 ml
Colloid: 500 ml
PRBC infusion: 2400 ml
VCM administration:
Topical spraying of vancomycin (1 g) on the dura mater and into the mascularis layer.
Postoperative sequelae:
The patient was extubated after surgery, and discharged from hospital uneventfully.
6 Male; 66-yr; 175 cm/ 80 kg
BMI: 26.1
Diagnosis:
Lumbar stenosis (L3–5)
Surgery:
Posterior decompression, fixation and fusion of lumbar spine.
Medical and allergy history:
Carotid artery stenosis
Diabetes Mellitus
Time of occurrence:
Sudden cardiac arrest 10 min after extubation (approximately 45 min after initiation of wound closure) with full recovery from anesthesia and without any discomfort complaint.
Signs and symptoms:
Cardiac arrest and persistent VF
Skin and airway symptoms: none.
Management:
Continuous CPR
Persistent VF was treated with repeated defibrillation
Boluses of adrenaline (a total of 6 mg) and amiodarone.
Fluid resuscitation and blood transfusion.
Preoperative HGB value: 143
Intraoperative minimum value of HGB: 78
Blood loss: 1000 ml
Urine: 850 ml
Fluid and blood product infusion:
Crystalloid: 4400 ml
Colloid: 1000 ml
PRBC infusion: 1200 ml
Infused autologous blood: 600 ml
VCM administration:
Topical spraying of vancomycin (3 g) on the dura mater and into the mascularis.
Postoperative sequelae:
The patient was reintubated and transferred to ICU after ROSC. The patient was diagnosed as hypoxic encephalopathy and remained in a coma state. Tracheotomy was performed 2 weeks after surgery, and the patient was transferred to a nursing home for rehabilitation 1 month after orthopedic surgery.
7 Female; 43-yr; 155 cm / 54 kg
BMI: 22.4
Diagnosis:
Thoracic kyphosis (T7-T8)
Surgery:
Osteotomy for kyphosis of thoracic spine (T7-T8).
Medical and allergy history:
nil relevant.
Time of occurrence:
subcutaneous layer closure, 30 min after initiation of wound closure.
Signs and symptoms:
HR:tachycardia
NBP: 60/30 mmHg
SpO2 82%
Skin and airway symptoms: none.
Management:
Boluses of phenylephrine and ephedrine;
Continuous infusion of noradrenaline (0.05–0.1 μg/kg/min)
Fluid resuscitation and blood transfusion.
Preoperative HGB value: 138
Intraoperative minimum value of HGB: 95
Blood loss: 1200 ml
Urine: 1900 ml
Fluid and blood product infusion:
Crystalloid: 4700 ml
Colloid: 1000 ml
PRBC infusion: 1200 ml
Infused autologous blood: 470 ml
VCM administration:
Topical spraying of vancomycin (1 g) on the dura mater and into the mascularis layer.
Postoperative sequelae:
The patient was transferred to ICU for optimal monitoring and recovered uneventfully.
Abbreviations: NBP Non-invasive blood pressure; ABP Arterial blood pressure; (NBP is noted when ABP is not available.) VF Ventricular fibrillation; CPR Cardiopulmonary Resuscitation; HGB Hemoglobin; VCM Vancomycin; PRBC Packed red blood cell; ROSC Return of spontaneous circulation
Case presentation
The first case we encountered was a 68-yr female with past medical history of hypertension and surgical treated retina detachment, who underwent posterior decompression, fixation and fusion of lumbar spine due to lumbar stenosis (L3-S1). The operation was uneventful until sudden circulatory collapse occurred during the process of rinsing mascularis and superficial fascia layer whilst closing the wound. A sudden drop in arterial blood pressure (ABP) (130/60 mmHg to 30/20 mmHg), increased HR (60 bpm to 100 bpm) with elevated ST-segment and significant decrease of PetCO2 (31 mmHg to 16 mmHg) were noticed, with undetectable pulse oximetry read. The patient was turned to supine position immediately and managed with boluses (40–100 μg) and a continuous infusion of noradrenaline (0.01–0.04 μg/kg/min) for approximately 45 min. The circulation was gradually stabilized. No rash, erythema, or bronchospasm were noted. The bilateral breath sounds were equal and the airway pressure remained normal. We continued treatments of fluid resuscitation and blood transfusion with corticosteroid and ice cap to prevent hypoxic-ischemic encephalopathy. Intraoperative emergency consultations and immediate examinations of 12-lead ECG, point-of-care transthoracic echocardiography (TTE), and full panel laboratory tests were performed. However, these results did not support the causes of sudden cardiac dysfunction (the pump) including mechanical obstruction (pericardial tamponade and massive pulmonary embolus), acute myocardial infarction, acute valvular insufficiency, and arrhythmia. Vascular catastrophes were excluded and there were no signs of sepsis. We also examined the intravascular volume function (the tank) by performing the TTE, and ruled out intraperitoneal major hemorrhage which we once encountered (caused by inadvertent piercing of iliac artery when placing probe during lumbar surgery) by examination of abdominal ultrasound and hemoglobin level; Volume status was evaluated by measuring CVP, urine output, infused fluid volume; Surgical blood loss was reviewed to exclude hemorrhage shock and hypovolemia. As no special medications were given except anesthetic maintenance drugs, and no signs of mottled skin or bronchospasm were noticed, anaphylaxis was not considered at that time. After restoring circulatory stability, the surgery preceded uneventfully. The patient was discharged from hospital 7 days later.
It was intriguing that within 1 month, another case of circulatory collapse happened during wound closure in spine surgery performed by the same orthopedic surgeon. The intraoperative clinical manifestations were very similar to the previous one. Hemodynamic resuscitation were initiated immediately with repeated boluses and continuous infusion of noradrenaline (0.05–0.4 μg/kg/min) and adrenaline (0.5–0.15 μg/kg/min). After stabilizing the circulation 4 h later, the patient was extubated and transferred to ICU due to neurological symptoms (unable to follow instructions after full recovery from anesthesia). Postoperative imaging revealed intracranial micro hemorrhagic foci in the subdural and subarachnoid space. The patient was discharged from hospital without any neurological sequelae.
With further exploration and analysis of the similarities of these two cases, we found that local application of vancomycin (VCM) powder was used in these two patients to prevent postoperative surgical site infections (SSIs) during wound closure (0.5 g VCM loaded with bone debris into the cage and another 0.5 g sprayed on the dura mater and into the mascularis). Ramamani Mariappan reported a case of circulatory collapse after topical application of vancomycin powder during spine surgery, which exhibited almost the same clinical course as ours [2]. It was speculated that the rapid absorption of VCM applied to the surgical wound caused an anaphylaxis reaction and circulatory collapse. The reaction occurred approximately 30 min after the application and persisted for 6 h. The serum tryptase level was not elevated, suggesting that VCM caused a direct histamine release, which is in keeping with our current understanding. A similar case reported a 74-year-old woman who underwent a primary total knee replacement presented with red man syndrome in the PACU 45 min after release of tourniquet following the use of VCM-loaded bone cement. The patient remained fully conscious despite a sudden drop in blood pressure to 47/34 mmHg [3]. Therefore, local application of VCM may pose the risk of causing severe circulatory adverse effect.
Similar circulatory collapse cases in spine surgery without definitive causes during wound closure or shortly after surgery, though rare, were encountered in our institution. Therefore we retrospectively analyzed these cases for the past 2 years, and asked the anesthesiologists and orthopedic surgeons in charge for further information. A total of 7 cases were collected (Table 1). There were 3 males and 4 females, the median age was 66 y (43–74 y), and the averaged BMI was 24.39 ± 1.51 (22.3–26.1). It was interesting to note that these cases were all associated with topical application of VCM powder (Table 1). In these 7 cases, the onset time of severe circulatory fluctuation was 30 min in 5 cases, 50 min in one case (applied with 1 g of VCM), and approximately 45 min in another case (locally applied 3 g of VCM), respectively. Most of the cases (6/7) with severe circulatory fluctuation were corrected without severe sequelae. While in one case in which 3 g of VCM was applied on the dura mater and into the mascularis during wound closure, sudden cardiac arrest happened shortly after the patient had fully recovered from the anesthetic, following surgery and extubation in the OR. CPR was initiated immediately. The patient was reintubated and ventilated mechanically. The persistent VF was treated with continuous chest compressions and repeated defibrillation, with boluses of adrenaline (a total of 6 mg) and amiodarone. After 50 min of continuous CPR, with fluid resuscitation and blood transfusion, the patient was transferred to ICU following the return of spontaneous circulation and reverting into sinus rhythm. However, the patient remained in a comatose state due to hypoxic-hypoxic encephalopathy, and tracheotomy was performed 2 weeks later.
Discussion and conclusion
Vancomycin and anaphylaxis reaction
“International Consensus on (ICON) Anaphylaxis” define anaphylaxis as “a serious, generalized or systemic, allergic or hypersensitivity reaction that can be life threatening or fatal” [4]. It has been demonstrated that there exists IgE-dependent and three IgE-independent mechanisms in anaphylaxis pathophysiology [5]. VCM could directly activate mast cells to release histamine and other mediators through an IgE-independent mechanism that is calcium-, phospholipase C–, and phospholipase A2–dependent but otherwise unknown [5, 6]. Vancomycin-induced direct histamine release is also infusion rate dependent [7]. This IgE-independent anaphylaxis reaction generally disappears within 20 mins, but may linger for hours. The most common manifestation is a sudden drop in blood pressure, which is related to the negative inotropic effect and the vasodilator action stimulated by the histamine release. Alteration in vascular tone is also a common feature of anaphylactic shock [8]. Richter J and colleagues demonstrated in rats that VCM could directly influence the vascular tonus, affecting the microcirculation [9].
The VCM reactions studied in the pediatric population revealed that non-IgE mediated reaction accounts for the vast majority of reactions (92%; prevalence, 5.4–5.8%), whereas possible IgE-mediated vancomycin reactions were exceedingly rare (prevalence, 0.0–0.37%) [7]. For adults, the reported incidence of non-IgE mediated reaction varies between 3.7 and 47% in infected patients and 90% in healthy volunteers [2]. Elevated serum mast cell tryptase is a valuable indicator for diagnosing Ig-E mediated anaphylactic reaction. However, it is not useful in determining a non-IgE mediated anaphylactic reaction caused by histamine release [2]. Detection of histamine concentration in clinical blood specimens is difficult due to its extremely short half-life, and histamine is not a mast cell specific product [10]. As this study is retrospective in nature, and our hospital does not perform examination of serum tryptase and histamine concentration, we could not differentiate whether the adverse effects were caused by VCM induced IgE-mediated or non-IgE mediated reaction.
Topical application of vancomycin powder and surgical site infections
VCM is effective in fighting Gram-positive bacteria related severe infections [11]. While the actual utility of local application of VCM is controversial. After the first reported topical application of VCM by orthopedic surgeons to reduce postoperative surgical site infections (SSIs) rate [12], a large number of meta-analyses, retrospective cohort studies, and randomized controlled trials were published to assess the power of this method in preventing SSIs. Recent findings from large-scale propensity score matched analyses, meta analyses, RCTs studies, and observational studies of spine surgeries and knee arthroplasties all demonstrated that the intrawound VCM powder application may not decrease SSIs, but may increase postoperative complications [13–19].
VCM is an antibiotic that was considered safe in local application and has been widely used in hospitals. However, dose recommendations, dilutions, monitoring, infusion types and rates are still controversial [20]. There’s no defined time or situation during surgery when local VCM should be applied. Some may load VCM powder with bone debris into the cage, or apply VCM powder directly onto the dura mater or after closure of the fascia, whereas other studies reported that VCM powder was applied in the subfascial layer [2, 13]. However, intrawound absorption rate of VCM powder is uncontrollable as this depends on multiple factors, such as the extent and degree of tissue/muscle damaged by surgical manipulation, anatomic location where VCM powder is placed (mixed with bone debris, or between muscularis layers that are abundant with blood supply), and the surgeon’s suturing maneuvers (the flushing saline would leak from upper layer into the layer where VCM powder is deposited). These factors all pose potential risk of causing rapid drug dissolution and accelerated absorption into the circulatory system. Moreover, individual’s adverse reactions to VCM varied. These incidental events may be accidentally linked and lead to severe outcome. Since intravenous administration of VCM could lead to adverse effects, it is theoretically possible that local application of VCM powder may cause similar clinical manifestation.
Topical application of VCM was intended to achieve the effect of providing high local concentrations while avoiding high systemic levels and the risk of bacterial resistance. The serum concentration level peaks at 30 min and then declines to baseline at 6 h [2]. This may explain the delayed and unpredictable occurrence of anaphylaxis reactions after local application of VCM powder, due to the uncertainty of the drug absorption rate and individual reaction differences. The instructed therapeutic dosage of VCM is 30 mg/kg/day which should be fractioned in 2 or 3 doses. Moreover, the infusion rate should be within 10 mg/min, and last for more than 60 min. For elderly patients, this dosage should be reduced [21, 22]. Although the most commonly used dose of intrawound VCM is 1 g, some authors reported that they altered the dose according to the length of the incision [23]. VCM is not the first-choice antibiotic as its adverse effects are frequently reported including hypotension and tachycardia, phlebitis, nephrotoxicity, ototoxicity, hypersensitivity reactions, red man syndrome, neutropenia, chills, fever, interstitial nephritis, etc. [13]. As VCM induced adverse reactions are dose and infusion-rate dependent, doctors should be highly vigilant to over-dosing which might bring disastrous results.
Other issues related to shock
In this case series, the typical signs of erythema and redness (red man syndrome) have not appeared, which resemble the previous case reported by Mariappan R and colleagues [2]. The lack of skin flushing may be the result of reduced perfusion due to circulatory shock or the adverse effect of VCM mainly manifested as severe alteration of vascular tonus [8, 9]. In our experience, a rapid but low dose intravenous infusion of VCM induced anaphylaxis reaction was not necessarily associated with skin manifestations. Whether this is related to racial differences or rapid absorption of low dose VCM was not known. However, the clinical features of hypotension, tachycadia and low oxygenation were notable.
For this case series, as there is no definitive laboratory examination or gold standard to help reach a definitive diagnosis of VCM induced anaphylaxis reaction, the conclusions were made upon differential diagnosis based on clinical manifestations and the timing of the shock. Other possible causes or contributing factors for the development of severe hypotension and shock need to be considered. For example, restrictive fluid therapy during surgical procedure and restrictive blood transfusion strategy leading to hypovolemia and hypotension, complicated with unseen bleeding from surgical site and other compounding factors such as hypoproteinemia and unaltered anesthetic depth during wound closure.
Another issue needs to be addressed is that there’s a notable decrease in hemoglobin (HGB) concentration in all cases when severe hypotension occurred. However, the hemorrhagic shock induced by surgical blood loss was ruled out. We speculate that this might be due to the infusion of large amounts of fluid during resuscitation. It is reported that the administration of 500 ml of fluids may acutely decrease the HGB concentration by about 1 g/dl, or about 8%, by “dilutional anemia” [24]. In septic shock patients, approximately 30% decrease of hematocrit was commonly observed in patients receiving large amounts of fluids during resuscitation, which further indicates more blood transfusion [25]. In the current study, the HGB concentrations were all measured after the initiation of fluid resuscitation and this may at least partially explained the sharp decrease of the HGB level (Table 1). When severe hypotension with unknown causes occur, initial management is to infuse large amounts of fluid with vaso-constrictive drugs. The iatrogenic hemodilution related blood transfusion may result in dilutional coagulopathy and increase surgical bleeding. This then leads to a decreased HGB level below the acceptable transfusion threshold, leading to further blood transfusion in the absence of significant blood loss [26]. This is especially true when in the scenario of the existence of suspected hemorrhagic shock.
In conclusion, local application of VCM powder during wound closure could cause delayed occurrence of severe hypotension and shock in spine surgery. Hemodynamic changes may be under-emphasized and under-reported as in most cases, this hemodynamic reaction is easy to correct and normally wouldn’t cause serious consequences. However, the actual occurrence is not rare and this might be confused with hypovolemia or anesthetic induced hypotension. Surgeons and anesthesiologists should be highly aware of VCM induced IgE-independent anaphylaxis reactions. The differential diagnosis of anaphylactic shock must be taken into consideration in patients with acute hypotension during or immediately after wound closure. Prompt laboratory analysis of serum tryptase and histamine concentration could help differentiate the causes. Moreover, since controversies still exist in the actual effect of intrawound application of VCM powder to reduce SSIs in spine surgery, local application of this drug should be used with caution.
Abbreviations
VCMVancomycin
ABPArterial blood pressure
TTETransthoracic echocardiography
Publisher’s Note
Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
We sincerely thank our colleagues from anesthesia (Dr. XW, Dr. CW, Dr. WL, Dr. JY, Dr. YW, Dr. CN, Dr. CX, Dr. YT, Dr. HW, Dr. HT, Dr. WW, Dr. YT, Dr. XJ, HL, Dr. HW, Dr. HZ, Dr. YW, and Dr. BW) and surgical department (Dr. YD, Dr. YL, Dr. FZ, Dr. QQ, and Dr. ZC) for providing and verifying the cases.
The authors have completed the CARE reporting checklist.
Authors’ contributions
Guarantor of integrity of entire study: XZ, WZ, ML, XG. Literature research: XZ, WZ. Case study and follow-up: XZ, WZ. Manuscript preparation: XZ, WZ. Manuscript editing and revision: ML, XG. Manuscript final version approval: ML, XG. All authors have read and approved the manuscript.
Funding
This work was supported by the Clinical Key Project of Peking University Third Hospital, Grants No. BYSY2017001.
The role of the funder: study design, decision to submit the manuscript for publication.
Availability of data and materials
All data generated or analyzed during this study are included in this published article. More detailed information could be find in Table 1.
Ethics approval and consent to participate
This case was performed according to the ethical guidelines of the Helsinki Declaration and was approved by the Human Ethics Committee of Peking University Third Hospital. All the authors listed in the manuscript consent to participate the study. The consent for publication from patient or their relatives were collected retrospectively.
Consent for publication
As this is a retrospective case study, written informed consent to publish this manuscript were collected from patients or their relatives retrospectively. The proof of consent to publish from study participants can be requested at any time.
Competing interests
The author(s) declare no competing interests. | Recovered | ReactionOutcome | CC BY | 33407142 | 18,839,984 | 2021-01-06 |
Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Angiocentric lymphoma'. | Chronic active EBV infection in refractory enteritis with longitudinal ulcers with a cobblestone appearance: an autopsied case report.
BACKGROUND
Chronic active Epstein-Barr virus infection (CAEBV) is defined as Epstein-Barr virus (EBV)-positive T/NK cell-related neoplasia, and its major clinical symptom is systemic inflammation presenting as infectious mononucleocytosis, whereas enteritis and diarrhea are minor clinical symptoms. The complex mixture of tumorigenic processes of EBV-positive cells and physical symptoms of systemic inflammatory disease constitutes the varied phenotypes of CAEBV. Herein, we describe a case of CAEBV that was initially diagnosed as Crohn's disease (CD) based on ileal ulcers and clinical symptoms of enteritis.
METHODS
A 19-year-old woman complained of abdominal pain and fever. Blood examination showed normal blood cell counts without atypical lymphocyte but detected modest inflammation, hypoalbuminemia, slight liver dysfunction, and evidence of past EBV infection. The esophagogastroduodenoscopic findings were normal. However, colonoscopy revealed a few small ulcers in the terminal ileum. The jejunum and ileum also exhibited various forms of ulcers, exhibiting a cobblestone appearance, on capsule endoscopy. Based on these clinical findings, she was strongly suspected with CD. In the course of treatment by steroid and biologics for refractory enteritis, skin ulcers appeared about 50 months after her initial hospital visit. Immunohistology of her skin biopsy revealed proliferation of EBV-encoded small RNA (EBER)-positive atypical lymphocytes. We retrospectively assessed her previous ileal ulcer biopsy before treatment and found many EBER-positive lymphocytes. Blood EBV DNA was also positive. Therefore, she was diagnosed with extranodal NK/T-cell lymphoma with CAEBV-related enteritis rather than CD. She was treated with cyclosporine and prednisolone combination therapy for CAEBV-related systemic inflammation and chemotherapy for malignant lymphoma. Unfortunately, her disease continued to progress, leading to multiple organ failure and death at the age of 23 years.
CONCLUSIONS
Clinicians need to remember the possibility of CAEBV as a differential diagnosis of refractory enteritis. Enteritis with intestinal ulcer is a rare symptom of CAEBV, and it is impossible to acquire a definitive diagnosis by ulcer morphology only. In cases where the possibility of CAEBV remains, tissue EBVR expression should be checked by in situ hybridization and blood EBV DNA.
Background
Enteritis is an inflammatory disease of the small intestine caused by some factors, such as bacterial or viral infections, ischemia, vasculitis, chemical or radiological tissue damage, and immune disorders including inflammatory bowel disease (IBD), with phenotype variation [1]. In fact, few cases of chronic active Epstein–Barr virus (CAEBV) reveal enteritis [2–4]. Previously, CAEBV was thought to be a rare child disease limitedly occurring in the East Asia. However, CAEBV has been recently found to occur worldwide with no relation to patient’s age [5]. Although CAEBV is a phenotype of EBV-lymphoproliferative disorders, its major clinical symptom is systemic inflammation presenting as infectious mononucleosis (IM) and enteritis as well as diarrhea are minor clinical symptoms. The complex mixture of tumorigenic processes associated with EBV-positive cells and the physical symptoms of inflammatory systemic disease constitute the varied phenotypes of CAEBV. The median period between the first visit and the definite diagnosis of CAEBV was 20 months. This extended duration was mainly due to the need to first exclude other diseases or cases where patients were diagnosed with unknown fever [6]. Although CAEBV generally presents with IM-like symptoms, we recently experienced a case of a young woman with CAEBV that appeared with refractory enteritis and was indistinguishable from Crohn’s disease (CD). This report of an autopsied CAEBV case will be of educational help, given the difficulty in acquiring a definite diagnosis.
Case presentation
A 19-year-old woman was referred to our hospital for intermittent abdominal pain and continuous fever which had persisted for a month. She had no obvious medical or familial history. Physical examination revealed no morbid lymph node swelling or skin abnormalities. Blood examination showed normal blood cell counts and no presence of atypical lymphocytes. Biochemical or immunoserum analysis revealed modest inflammation, hypoalbuminemia, slight liver dysfunction, and evidence of past EBV infection (Additional file 1: Table S1). Although esophagogastroduodenoscopy revealed normal findings, colonoscopy revealed a few small ulcers in the terminal ileum (Additional file 3: Fig. 1). Enhanced computed tomography showed obvious wall thickness of the small intestine, whereas no significant finding was detected by balloon intestinal endoscopy in the distal ileum. However, various types of ulcers surrounded by completely normal mucosa were found on the jejunum and proximal ileum by capsule endoscopy (CE) (Fig. 1). Additionally, multiple aphthous and some linear ulcers were observed on the jejunum, whereas circular ulcers and longitudinal ulcers with a cobblestone appearance were detected on the ileum. The possibility of intestinal tuberculosis and infectious gastroenteritis were serologically and culturally excluded. Although there were no histological findings of noncaseating granuloma on her digestive organs, she was strongly suspected with CD based on her age, clinical symptoms, and the morphology of the characteristic ulcers (Fig. 2). Consequently, the patient was treated with an elemental diet, mesalamine, and prednisolone for induction therapy. Although this treatment seemed to be partially effective, her symptoms recurred according to the tapering of prednisolone, and she was subsequently switched to adalimumab (ADA). Her clinical symptoms tended to be gradually modest, and the maintenance ADA therapy was effective for some time. The second CE revealed a definite improvement of the intestinal ulcers (Fig. 3a, b); however, 21 months after the initiation of treatment, her intermittent fever and repeated abdominal pain recurred, and re-induction therapy with prednisolone was restarted (Fig. 2). She remained stable for 9 months, before complaining of slight abdominal pain. We set a dose escalation of ADA with the addition of azathioprine; this seemed to be effective, and almost all of the ulcers disappeared, except for a few small erosions on the intestine (Fig. 3c, d). She next relapsed approximately 10 months later, and ADA was switched to ustekinumab (USK). However, this treatment was not sufficient, and prednisolone was added to USK for clinical improvement. Unfortunately, disease management was difficult regardless of these treatments, and skin ulcers appeared about 50 months after her initial hospital visit (Fig. 4a). Immunohistology of her skin biopsy revealed proliferation of EBV-encoded small RNA (EBER)-positive atypical lymphocytes (Fig. 4b, c). Retrospective assessments of the previous ileal ulcer biopsy before treatment demonstrated many EBER-positive lymphocytes, indicating that she had been in a continuously active EBV infection state (Fig. 4d, e). The blood level of EBV-DNA was also clearly positive (1.5 × 104 copy/WBC × 106). Consequently, she was diagnosed with extranodal NK/T-cell lymphoma (nasal type) related to CAEBV. Advanced-stage malignant lymphoma invading the skin was seen. Then, she was treated with a combination of cyclosporine A and prednisolone for her systemic inflammation related to CAEBV and followed by a systemic chemotherapy for malignant lymphoma. After completing the CHOP chemotherapy (cyclophosphamide, doxorubicin, vincristine, and prednisolone), she gradually showed intermediate liver injury as well as cholestasis, based on which she was diagnosed with secondary hemophagocytic lymphohistiocytosis (HLH) caused by CAEBV. Though etoposide and methylprednisolone combination therapy transiently improved her liver injury and jaundice, CHOP insufficiently controlled the progression of CAEBV. Hence, the combination therapy of etoposide, cytosine arabinoside, l-asparaginase, methylprednisolone, and prednisolone (ESCAP) was preferred over the CHOP therapy. However, her liver injury and jaundice related to HLH rapidly worsened during the recovery period after the first ESCAP therapy. Unfortunately, her disease progression could not be regulated at all and she finally fell into the stage of multiple organ failure; she died at the age of 23 years, 55 months after her first hospital visit. An autopsy was performed with the consent from her parents. Macroscopic findings showed no evidence of ulcer or stenotic changes on her digestive organs, including the small intestine (Fig. 5a). Microscopic findings showed no evidence of noncaseating granuloma on digestive organs and a remarkable proliferation of lymphocytes in the intra-mucosal/submucosal space of the small intestine (Fig. 5b, c).Fig. 1 Various forms of ulcers on digestive organs detected by capsule endoscopy prior to treatment. The surrounding mucosa was free from inflammation. a Multiple aphthous ulcers on the jejunum. b Liner ulcers on the jejunum. c Longitudinal ulcers with a cobblestone appearance on the ileum. d Circular ulcers on ileum
Fig. 2 Entire clinical course of the present case
Fig. 3 Findings of the second capsule endoscopic examination. a, b Ulcer scars on the jejunum and ileum (18 months after the first treatment). c, d Small recurrent erosions on the jejunum and ileum (42 months after the first treatment)
Fig. 4 Histological findings of extranodal NK/T-cell lymphoma (nasal type) associated with continuously activated EBV infection. a Macroscopic finding of skin ulcer on the patient’s thigh, which occurred more than 4 years after the initiation of medical treatment. b Microscopic finding of H&E staining of the skin ulcer. c Microscopic findings revealed high proliferation of EBER-positive atypical lymphocytes in the diseased skin. d Microscopic finding of H&E staining in the intestinal ulcer. e Microscopic immunohistological findings of ileal ulcerative lesions revealed moderate infiltration of many EBER-positive lymphocytes, which demonstrated continuously active EBV infection
Fig. 5 Histological findings of the autopsied small intestine. a Macroscopic observation revealed neither ulcerative changes nor stenotic changes in the small intestine. b Microscopic finding of H&E staining of the intestinal tissue. c Microscopic observation revealed mild lymphocyte proliferation with no atrophy of the intestinal villi (large magnification of H&E staining)
Discussion and conclusion
Chachu and Osterman concluded that "Thoughtful consideration and evaluation of these other potential etiologies through patient history and physical examination, laboratory tests, endoscopic evaluation with targeted biopsies of lesions, and cross-sectional imaging is required to evaluate any patient presenting with symptoms consistent with IBD" [7]. However, it is difficult to completely distinguish CAEBV enteritis from IBD by endoscopic findings only, and it is important to comprehend the clinical features of each disease. To appropriately diagnose CAEBV, it is important to remember the possibility of CAEBV as a differential diagnosis of systemic inflammation [8]. When CAEBV is suspected, the EBV-DNA level in peripheral blood should be checked, even in immunologically denied cases of acute EBV infection. Identification of EBV-infected T and NK cells should be performed for definite diagnosis of CAEBV. Moreover, in situ hybridization (ISH) of EBER by pathological examination and EBV-DNA analysis by flow cytometry should be performed. More details are described in the latest diagnostic criteria of CAEBV [5, 9].
To our knowledge, the first report of a case with gastrointestinal tract complications of CAEBV had serious colorectal bleeding [10]. Later, in the 2000s, there were several reports of CAEBV with gastrointestinal tract complications, which had initially been misdiagnosed as IBD [2–4]. Approximately 6% CAEBV-related deaths originated from intestinal bleeding or perforation [6]. As summarized in the Additional file 2: Table S2, the ulcer morphology of “cobblestone appearance” characteristic of CD [11] was first found in our current case, but this was not observed in all 27 previously reported CAEBV-related enteritis cases [2–4, 10, 12, 13]. According to the endoscopic features of these 28 cases, the diseased lesion was located in the colon (13 cases), small intestine (five cases), concomitant colon and small intestine (five cases), concomitant colon and ileocecal junction (one case), concomitant colon and stomach (one case), ileocecal junction (one case), and unknown location (two cases). Ulcer morphologies have generally been reported as small, shallow, irregular-shaped, and scattered, with the exception of eight cases of huge and profound ulcers. There was also a previous case in which the entire intestinal mucosa displayed lymphangiectasia [3]. In our case, many small aphthous ulcers were found in the whole intestine, and a cobblestone appearance was observed, especially in the ileum, whereas no ulcer was found in the colon. These aphthous ulcers remained after intensive treatment with steroids and biologics. Based on these findings, CAEBV-related enteritis might present various ulcer morphologies depending on the reaction of each therapeutic treatment and/or time course. To detect intestinal lesions, we adopted CE, which has been increasingly used worldwide since its establishment in 2000 [14]. With the advent of CE, various diseases have been clearly visualized, resulting in a paradigm shift in the diagnosis and treatment of small bowel disease. According to a nationwide study in Japan, the frequent findings of CE in patients with CD include cobblestone appearance (occurrence rate: 33%), longitudinal ulcer (78%), irregular ulcer (84%), liner erosion (90%), irregular erosion (89%), circumferential alignment of diminutive lesions (75%), and longitudinal alignment of diminutive lesions (56%) [15]. In this previous study, Esaki et al. observed that the endoscopic diagnosis varied in endoscopist’s clinical knowledge and proficiency; hence, this issue should be overcome. In this case, CD was most probable because ulcers with a cobblestone appearance were detected in the ileum. However, other characteristic findings, such as the bamboo joint-like appearance of the gastric mucosa in esophagogastroduodenoscopy, focally enhanced gastritis, and granuloma on histological evaluation were not actually confirmed.
Thus, a final diagnosis should be comprehensively made based on physical symptoms, medical histories, clinical findings, and culture, imaging, and pathological tests. Even if the characteristic endoscopic findings of specific enteritis are detected, differential diagnosis based only on these findings will be difficult because the characteristic findings of endoscopy do not always correspond to the specific disease. Some enteric diseases might show similar endoscopic appearances, whereas the same disease might demonstrate various phenotypes depending on the time course and severity.
Unfortunately, no successful treatment for CAEBV has yet been established, and further research is needed to improve the outcome in the future [16, 17]. Therefore, it is crucial for clinicians to definitely diagnose CAEBV as quickly as possible.
In conclusion, we diagnosed a rare case of CAEBV, with refractory enteritis as the main clinical symptom and without manifestation of a typical IM feature. Diagnosing CAEBV by ulcer morphology is difficult, even with CE and routine histopathological examination only; thus, clinicians should consider CAEBV as a differential diagnosis of refractory enteritis in younger patients and eagerly check blood EBV-DNA and EBER expression levels by ISH.
Patient perspective
The patient's mother kindly told the authors that the patient had decided to fight her disease, though she had well realized the features and general prognosis of CAEBV.
Supplementary Information
Additional file 1: Supplementary Table S1. Results of her blood test on the first admission.
Additional file 2: Supplementary Table S2. Clinical features of the reported CAEBV cases.
Additional file 3: Figure S1. Endoscopic findings of each digestive organ before treatment. (a) Esophagus, (b) stomach, (c) duodenum, (d) terminal ileum, (e) colon, and (f) rectum. Arrow indicates an ulcerative lesion on the terminal ileum.
Abbreviations
CAEBVChronic active Epstein–Barr virus infection
EBVEpstein–Barr virus
CDCrohn’s disease
IBDInflammatory bowel disease
IMInfectious mononucleosis
CECapsule endoscopy
ADAAdalimumab
USKUstekinumab
EBEREBV-encoded small mRNA
ISHIn situ hybridization
HLHHemophagocytic lymphohistiocytosis
Publisher's Note
Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
Supplementary Information
The online version contains supplementary material available at 10.1186/s12876-020-01589-1.
Acknowledgements
The authors deeply appreciate the mercy of the patient and her parents for accepting the autopsy and publication of this report on her illness.
Authors’ contributions
Writing: YA and KM. Editing: KM. Figure preparation: NS, SN, SK, MU, HM, EI, and H Yagi. Supervision: TN, H Yoshiji, and EK. All authors have read and approved the final version of this manuscript.
Funding
There is nothing to declare.
Availability of data and materials
Data on this case not reported in the manuscript are available from the corresponding author upon reasonable request.
Ethics approval and consent to participate
Ethics committee approval is not required for a single presentation retrospectively. In accordance with the “Patient Rights Regulation” (Date: 01.08.1998; Issue: 23420), which was prepared in accordance with international standards, verbal and wet signed written consent was obtained from the patient under the title of “Consent to publish” to publish patient information and support public health.
Consent for publication
The parents of the patient provided written consent for reporting her case in an international published medical journal, including clinical details and images.
Competing interests
The authors confirm that there are no conflicts of interest to declare. | ADALIMUMAB, ASPARAGINASE, CYCLOPHOSPHAMIDE, CYCLOSPORINE, CYTARABINE, DOXORUBICIN, ETOPOSIDE, MESALAMINE, METHYLPREDNISOLONE, PREDNISOLONE, VINCRISTINE | DrugsGivenReaction | CC BY | 33407170 | 19,246,748 | 2021-01-06 |
Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Condition aggravated'. | Chronic active EBV infection in refractory enteritis with longitudinal ulcers with a cobblestone appearance: an autopsied case report.
BACKGROUND
Chronic active Epstein-Barr virus infection (CAEBV) is defined as Epstein-Barr virus (EBV)-positive T/NK cell-related neoplasia, and its major clinical symptom is systemic inflammation presenting as infectious mononucleocytosis, whereas enteritis and diarrhea are minor clinical symptoms. The complex mixture of tumorigenic processes of EBV-positive cells and physical symptoms of systemic inflammatory disease constitutes the varied phenotypes of CAEBV. Herein, we describe a case of CAEBV that was initially diagnosed as Crohn's disease (CD) based on ileal ulcers and clinical symptoms of enteritis.
METHODS
A 19-year-old woman complained of abdominal pain and fever. Blood examination showed normal blood cell counts without atypical lymphocyte but detected modest inflammation, hypoalbuminemia, slight liver dysfunction, and evidence of past EBV infection. The esophagogastroduodenoscopic findings were normal. However, colonoscopy revealed a few small ulcers in the terminal ileum. The jejunum and ileum also exhibited various forms of ulcers, exhibiting a cobblestone appearance, on capsule endoscopy. Based on these clinical findings, she was strongly suspected with CD. In the course of treatment by steroid and biologics for refractory enteritis, skin ulcers appeared about 50 months after her initial hospital visit. Immunohistology of her skin biopsy revealed proliferation of EBV-encoded small RNA (EBER)-positive atypical lymphocytes. We retrospectively assessed her previous ileal ulcer biopsy before treatment and found many EBER-positive lymphocytes. Blood EBV DNA was also positive. Therefore, she was diagnosed with extranodal NK/T-cell lymphoma with CAEBV-related enteritis rather than CD. She was treated with cyclosporine and prednisolone combination therapy for CAEBV-related systemic inflammation and chemotherapy for malignant lymphoma. Unfortunately, her disease continued to progress, leading to multiple organ failure and death at the age of 23 years.
CONCLUSIONS
Clinicians need to remember the possibility of CAEBV as a differential diagnosis of refractory enteritis. Enteritis with intestinal ulcer is a rare symptom of CAEBV, and it is impossible to acquire a definitive diagnosis by ulcer morphology only. In cases where the possibility of CAEBV remains, tissue EBVR expression should be checked by in situ hybridization and blood EBV DNA.
Background
Enteritis is an inflammatory disease of the small intestine caused by some factors, such as bacterial or viral infections, ischemia, vasculitis, chemical or radiological tissue damage, and immune disorders including inflammatory bowel disease (IBD), with phenotype variation [1]. In fact, few cases of chronic active Epstein–Barr virus (CAEBV) reveal enteritis [2–4]. Previously, CAEBV was thought to be a rare child disease limitedly occurring in the East Asia. However, CAEBV has been recently found to occur worldwide with no relation to patient’s age [5]. Although CAEBV is a phenotype of EBV-lymphoproliferative disorders, its major clinical symptom is systemic inflammation presenting as infectious mononucleosis (IM) and enteritis as well as diarrhea are minor clinical symptoms. The complex mixture of tumorigenic processes associated with EBV-positive cells and the physical symptoms of inflammatory systemic disease constitute the varied phenotypes of CAEBV. The median period between the first visit and the definite diagnosis of CAEBV was 20 months. This extended duration was mainly due to the need to first exclude other diseases or cases where patients were diagnosed with unknown fever [6]. Although CAEBV generally presents with IM-like symptoms, we recently experienced a case of a young woman with CAEBV that appeared with refractory enteritis and was indistinguishable from Crohn’s disease (CD). This report of an autopsied CAEBV case will be of educational help, given the difficulty in acquiring a definite diagnosis.
Case presentation
A 19-year-old woman was referred to our hospital for intermittent abdominal pain and continuous fever which had persisted for a month. She had no obvious medical or familial history. Physical examination revealed no morbid lymph node swelling or skin abnormalities. Blood examination showed normal blood cell counts and no presence of atypical lymphocytes. Biochemical or immunoserum analysis revealed modest inflammation, hypoalbuminemia, slight liver dysfunction, and evidence of past EBV infection (Additional file 1: Table S1). Although esophagogastroduodenoscopy revealed normal findings, colonoscopy revealed a few small ulcers in the terminal ileum (Additional file 3: Fig. 1). Enhanced computed tomography showed obvious wall thickness of the small intestine, whereas no significant finding was detected by balloon intestinal endoscopy in the distal ileum. However, various types of ulcers surrounded by completely normal mucosa were found on the jejunum and proximal ileum by capsule endoscopy (CE) (Fig. 1). Additionally, multiple aphthous and some linear ulcers were observed on the jejunum, whereas circular ulcers and longitudinal ulcers with a cobblestone appearance were detected on the ileum. The possibility of intestinal tuberculosis and infectious gastroenteritis were serologically and culturally excluded. Although there were no histological findings of noncaseating granuloma on her digestive organs, she was strongly suspected with CD based on her age, clinical symptoms, and the morphology of the characteristic ulcers (Fig. 2). Consequently, the patient was treated with an elemental diet, mesalamine, and prednisolone for induction therapy. Although this treatment seemed to be partially effective, her symptoms recurred according to the tapering of prednisolone, and she was subsequently switched to adalimumab (ADA). Her clinical symptoms tended to be gradually modest, and the maintenance ADA therapy was effective for some time. The second CE revealed a definite improvement of the intestinal ulcers (Fig. 3a, b); however, 21 months after the initiation of treatment, her intermittent fever and repeated abdominal pain recurred, and re-induction therapy with prednisolone was restarted (Fig. 2). She remained stable for 9 months, before complaining of slight abdominal pain. We set a dose escalation of ADA with the addition of azathioprine; this seemed to be effective, and almost all of the ulcers disappeared, except for a few small erosions on the intestine (Fig. 3c, d). She next relapsed approximately 10 months later, and ADA was switched to ustekinumab (USK). However, this treatment was not sufficient, and prednisolone was added to USK for clinical improvement. Unfortunately, disease management was difficult regardless of these treatments, and skin ulcers appeared about 50 months after her initial hospital visit (Fig. 4a). Immunohistology of her skin biopsy revealed proliferation of EBV-encoded small RNA (EBER)-positive atypical lymphocytes (Fig. 4b, c). Retrospective assessments of the previous ileal ulcer biopsy before treatment demonstrated many EBER-positive lymphocytes, indicating that she had been in a continuously active EBV infection state (Fig. 4d, e). The blood level of EBV-DNA was also clearly positive (1.5 × 104 copy/WBC × 106). Consequently, she was diagnosed with extranodal NK/T-cell lymphoma (nasal type) related to CAEBV. Advanced-stage malignant lymphoma invading the skin was seen. Then, she was treated with a combination of cyclosporine A and prednisolone for her systemic inflammation related to CAEBV and followed by a systemic chemotherapy for malignant lymphoma. After completing the CHOP chemotherapy (cyclophosphamide, doxorubicin, vincristine, and prednisolone), she gradually showed intermediate liver injury as well as cholestasis, based on which she was diagnosed with secondary hemophagocytic lymphohistiocytosis (HLH) caused by CAEBV. Though etoposide and methylprednisolone combination therapy transiently improved her liver injury and jaundice, CHOP insufficiently controlled the progression of CAEBV. Hence, the combination therapy of etoposide, cytosine arabinoside, l-asparaginase, methylprednisolone, and prednisolone (ESCAP) was preferred over the CHOP therapy. However, her liver injury and jaundice related to HLH rapidly worsened during the recovery period after the first ESCAP therapy. Unfortunately, her disease progression could not be regulated at all and she finally fell into the stage of multiple organ failure; she died at the age of 23 years, 55 months after her first hospital visit. An autopsy was performed with the consent from her parents. Macroscopic findings showed no evidence of ulcer or stenotic changes on her digestive organs, including the small intestine (Fig. 5a). Microscopic findings showed no evidence of noncaseating granuloma on digestive organs and a remarkable proliferation of lymphocytes in the intra-mucosal/submucosal space of the small intestine (Fig. 5b, c).Fig. 1 Various forms of ulcers on digestive organs detected by capsule endoscopy prior to treatment. The surrounding mucosa was free from inflammation. a Multiple aphthous ulcers on the jejunum. b Liner ulcers on the jejunum. c Longitudinal ulcers with a cobblestone appearance on the ileum. d Circular ulcers on ileum
Fig. 2 Entire clinical course of the present case
Fig. 3 Findings of the second capsule endoscopic examination. a, b Ulcer scars on the jejunum and ileum (18 months after the first treatment). c, d Small recurrent erosions on the jejunum and ileum (42 months after the first treatment)
Fig. 4 Histological findings of extranodal NK/T-cell lymphoma (nasal type) associated with continuously activated EBV infection. a Macroscopic finding of skin ulcer on the patient’s thigh, which occurred more than 4 years after the initiation of medical treatment. b Microscopic finding of H&E staining of the skin ulcer. c Microscopic findings revealed high proliferation of EBER-positive atypical lymphocytes in the diseased skin. d Microscopic finding of H&E staining in the intestinal ulcer. e Microscopic immunohistological findings of ileal ulcerative lesions revealed moderate infiltration of many EBER-positive lymphocytes, which demonstrated continuously active EBV infection
Fig. 5 Histological findings of the autopsied small intestine. a Macroscopic observation revealed neither ulcerative changes nor stenotic changes in the small intestine. b Microscopic finding of H&E staining of the intestinal tissue. c Microscopic observation revealed mild lymphocyte proliferation with no atrophy of the intestinal villi (large magnification of H&E staining)
Discussion and conclusion
Chachu and Osterman concluded that "Thoughtful consideration and evaluation of these other potential etiologies through patient history and physical examination, laboratory tests, endoscopic evaluation with targeted biopsies of lesions, and cross-sectional imaging is required to evaluate any patient presenting with symptoms consistent with IBD" [7]. However, it is difficult to completely distinguish CAEBV enteritis from IBD by endoscopic findings only, and it is important to comprehend the clinical features of each disease. To appropriately diagnose CAEBV, it is important to remember the possibility of CAEBV as a differential diagnosis of systemic inflammation [8]. When CAEBV is suspected, the EBV-DNA level in peripheral blood should be checked, even in immunologically denied cases of acute EBV infection. Identification of EBV-infected T and NK cells should be performed for definite diagnosis of CAEBV. Moreover, in situ hybridization (ISH) of EBER by pathological examination and EBV-DNA analysis by flow cytometry should be performed. More details are described in the latest diagnostic criteria of CAEBV [5, 9].
To our knowledge, the first report of a case with gastrointestinal tract complications of CAEBV had serious colorectal bleeding [10]. Later, in the 2000s, there were several reports of CAEBV with gastrointestinal tract complications, which had initially been misdiagnosed as IBD [2–4]. Approximately 6% CAEBV-related deaths originated from intestinal bleeding or perforation [6]. As summarized in the Additional file 2: Table S2, the ulcer morphology of “cobblestone appearance” characteristic of CD [11] was first found in our current case, but this was not observed in all 27 previously reported CAEBV-related enteritis cases [2–4, 10, 12, 13]. According to the endoscopic features of these 28 cases, the diseased lesion was located in the colon (13 cases), small intestine (five cases), concomitant colon and small intestine (five cases), concomitant colon and ileocecal junction (one case), concomitant colon and stomach (one case), ileocecal junction (one case), and unknown location (two cases). Ulcer morphologies have generally been reported as small, shallow, irregular-shaped, and scattered, with the exception of eight cases of huge and profound ulcers. There was also a previous case in which the entire intestinal mucosa displayed lymphangiectasia [3]. In our case, many small aphthous ulcers were found in the whole intestine, and a cobblestone appearance was observed, especially in the ileum, whereas no ulcer was found in the colon. These aphthous ulcers remained after intensive treatment with steroids and biologics. Based on these findings, CAEBV-related enteritis might present various ulcer morphologies depending on the reaction of each therapeutic treatment and/or time course. To detect intestinal lesions, we adopted CE, which has been increasingly used worldwide since its establishment in 2000 [14]. With the advent of CE, various diseases have been clearly visualized, resulting in a paradigm shift in the diagnosis and treatment of small bowel disease. According to a nationwide study in Japan, the frequent findings of CE in patients with CD include cobblestone appearance (occurrence rate: 33%), longitudinal ulcer (78%), irregular ulcer (84%), liner erosion (90%), irregular erosion (89%), circumferential alignment of diminutive lesions (75%), and longitudinal alignment of diminutive lesions (56%) [15]. In this previous study, Esaki et al. observed that the endoscopic diagnosis varied in endoscopist’s clinical knowledge and proficiency; hence, this issue should be overcome. In this case, CD was most probable because ulcers with a cobblestone appearance were detected in the ileum. However, other characteristic findings, such as the bamboo joint-like appearance of the gastric mucosa in esophagogastroduodenoscopy, focally enhanced gastritis, and granuloma on histological evaluation were not actually confirmed.
Thus, a final diagnosis should be comprehensively made based on physical symptoms, medical histories, clinical findings, and culture, imaging, and pathological tests. Even if the characteristic endoscopic findings of specific enteritis are detected, differential diagnosis based only on these findings will be difficult because the characteristic findings of endoscopy do not always correspond to the specific disease. Some enteric diseases might show similar endoscopic appearances, whereas the same disease might demonstrate various phenotypes depending on the time course and severity.
Unfortunately, no successful treatment for CAEBV has yet been established, and further research is needed to improve the outcome in the future [16, 17]. Therefore, it is crucial for clinicians to definitely diagnose CAEBV as quickly as possible.
In conclusion, we diagnosed a rare case of CAEBV, with refractory enteritis as the main clinical symptom and without manifestation of a typical IM feature. Diagnosing CAEBV by ulcer morphology is difficult, even with CE and routine histopathological examination only; thus, clinicians should consider CAEBV as a differential diagnosis of refractory enteritis in younger patients and eagerly check blood EBV-DNA and EBER expression levels by ISH.
Patient perspective
The patient's mother kindly told the authors that the patient had decided to fight her disease, though she had well realized the features and general prognosis of CAEBV.
Supplementary Information
Additional file 1: Supplementary Table S1. Results of her blood test on the first admission.
Additional file 2: Supplementary Table S2. Clinical features of the reported CAEBV cases.
Additional file 3: Figure S1. Endoscopic findings of each digestive organ before treatment. (a) Esophagus, (b) stomach, (c) duodenum, (d) terminal ileum, (e) colon, and (f) rectum. Arrow indicates an ulcerative lesion on the terminal ileum.
Abbreviations
CAEBVChronic active Epstein–Barr virus infection
EBVEpstein–Barr virus
CDCrohn’s disease
IBDInflammatory bowel disease
IMInfectious mononucleosis
CECapsule endoscopy
ADAAdalimumab
USKUstekinumab
EBEREBV-encoded small mRNA
ISHIn situ hybridization
HLHHemophagocytic lymphohistiocytosis
Publisher's Note
Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
Supplementary Information
The online version contains supplementary material available at 10.1186/s12876-020-01589-1.
Acknowledgements
The authors deeply appreciate the mercy of the patient and her parents for accepting the autopsy and publication of this report on her illness.
Authors’ contributions
Writing: YA and KM. Editing: KM. Figure preparation: NS, SN, SK, MU, HM, EI, and H Yagi. Supervision: TN, H Yoshiji, and EK. All authors have read and approved the final version of this manuscript.
Funding
There is nothing to declare.
Availability of data and materials
Data on this case not reported in the manuscript are available from the corresponding author upon reasonable request.
Ethics approval and consent to participate
Ethics committee approval is not required for a single presentation retrospectively. In accordance with the “Patient Rights Regulation” (Date: 01.08.1998; Issue: 23420), which was prepared in accordance with international standards, verbal and wet signed written consent was obtained from the patient under the title of “Consent to publish” to publish patient information and support public health.
Consent for publication
The parents of the patient provided written consent for reporting her case in an international published medical journal, including clinical details and images.
Competing interests
The authors confirm that there are no conflicts of interest to declare. | ADALIMUMAB, ASPARAGINASE, CYCLOPHOSPHAMIDE, CYCLOSPORINE, CYTARABINE, DOXORUBICIN, ETOPOSIDE, MESALAMINE, METHYLPREDNISOLONE, PREDNISOLONE, VINCRISTINE | DrugsGivenReaction | CC BY | 33407170 | 19,246,748 | 2021-01-06 |
Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Drug ineffective'. | Chronic active EBV infection in refractory enteritis with longitudinal ulcers with a cobblestone appearance: an autopsied case report.
BACKGROUND
Chronic active Epstein-Barr virus infection (CAEBV) is defined as Epstein-Barr virus (EBV)-positive T/NK cell-related neoplasia, and its major clinical symptom is systemic inflammation presenting as infectious mononucleocytosis, whereas enteritis and diarrhea are minor clinical symptoms. The complex mixture of tumorigenic processes of EBV-positive cells and physical symptoms of systemic inflammatory disease constitutes the varied phenotypes of CAEBV. Herein, we describe a case of CAEBV that was initially diagnosed as Crohn's disease (CD) based on ileal ulcers and clinical symptoms of enteritis.
METHODS
A 19-year-old woman complained of abdominal pain and fever. Blood examination showed normal blood cell counts without atypical lymphocyte but detected modest inflammation, hypoalbuminemia, slight liver dysfunction, and evidence of past EBV infection. The esophagogastroduodenoscopic findings were normal. However, colonoscopy revealed a few small ulcers in the terminal ileum. The jejunum and ileum also exhibited various forms of ulcers, exhibiting a cobblestone appearance, on capsule endoscopy. Based on these clinical findings, she was strongly suspected with CD. In the course of treatment by steroid and biologics for refractory enteritis, skin ulcers appeared about 50 months after her initial hospital visit. Immunohistology of her skin biopsy revealed proliferation of EBV-encoded small RNA (EBER)-positive atypical lymphocytes. We retrospectively assessed her previous ileal ulcer biopsy before treatment and found many EBER-positive lymphocytes. Blood EBV DNA was also positive. Therefore, she was diagnosed with extranodal NK/T-cell lymphoma with CAEBV-related enteritis rather than CD. She was treated with cyclosporine and prednisolone combination therapy for CAEBV-related systemic inflammation and chemotherapy for malignant lymphoma. Unfortunately, her disease continued to progress, leading to multiple organ failure and death at the age of 23 years.
CONCLUSIONS
Clinicians need to remember the possibility of CAEBV as a differential diagnosis of refractory enteritis. Enteritis with intestinal ulcer is a rare symptom of CAEBV, and it is impossible to acquire a definitive diagnosis by ulcer morphology only. In cases where the possibility of CAEBV remains, tissue EBVR expression should be checked by in situ hybridization and blood EBV DNA.
Background
Enteritis is an inflammatory disease of the small intestine caused by some factors, such as bacterial or viral infections, ischemia, vasculitis, chemical or radiological tissue damage, and immune disorders including inflammatory bowel disease (IBD), with phenotype variation [1]. In fact, few cases of chronic active Epstein–Barr virus (CAEBV) reveal enteritis [2–4]. Previously, CAEBV was thought to be a rare child disease limitedly occurring in the East Asia. However, CAEBV has been recently found to occur worldwide with no relation to patient’s age [5]. Although CAEBV is a phenotype of EBV-lymphoproliferative disorders, its major clinical symptom is systemic inflammation presenting as infectious mononucleosis (IM) and enteritis as well as diarrhea are minor clinical symptoms. The complex mixture of tumorigenic processes associated with EBV-positive cells and the physical symptoms of inflammatory systemic disease constitute the varied phenotypes of CAEBV. The median period between the first visit and the definite diagnosis of CAEBV was 20 months. This extended duration was mainly due to the need to first exclude other diseases or cases where patients were diagnosed with unknown fever [6]. Although CAEBV generally presents with IM-like symptoms, we recently experienced a case of a young woman with CAEBV that appeared with refractory enteritis and was indistinguishable from Crohn’s disease (CD). This report of an autopsied CAEBV case will be of educational help, given the difficulty in acquiring a definite diagnosis.
Case presentation
A 19-year-old woman was referred to our hospital for intermittent abdominal pain and continuous fever which had persisted for a month. She had no obvious medical or familial history. Physical examination revealed no morbid lymph node swelling or skin abnormalities. Blood examination showed normal blood cell counts and no presence of atypical lymphocytes. Biochemical or immunoserum analysis revealed modest inflammation, hypoalbuminemia, slight liver dysfunction, and evidence of past EBV infection (Additional file 1: Table S1). Although esophagogastroduodenoscopy revealed normal findings, colonoscopy revealed a few small ulcers in the terminal ileum (Additional file 3: Fig. 1). Enhanced computed tomography showed obvious wall thickness of the small intestine, whereas no significant finding was detected by balloon intestinal endoscopy in the distal ileum. However, various types of ulcers surrounded by completely normal mucosa were found on the jejunum and proximal ileum by capsule endoscopy (CE) (Fig. 1). Additionally, multiple aphthous and some linear ulcers were observed on the jejunum, whereas circular ulcers and longitudinal ulcers with a cobblestone appearance were detected on the ileum. The possibility of intestinal tuberculosis and infectious gastroenteritis were serologically and culturally excluded. Although there were no histological findings of noncaseating granuloma on her digestive organs, she was strongly suspected with CD based on her age, clinical symptoms, and the morphology of the characteristic ulcers (Fig. 2). Consequently, the patient was treated with an elemental diet, mesalamine, and prednisolone for induction therapy. Although this treatment seemed to be partially effective, her symptoms recurred according to the tapering of prednisolone, and she was subsequently switched to adalimumab (ADA). Her clinical symptoms tended to be gradually modest, and the maintenance ADA therapy was effective for some time. The second CE revealed a definite improvement of the intestinal ulcers (Fig. 3a, b); however, 21 months after the initiation of treatment, her intermittent fever and repeated abdominal pain recurred, and re-induction therapy with prednisolone was restarted (Fig. 2). She remained stable for 9 months, before complaining of slight abdominal pain. We set a dose escalation of ADA with the addition of azathioprine; this seemed to be effective, and almost all of the ulcers disappeared, except for a few small erosions on the intestine (Fig. 3c, d). She next relapsed approximately 10 months later, and ADA was switched to ustekinumab (USK). However, this treatment was not sufficient, and prednisolone was added to USK for clinical improvement. Unfortunately, disease management was difficult regardless of these treatments, and skin ulcers appeared about 50 months after her initial hospital visit (Fig. 4a). Immunohistology of her skin biopsy revealed proliferation of EBV-encoded small RNA (EBER)-positive atypical lymphocytes (Fig. 4b, c). Retrospective assessments of the previous ileal ulcer biopsy before treatment demonstrated many EBER-positive lymphocytes, indicating that she had been in a continuously active EBV infection state (Fig. 4d, e). The blood level of EBV-DNA was also clearly positive (1.5 × 104 copy/WBC × 106). Consequently, she was diagnosed with extranodal NK/T-cell lymphoma (nasal type) related to CAEBV. Advanced-stage malignant lymphoma invading the skin was seen. Then, she was treated with a combination of cyclosporine A and prednisolone for her systemic inflammation related to CAEBV and followed by a systemic chemotherapy for malignant lymphoma. After completing the CHOP chemotherapy (cyclophosphamide, doxorubicin, vincristine, and prednisolone), she gradually showed intermediate liver injury as well as cholestasis, based on which she was diagnosed with secondary hemophagocytic lymphohistiocytosis (HLH) caused by CAEBV. Though etoposide and methylprednisolone combination therapy transiently improved her liver injury and jaundice, CHOP insufficiently controlled the progression of CAEBV. Hence, the combination therapy of etoposide, cytosine arabinoside, l-asparaginase, methylprednisolone, and prednisolone (ESCAP) was preferred over the CHOP therapy. However, her liver injury and jaundice related to HLH rapidly worsened during the recovery period after the first ESCAP therapy. Unfortunately, her disease progression could not be regulated at all and she finally fell into the stage of multiple organ failure; she died at the age of 23 years, 55 months after her first hospital visit. An autopsy was performed with the consent from her parents. Macroscopic findings showed no evidence of ulcer or stenotic changes on her digestive organs, including the small intestine (Fig. 5a). Microscopic findings showed no evidence of noncaseating granuloma on digestive organs and a remarkable proliferation of lymphocytes in the intra-mucosal/submucosal space of the small intestine (Fig. 5b, c).Fig. 1 Various forms of ulcers on digestive organs detected by capsule endoscopy prior to treatment. The surrounding mucosa was free from inflammation. a Multiple aphthous ulcers on the jejunum. b Liner ulcers on the jejunum. c Longitudinal ulcers with a cobblestone appearance on the ileum. d Circular ulcers on ileum
Fig. 2 Entire clinical course of the present case
Fig. 3 Findings of the second capsule endoscopic examination. a, b Ulcer scars on the jejunum and ileum (18 months after the first treatment). c, d Small recurrent erosions on the jejunum and ileum (42 months after the first treatment)
Fig. 4 Histological findings of extranodal NK/T-cell lymphoma (nasal type) associated with continuously activated EBV infection. a Macroscopic finding of skin ulcer on the patient’s thigh, which occurred more than 4 years after the initiation of medical treatment. b Microscopic finding of H&E staining of the skin ulcer. c Microscopic findings revealed high proliferation of EBER-positive atypical lymphocytes in the diseased skin. d Microscopic finding of H&E staining in the intestinal ulcer. e Microscopic immunohistological findings of ileal ulcerative lesions revealed moderate infiltration of many EBER-positive lymphocytes, which demonstrated continuously active EBV infection
Fig. 5 Histological findings of the autopsied small intestine. a Macroscopic observation revealed neither ulcerative changes nor stenotic changes in the small intestine. b Microscopic finding of H&E staining of the intestinal tissue. c Microscopic observation revealed mild lymphocyte proliferation with no atrophy of the intestinal villi (large magnification of H&E staining)
Discussion and conclusion
Chachu and Osterman concluded that "Thoughtful consideration and evaluation of these other potential etiologies through patient history and physical examination, laboratory tests, endoscopic evaluation with targeted biopsies of lesions, and cross-sectional imaging is required to evaluate any patient presenting with symptoms consistent with IBD" [7]. However, it is difficult to completely distinguish CAEBV enteritis from IBD by endoscopic findings only, and it is important to comprehend the clinical features of each disease. To appropriately diagnose CAEBV, it is important to remember the possibility of CAEBV as a differential diagnosis of systemic inflammation [8]. When CAEBV is suspected, the EBV-DNA level in peripheral blood should be checked, even in immunologically denied cases of acute EBV infection. Identification of EBV-infected T and NK cells should be performed for definite diagnosis of CAEBV. Moreover, in situ hybridization (ISH) of EBER by pathological examination and EBV-DNA analysis by flow cytometry should be performed. More details are described in the latest diagnostic criteria of CAEBV [5, 9].
To our knowledge, the first report of a case with gastrointestinal tract complications of CAEBV had serious colorectal bleeding [10]. Later, in the 2000s, there were several reports of CAEBV with gastrointestinal tract complications, which had initially been misdiagnosed as IBD [2–4]. Approximately 6% CAEBV-related deaths originated from intestinal bleeding or perforation [6]. As summarized in the Additional file 2: Table S2, the ulcer morphology of “cobblestone appearance” characteristic of CD [11] was first found in our current case, but this was not observed in all 27 previously reported CAEBV-related enteritis cases [2–4, 10, 12, 13]. According to the endoscopic features of these 28 cases, the diseased lesion was located in the colon (13 cases), small intestine (five cases), concomitant colon and small intestine (five cases), concomitant colon and ileocecal junction (one case), concomitant colon and stomach (one case), ileocecal junction (one case), and unknown location (two cases). Ulcer morphologies have generally been reported as small, shallow, irregular-shaped, and scattered, with the exception of eight cases of huge and profound ulcers. There was also a previous case in which the entire intestinal mucosa displayed lymphangiectasia [3]. In our case, many small aphthous ulcers were found in the whole intestine, and a cobblestone appearance was observed, especially in the ileum, whereas no ulcer was found in the colon. These aphthous ulcers remained after intensive treatment with steroids and biologics. Based on these findings, CAEBV-related enteritis might present various ulcer morphologies depending on the reaction of each therapeutic treatment and/or time course. To detect intestinal lesions, we adopted CE, which has been increasingly used worldwide since its establishment in 2000 [14]. With the advent of CE, various diseases have been clearly visualized, resulting in a paradigm shift in the diagnosis and treatment of small bowel disease. According to a nationwide study in Japan, the frequent findings of CE in patients with CD include cobblestone appearance (occurrence rate: 33%), longitudinal ulcer (78%), irregular ulcer (84%), liner erosion (90%), irregular erosion (89%), circumferential alignment of diminutive lesions (75%), and longitudinal alignment of diminutive lesions (56%) [15]. In this previous study, Esaki et al. observed that the endoscopic diagnosis varied in endoscopist’s clinical knowledge and proficiency; hence, this issue should be overcome. In this case, CD was most probable because ulcers with a cobblestone appearance were detected in the ileum. However, other characteristic findings, such as the bamboo joint-like appearance of the gastric mucosa in esophagogastroduodenoscopy, focally enhanced gastritis, and granuloma on histological evaluation were not actually confirmed.
Thus, a final diagnosis should be comprehensively made based on physical symptoms, medical histories, clinical findings, and culture, imaging, and pathological tests. Even if the characteristic endoscopic findings of specific enteritis are detected, differential diagnosis based only on these findings will be difficult because the characteristic findings of endoscopy do not always correspond to the specific disease. Some enteric diseases might show similar endoscopic appearances, whereas the same disease might demonstrate various phenotypes depending on the time course and severity.
Unfortunately, no successful treatment for CAEBV has yet been established, and further research is needed to improve the outcome in the future [16, 17]. Therefore, it is crucial for clinicians to definitely diagnose CAEBV as quickly as possible.
In conclusion, we diagnosed a rare case of CAEBV, with refractory enteritis as the main clinical symptom and without manifestation of a typical IM feature. Diagnosing CAEBV by ulcer morphology is difficult, even with CE and routine histopathological examination only; thus, clinicians should consider CAEBV as a differential diagnosis of refractory enteritis in younger patients and eagerly check blood EBV-DNA and EBER expression levels by ISH.
Patient perspective
The patient's mother kindly told the authors that the patient had decided to fight her disease, though she had well realized the features and general prognosis of CAEBV.
Supplementary Information
Additional file 1: Supplementary Table S1. Results of her blood test on the first admission.
Additional file 2: Supplementary Table S2. Clinical features of the reported CAEBV cases.
Additional file 3: Figure S1. Endoscopic findings of each digestive organ before treatment. (a) Esophagus, (b) stomach, (c) duodenum, (d) terminal ileum, (e) colon, and (f) rectum. Arrow indicates an ulcerative lesion on the terminal ileum.
Abbreviations
CAEBVChronic active Epstein–Barr virus infection
EBVEpstein–Barr virus
CDCrohn’s disease
IBDInflammatory bowel disease
IMInfectious mononucleosis
CECapsule endoscopy
ADAAdalimumab
USKUstekinumab
EBEREBV-encoded small mRNA
ISHIn situ hybridization
HLHHemophagocytic lymphohistiocytosis
Publisher's Note
Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
Supplementary Information
The online version contains supplementary material available at 10.1186/s12876-020-01589-1.
Acknowledgements
The authors deeply appreciate the mercy of the patient and her parents for accepting the autopsy and publication of this report on her illness.
Authors’ contributions
Writing: YA and KM. Editing: KM. Figure preparation: NS, SN, SK, MU, HM, EI, and H Yagi. Supervision: TN, H Yoshiji, and EK. All authors have read and approved the final version of this manuscript.
Funding
There is nothing to declare.
Availability of data and materials
Data on this case not reported in the manuscript are available from the corresponding author upon reasonable request.
Ethics approval and consent to participate
Ethics committee approval is not required for a single presentation retrospectively. In accordance with the “Patient Rights Regulation” (Date: 01.08.1998; Issue: 23420), which was prepared in accordance with international standards, verbal and wet signed written consent was obtained from the patient under the title of “Consent to publish” to publish patient information and support public health.
Consent for publication
The parents of the patient provided written consent for reporting her case in an international published medical journal, including clinical details and images.
Competing interests
The authors confirm that there are no conflicts of interest to declare. | ADALIMUMAB, ASPARAGINASE, CYCLOPHOSPHAMIDE, CYCLOSPORINE, CYTARABINE, DOXORUBICIN, ETOPOSIDE, MESALAMINE, METHYLPREDNISOLONE, PREDNISOLONE, VINCRISTINE | DrugsGivenReaction | CC BY | 33407170 | 19,246,748 | 2021-01-06 |
Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Enteritis'. | Chronic active EBV infection in refractory enteritis with longitudinal ulcers with a cobblestone appearance: an autopsied case report.
BACKGROUND
Chronic active Epstein-Barr virus infection (CAEBV) is defined as Epstein-Barr virus (EBV)-positive T/NK cell-related neoplasia, and its major clinical symptom is systemic inflammation presenting as infectious mononucleocytosis, whereas enteritis and diarrhea are minor clinical symptoms. The complex mixture of tumorigenic processes of EBV-positive cells and physical symptoms of systemic inflammatory disease constitutes the varied phenotypes of CAEBV. Herein, we describe a case of CAEBV that was initially diagnosed as Crohn's disease (CD) based on ileal ulcers and clinical symptoms of enteritis.
METHODS
A 19-year-old woman complained of abdominal pain and fever. Blood examination showed normal blood cell counts without atypical lymphocyte but detected modest inflammation, hypoalbuminemia, slight liver dysfunction, and evidence of past EBV infection. The esophagogastroduodenoscopic findings were normal. However, colonoscopy revealed a few small ulcers in the terminal ileum. The jejunum and ileum also exhibited various forms of ulcers, exhibiting a cobblestone appearance, on capsule endoscopy. Based on these clinical findings, she was strongly suspected with CD. In the course of treatment by steroid and biologics for refractory enteritis, skin ulcers appeared about 50 months after her initial hospital visit. Immunohistology of her skin biopsy revealed proliferation of EBV-encoded small RNA (EBER)-positive atypical lymphocytes. We retrospectively assessed her previous ileal ulcer biopsy before treatment and found many EBER-positive lymphocytes. Blood EBV DNA was also positive. Therefore, she was diagnosed with extranodal NK/T-cell lymphoma with CAEBV-related enteritis rather than CD. She was treated with cyclosporine and prednisolone combination therapy for CAEBV-related systemic inflammation and chemotherapy for malignant lymphoma. Unfortunately, her disease continued to progress, leading to multiple organ failure and death at the age of 23 years.
CONCLUSIONS
Clinicians need to remember the possibility of CAEBV as a differential diagnosis of refractory enteritis. Enteritis with intestinal ulcer is a rare symptom of CAEBV, and it is impossible to acquire a definitive diagnosis by ulcer morphology only. In cases where the possibility of CAEBV remains, tissue EBVR expression should be checked by in situ hybridization and blood EBV DNA.
Background
Enteritis is an inflammatory disease of the small intestine caused by some factors, such as bacterial or viral infections, ischemia, vasculitis, chemical or radiological tissue damage, and immune disorders including inflammatory bowel disease (IBD), with phenotype variation [1]. In fact, few cases of chronic active Epstein–Barr virus (CAEBV) reveal enteritis [2–4]. Previously, CAEBV was thought to be a rare child disease limitedly occurring in the East Asia. However, CAEBV has been recently found to occur worldwide with no relation to patient’s age [5]. Although CAEBV is a phenotype of EBV-lymphoproliferative disorders, its major clinical symptom is systemic inflammation presenting as infectious mononucleosis (IM) and enteritis as well as diarrhea are minor clinical symptoms. The complex mixture of tumorigenic processes associated with EBV-positive cells and the physical symptoms of inflammatory systemic disease constitute the varied phenotypes of CAEBV. The median period between the first visit and the definite diagnosis of CAEBV was 20 months. This extended duration was mainly due to the need to first exclude other diseases or cases where patients were diagnosed with unknown fever [6]. Although CAEBV generally presents with IM-like symptoms, we recently experienced a case of a young woman with CAEBV that appeared with refractory enteritis and was indistinguishable from Crohn’s disease (CD). This report of an autopsied CAEBV case will be of educational help, given the difficulty in acquiring a definite diagnosis.
Case presentation
A 19-year-old woman was referred to our hospital for intermittent abdominal pain and continuous fever which had persisted for a month. She had no obvious medical or familial history. Physical examination revealed no morbid lymph node swelling or skin abnormalities. Blood examination showed normal blood cell counts and no presence of atypical lymphocytes. Biochemical or immunoserum analysis revealed modest inflammation, hypoalbuminemia, slight liver dysfunction, and evidence of past EBV infection (Additional file 1: Table S1). Although esophagogastroduodenoscopy revealed normal findings, colonoscopy revealed a few small ulcers in the terminal ileum (Additional file 3: Fig. 1). Enhanced computed tomography showed obvious wall thickness of the small intestine, whereas no significant finding was detected by balloon intestinal endoscopy in the distal ileum. However, various types of ulcers surrounded by completely normal mucosa were found on the jejunum and proximal ileum by capsule endoscopy (CE) (Fig. 1). Additionally, multiple aphthous and some linear ulcers were observed on the jejunum, whereas circular ulcers and longitudinal ulcers with a cobblestone appearance were detected on the ileum. The possibility of intestinal tuberculosis and infectious gastroenteritis were serologically and culturally excluded. Although there were no histological findings of noncaseating granuloma on her digestive organs, she was strongly suspected with CD based on her age, clinical symptoms, and the morphology of the characteristic ulcers (Fig. 2). Consequently, the patient was treated with an elemental diet, mesalamine, and prednisolone for induction therapy. Although this treatment seemed to be partially effective, her symptoms recurred according to the tapering of prednisolone, and she was subsequently switched to adalimumab (ADA). Her clinical symptoms tended to be gradually modest, and the maintenance ADA therapy was effective for some time. The second CE revealed a definite improvement of the intestinal ulcers (Fig. 3a, b); however, 21 months after the initiation of treatment, her intermittent fever and repeated abdominal pain recurred, and re-induction therapy with prednisolone was restarted (Fig. 2). She remained stable for 9 months, before complaining of slight abdominal pain. We set a dose escalation of ADA with the addition of azathioprine; this seemed to be effective, and almost all of the ulcers disappeared, except for a few small erosions on the intestine (Fig. 3c, d). She next relapsed approximately 10 months later, and ADA was switched to ustekinumab (USK). However, this treatment was not sufficient, and prednisolone was added to USK for clinical improvement. Unfortunately, disease management was difficult regardless of these treatments, and skin ulcers appeared about 50 months after her initial hospital visit (Fig. 4a). Immunohistology of her skin biopsy revealed proliferation of EBV-encoded small RNA (EBER)-positive atypical lymphocytes (Fig. 4b, c). Retrospective assessments of the previous ileal ulcer biopsy before treatment demonstrated many EBER-positive lymphocytes, indicating that she had been in a continuously active EBV infection state (Fig. 4d, e). The blood level of EBV-DNA was also clearly positive (1.5 × 104 copy/WBC × 106). Consequently, she was diagnosed with extranodal NK/T-cell lymphoma (nasal type) related to CAEBV. Advanced-stage malignant lymphoma invading the skin was seen. Then, she was treated with a combination of cyclosporine A and prednisolone for her systemic inflammation related to CAEBV and followed by a systemic chemotherapy for malignant lymphoma. After completing the CHOP chemotherapy (cyclophosphamide, doxorubicin, vincristine, and prednisolone), she gradually showed intermediate liver injury as well as cholestasis, based on which she was diagnosed with secondary hemophagocytic lymphohistiocytosis (HLH) caused by CAEBV. Though etoposide and methylprednisolone combination therapy transiently improved her liver injury and jaundice, CHOP insufficiently controlled the progression of CAEBV. Hence, the combination therapy of etoposide, cytosine arabinoside, l-asparaginase, methylprednisolone, and prednisolone (ESCAP) was preferred over the CHOP therapy. However, her liver injury and jaundice related to HLH rapidly worsened during the recovery period after the first ESCAP therapy. Unfortunately, her disease progression could not be regulated at all and she finally fell into the stage of multiple organ failure; she died at the age of 23 years, 55 months after her first hospital visit. An autopsy was performed with the consent from her parents. Macroscopic findings showed no evidence of ulcer or stenotic changes on her digestive organs, including the small intestine (Fig. 5a). Microscopic findings showed no evidence of noncaseating granuloma on digestive organs and a remarkable proliferation of lymphocytes in the intra-mucosal/submucosal space of the small intestine (Fig. 5b, c).Fig. 1 Various forms of ulcers on digestive organs detected by capsule endoscopy prior to treatment. The surrounding mucosa was free from inflammation. a Multiple aphthous ulcers on the jejunum. b Liner ulcers on the jejunum. c Longitudinal ulcers with a cobblestone appearance on the ileum. d Circular ulcers on ileum
Fig. 2 Entire clinical course of the present case
Fig. 3 Findings of the second capsule endoscopic examination. a, b Ulcer scars on the jejunum and ileum (18 months after the first treatment). c, d Small recurrent erosions on the jejunum and ileum (42 months after the first treatment)
Fig. 4 Histological findings of extranodal NK/T-cell lymphoma (nasal type) associated with continuously activated EBV infection. a Macroscopic finding of skin ulcer on the patient’s thigh, which occurred more than 4 years after the initiation of medical treatment. b Microscopic finding of H&E staining of the skin ulcer. c Microscopic findings revealed high proliferation of EBER-positive atypical lymphocytes in the diseased skin. d Microscopic finding of H&E staining in the intestinal ulcer. e Microscopic immunohistological findings of ileal ulcerative lesions revealed moderate infiltration of many EBER-positive lymphocytes, which demonstrated continuously active EBV infection
Fig. 5 Histological findings of the autopsied small intestine. a Macroscopic observation revealed neither ulcerative changes nor stenotic changes in the small intestine. b Microscopic finding of H&E staining of the intestinal tissue. c Microscopic observation revealed mild lymphocyte proliferation with no atrophy of the intestinal villi (large magnification of H&E staining)
Discussion and conclusion
Chachu and Osterman concluded that "Thoughtful consideration and evaluation of these other potential etiologies through patient history and physical examination, laboratory tests, endoscopic evaluation with targeted biopsies of lesions, and cross-sectional imaging is required to evaluate any patient presenting with symptoms consistent with IBD" [7]. However, it is difficult to completely distinguish CAEBV enteritis from IBD by endoscopic findings only, and it is important to comprehend the clinical features of each disease. To appropriately diagnose CAEBV, it is important to remember the possibility of CAEBV as a differential diagnosis of systemic inflammation [8]. When CAEBV is suspected, the EBV-DNA level in peripheral blood should be checked, even in immunologically denied cases of acute EBV infection. Identification of EBV-infected T and NK cells should be performed for definite diagnosis of CAEBV. Moreover, in situ hybridization (ISH) of EBER by pathological examination and EBV-DNA analysis by flow cytometry should be performed. More details are described in the latest diagnostic criteria of CAEBV [5, 9].
To our knowledge, the first report of a case with gastrointestinal tract complications of CAEBV had serious colorectal bleeding [10]. Later, in the 2000s, there were several reports of CAEBV with gastrointestinal tract complications, which had initially been misdiagnosed as IBD [2–4]. Approximately 6% CAEBV-related deaths originated from intestinal bleeding or perforation [6]. As summarized in the Additional file 2: Table S2, the ulcer morphology of “cobblestone appearance” characteristic of CD [11] was first found in our current case, but this was not observed in all 27 previously reported CAEBV-related enteritis cases [2–4, 10, 12, 13]. According to the endoscopic features of these 28 cases, the diseased lesion was located in the colon (13 cases), small intestine (five cases), concomitant colon and small intestine (five cases), concomitant colon and ileocecal junction (one case), concomitant colon and stomach (one case), ileocecal junction (one case), and unknown location (two cases). Ulcer morphologies have generally been reported as small, shallow, irregular-shaped, and scattered, with the exception of eight cases of huge and profound ulcers. There was also a previous case in which the entire intestinal mucosa displayed lymphangiectasia [3]. In our case, many small aphthous ulcers were found in the whole intestine, and a cobblestone appearance was observed, especially in the ileum, whereas no ulcer was found in the colon. These aphthous ulcers remained after intensive treatment with steroids and biologics. Based on these findings, CAEBV-related enteritis might present various ulcer morphologies depending on the reaction of each therapeutic treatment and/or time course. To detect intestinal lesions, we adopted CE, which has been increasingly used worldwide since its establishment in 2000 [14]. With the advent of CE, various diseases have been clearly visualized, resulting in a paradigm shift in the diagnosis and treatment of small bowel disease. According to a nationwide study in Japan, the frequent findings of CE in patients with CD include cobblestone appearance (occurrence rate: 33%), longitudinal ulcer (78%), irregular ulcer (84%), liner erosion (90%), irregular erosion (89%), circumferential alignment of diminutive lesions (75%), and longitudinal alignment of diminutive lesions (56%) [15]. In this previous study, Esaki et al. observed that the endoscopic diagnosis varied in endoscopist’s clinical knowledge and proficiency; hence, this issue should be overcome. In this case, CD was most probable because ulcers with a cobblestone appearance were detected in the ileum. However, other characteristic findings, such as the bamboo joint-like appearance of the gastric mucosa in esophagogastroduodenoscopy, focally enhanced gastritis, and granuloma on histological evaluation were not actually confirmed.
Thus, a final diagnosis should be comprehensively made based on physical symptoms, medical histories, clinical findings, and culture, imaging, and pathological tests. Even if the characteristic endoscopic findings of specific enteritis are detected, differential diagnosis based only on these findings will be difficult because the characteristic findings of endoscopy do not always correspond to the specific disease. Some enteric diseases might show similar endoscopic appearances, whereas the same disease might demonstrate various phenotypes depending on the time course and severity.
Unfortunately, no successful treatment for CAEBV has yet been established, and further research is needed to improve the outcome in the future [16, 17]. Therefore, it is crucial for clinicians to definitely diagnose CAEBV as quickly as possible.
In conclusion, we diagnosed a rare case of CAEBV, with refractory enteritis as the main clinical symptom and without manifestation of a typical IM feature. Diagnosing CAEBV by ulcer morphology is difficult, even with CE and routine histopathological examination only; thus, clinicians should consider CAEBV as a differential diagnosis of refractory enteritis in younger patients and eagerly check blood EBV-DNA and EBER expression levels by ISH.
Patient perspective
The patient's mother kindly told the authors that the patient had decided to fight her disease, though she had well realized the features and general prognosis of CAEBV.
Supplementary Information
Additional file 1: Supplementary Table S1. Results of her blood test on the first admission.
Additional file 2: Supplementary Table S2. Clinical features of the reported CAEBV cases.
Additional file 3: Figure S1. Endoscopic findings of each digestive organ before treatment. (a) Esophagus, (b) stomach, (c) duodenum, (d) terminal ileum, (e) colon, and (f) rectum. Arrow indicates an ulcerative lesion on the terminal ileum.
Abbreviations
CAEBVChronic active Epstein–Barr virus infection
EBVEpstein–Barr virus
CDCrohn’s disease
IBDInflammatory bowel disease
IMInfectious mononucleosis
CECapsule endoscopy
ADAAdalimumab
USKUstekinumab
EBEREBV-encoded small mRNA
ISHIn situ hybridization
HLHHemophagocytic lymphohistiocytosis
Publisher's Note
Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
Supplementary Information
The online version contains supplementary material available at 10.1186/s12876-020-01589-1.
Acknowledgements
The authors deeply appreciate the mercy of the patient and her parents for accepting the autopsy and publication of this report on her illness.
Authors’ contributions
Writing: YA and KM. Editing: KM. Figure preparation: NS, SN, SK, MU, HM, EI, and H Yagi. Supervision: TN, H Yoshiji, and EK. All authors have read and approved the final version of this manuscript.
Funding
There is nothing to declare.
Availability of data and materials
Data on this case not reported in the manuscript are available from the corresponding author upon reasonable request.
Ethics approval and consent to participate
Ethics committee approval is not required for a single presentation retrospectively. In accordance with the “Patient Rights Regulation” (Date: 01.08.1998; Issue: 23420), which was prepared in accordance with international standards, verbal and wet signed written consent was obtained from the patient under the title of “Consent to publish” to publish patient information and support public health.
Consent for publication
The parents of the patient provided written consent for reporting her case in an international published medical journal, including clinical details and images.
Competing interests
The authors confirm that there are no conflicts of interest to declare. | ADALIMUMAB, AZATHIOPRINE | DrugsGivenReaction | CC BY | 33407170 | 19,233,908 | 2021-01-06 |
Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Epstein-Barr virus infection'. | Chronic active EBV infection in refractory enteritis with longitudinal ulcers with a cobblestone appearance: an autopsied case report.
BACKGROUND
Chronic active Epstein-Barr virus infection (CAEBV) is defined as Epstein-Barr virus (EBV)-positive T/NK cell-related neoplasia, and its major clinical symptom is systemic inflammation presenting as infectious mononucleocytosis, whereas enteritis and diarrhea are minor clinical symptoms. The complex mixture of tumorigenic processes of EBV-positive cells and physical symptoms of systemic inflammatory disease constitutes the varied phenotypes of CAEBV. Herein, we describe a case of CAEBV that was initially diagnosed as Crohn's disease (CD) based on ileal ulcers and clinical symptoms of enteritis.
METHODS
A 19-year-old woman complained of abdominal pain and fever. Blood examination showed normal blood cell counts without atypical lymphocyte but detected modest inflammation, hypoalbuminemia, slight liver dysfunction, and evidence of past EBV infection. The esophagogastroduodenoscopic findings were normal. However, colonoscopy revealed a few small ulcers in the terminal ileum. The jejunum and ileum also exhibited various forms of ulcers, exhibiting a cobblestone appearance, on capsule endoscopy. Based on these clinical findings, she was strongly suspected with CD. In the course of treatment by steroid and biologics for refractory enteritis, skin ulcers appeared about 50 months after her initial hospital visit. Immunohistology of her skin biopsy revealed proliferation of EBV-encoded small RNA (EBER)-positive atypical lymphocytes. We retrospectively assessed her previous ileal ulcer biopsy before treatment and found many EBER-positive lymphocytes. Blood EBV DNA was also positive. Therefore, she was diagnosed with extranodal NK/T-cell lymphoma with CAEBV-related enteritis rather than CD. She was treated with cyclosporine and prednisolone combination therapy for CAEBV-related systemic inflammation and chemotherapy for malignant lymphoma. Unfortunately, her disease continued to progress, leading to multiple organ failure and death at the age of 23 years.
CONCLUSIONS
Clinicians need to remember the possibility of CAEBV as a differential diagnosis of refractory enteritis. Enteritis with intestinal ulcer is a rare symptom of CAEBV, and it is impossible to acquire a definitive diagnosis by ulcer morphology only. In cases where the possibility of CAEBV remains, tissue EBVR expression should be checked by in situ hybridization and blood EBV DNA.
Background
Enteritis is an inflammatory disease of the small intestine caused by some factors, such as bacterial or viral infections, ischemia, vasculitis, chemical or radiological tissue damage, and immune disorders including inflammatory bowel disease (IBD), with phenotype variation [1]. In fact, few cases of chronic active Epstein–Barr virus (CAEBV) reveal enteritis [2–4]. Previously, CAEBV was thought to be a rare child disease limitedly occurring in the East Asia. However, CAEBV has been recently found to occur worldwide with no relation to patient’s age [5]. Although CAEBV is a phenotype of EBV-lymphoproliferative disorders, its major clinical symptom is systemic inflammation presenting as infectious mononucleosis (IM) and enteritis as well as diarrhea are minor clinical symptoms. The complex mixture of tumorigenic processes associated with EBV-positive cells and the physical symptoms of inflammatory systemic disease constitute the varied phenotypes of CAEBV. The median period between the first visit and the definite diagnosis of CAEBV was 20 months. This extended duration was mainly due to the need to first exclude other diseases or cases where patients were diagnosed with unknown fever [6]. Although CAEBV generally presents with IM-like symptoms, we recently experienced a case of a young woman with CAEBV that appeared with refractory enteritis and was indistinguishable from Crohn’s disease (CD). This report of an autopsied CAEBV case will be of educational help, given the difficulty in acquiring a definite diagnosis.
Case presentation
A 19-year-old woman was referred to our hospital for intermittent abdominal pain and continuous fever which had persisted for a month. She had no obvious medical or familial history. Physical examination revealed no morbid lymph node swelling or skin abnormalities. Blood examination showed normal blood cell counts and no presence of atypical lymphocytes. Biochemical or immunoserum analysis revealed modest inflammation, hypoalbuminemia, slight liver dysfunction, and evidence of past EBV infection (Additional file 1: Table S1). Although esophagogastroduodenoscopy revealed normal findings, colonoscopy revealed a few small ulcers in the terminal ileum (Additional file 3: Fig. 1). Enhanced computed tomography showed obvious wall thickness of the small intestine, whereas no significant finding was detected by balloon intestinal endoscopy in the distal ileum. However, various types of ulcers surrounded by completely normal mucosa were found on the jejunum and proximal ileum by capsule endoscopy (CE) (Fig. 1). Additionally, multiple aphthous and some linear ulcers were observed on the jejunum, whereas circular ulcers and longitudinal ulcers with a cobblestone appearance were detected on the ileum. The possibility of intestinal tuberculosis and infectious gastroenteritis were serologically and culturally excluded. Although there were no histological findings of noncaseating granuloma on her digestive organs, she was strongly suspected with CD based on her age, clinical symptoms, and the morphology of the characteristic ulcers (Fig. 2). Consequently, the patient was treated with an elemental diet, mesalamine, and prednisolone for induction therapy. Although this treatment seemed to be partially effective, her symptoms recurred according to the tapering of prednisolone, and she was subsequently switched to adalimumab (ADA). Her clinical symptoms tended to be gradually modest, and the maintenance ADA therapy was effective for some time. The second CE revealed a definite improvement of the intestinal ulcers (Fig. 3a, b); however, 21 months after the initiation of treatment, her intermittent fever and repeated abdominal pain recurred, and re-induction therapy with prednisolone was restarted (Fig. 2). She remained stable for 9 months, before complaining of slight abdominal pain. We set a dose escalation of ADA with the addition of azathioprine; this seemed to be effective, and almost all of the ulcers disappeared, except for a few small erosions on the intestine (Fig. 3c, d). She next relapsed approximately 10 months later, and ADA was switched to ustekinumab (USK). However, this treatment was not sufficient, and prednisolone was added to USK for clinical improvement. Unfortunately, disease management was difficult regardless of these treatments, and skin ulcers appeared about 50 months after her initial hospital visit (Fig. 4a). Immunohistology of her skin biopsy revealed proliferation of EBV-encoded small RNA (EBER)-positive atypical lymphocytes (Fig. 4b, c). Retrospective assessments of the previous ileal ulcer biopsy before treatment demonstrated many EBER-positive lymphocytes, indicating that she had been in a continuously active EBV infection state (Fig. 4d, e). The blood level of EBV-DNA was also clearly positive (1.5 × 104 copy/WBC × 106). Consequently, she was diagnosed with extranodal NK/T-cell lymphoma (nasal type) related to CAEBV. Advanced-stage malignant lymphoma invading the skin was seen. Then, she was treated with a combination of cyclosporine A and prednisolone for her systemic inflammation related to CAEBV and followed by a systemic chemotherapy for malignant lymphoma. After completing the CHOP chemotherapy (cyclophosphamide, doxorubicin, vincristine, and prednisolone), she gradually showed intermediate liver injury as well as cholestasis, based on which she was diagnosed with secondary hemophagocytic lymphohistiocytosis (HLH) caused by CAEBV. Though etoposide and methylprednisolone combination therapy transiently improved her liver injury and jaundice, CHOP insufficiently controlled the progression of CAEBV. Hence, the combination therapy of etoposide, cytosine arabinoside, l-asparaginase, methylprednisolone, and prednisolone (ESCAP) was preferred over the CHOP therapy. However, her liver injury and jaundice related to HLH rapidly worsened during the recovery period after the first ESCAP therapy. Unfortunately, her disease progression could not be regulated at all and she finally fell into the stage of multiple organ failure; she died at the age of 23 years, 55 months after her first hospital visit. An autopsy was performed with the consent from her parents. Macroscopic findings showed no evidence of ulcer or stenotic changes on her digestive organs, including the small intestine (Fig. 5a). Microscopic findings showed no evidence of noncaseating granuloma on digestive organs and a remarkable proliferation of lymphocytes in the intra-mucosal/submucosal space of the small intestine (Fig. 5b, c).Fig. 1 Various forms of ulcers on digestive organs detected by capsule endoscopy prior to treatment. The surrounding mucosa was free from inflammation. a Multiple aphthous ulcers on the jejunum. b Liner ulcers on the jejunum. c Longitudinal ulcers with a cobblestone appearance on the ileum. d Circular ulcers on ileum
Fig. 2 Entire clinical course of the present case
Fig. 3 Findings of the second capsule endoscopic examination. a, b Ulcer scars on the jejunum and ileum (18 months after the first treatment). c, d Small recurrent erosions on the jejunum and ileum (42 months after the first treatment)
Fig. 4 Histological findings of extranodal NK/T-cell lymphoma (nasal type) associated with continuously activated EBV infection. a Macroscopic finding of skin ulcer on the patient’s thigh, which occurred more than 4 years after the initiation of medical treatment. b Microscopic finding of H&E staining of the skin ulcer. c Microscopic findings revealed high proliferation of EBER-positive atypical lymphocytes in the diseased skin. d Microscopic finding of H&E staining in the intestinal ulcer. e Microscopic immunohistological findings of ileal ulcerative lesions revealed moderate infiltration of many EBER-positive lymphocytes, which demonstrated continuously active EBV infection
Fig. 5 Histological findings of the autopsied small intestine. a Macroscopic observation revealed neither ulcerative changes nor stenotic changes in the small intestine. b Microscopic finding of H&E staining of the intestinal tissue. c Microscopic observation revealed mild lymphocyte proliferation with no atrophy of the intestinal villi (large magnification of H&E staining)
Discussion and conclusion
Chachu and Osterman concluded that "Thoughtful consideration and evaluation of these other potential etiologies through patient history and physical examination, laboratory tests, endoscopic evaluation with targeted biopsies of lesions, and cross-sectional imaging is required to evaluate any patient presenting with symptoms consistent with IBD" [7]. However, it is difficult to completely distinguish CAEBV enteritis from IBD by endoscopic findings only, and it is important to comprehend the clinical features of each disease. To appropriately diagnose CAEBV, it is important to remember the possibility of CAEBV as a differential diagnosis of systemic inflammation [8]. When CAEBV is suspected, the EBV-DNA level in peripheral blood should be checked, even in immunologically denied cases of acute EBV infection. Identification of EBV-infected T and NK cells should be performed for definite diagnosis of CAEBV. Moreover, in situ hybridization (ISH) of EBER by pathological examination and EBV-DNA analysis by flow cytometry should be performed. More details are described in the latest diagnostic criteria of CAEBV [5, 9].
To our knowledge, the first report of a case with gastrointestinal tract complications of CAEBV had serious colorectal bleeding [10]. Later, in the 2000s, there were several reports of CAEBV with gastrointestinal tract complications, which had initially been misdiagnosed as IBD [2–4]. Approximately 6% CAEBV-related deaths originated from intestinal bleeding or perforation [6]. As summarized in the Additional file 2: Table S2, the ulcer morphology of “cobblestone appearance” characteristic of CD [11] was first found in our current case, but this was not observed in all 27 previously reported CAEBV-related enteritis cases [2–4, 10, 12, 13]. According to the endoscopic features of these 28 cases, the diseased lesion was located in the colon (13 cases), small intestine (five cases), concomitant colon and small intestine (five cases), concomitant colon and ileocecal junction (one case), concomitant colon and stomach (one case), ileocecal junction (one case), and unknown location (two cases). Ulcer morphologies have generally been reported as small, shallow, irregular-shaped, and scattered, with the exception of eight cases of huge and profound ulcers. There was also a previous case in which the entire intestinal mucosa displayed lymphangiectasia [3]. In our case, many small aphthous ulcers were found in the whole intestine, and a cobblestone appearance was observed, especially in the ileum, whereas no ulcer was found in the colon. These aphthous ulcers remained after intensive treatment with steroids and biologics. Based on these findings, CAEBV-related enteritis might present various ulcer morphologies depending on the reaction of each therapeutic treatment and/or time course. To detect intestinal lesions, we adopted CE, which has been increasingly used worldwide since its establishment in 2000 [14]. With the advent of CE, various diseases have been clearly visualized, resulting in a paradigm shift in the diagnosis and treatment of small bowel disease. According to a nationwide study in Japan, the frequent findings of CE in patients with CD include cobblestone appearance (occurrence rate: 33%), longitudinal ulcer (78%), irregular ulcer (84%), liner erosion (90%), irregular erosion (89%), circumferential alignment of diminutive lesions (75%), and longitudinal alignment of diminutive lesions (56%) [15]. In this previous study, Esaki et al. observed that the endoscopic diagnosis varied in endoscopist’s clinical knowledge and proficiency; hence, this issue should be overcome. In this case, CD was most probable because ulcers with a cobblestone appearance were detected in the ileum. However, other characteristic findings, such as the bamboo joint-like appearance of the gastric mucosa in esophagogastroduodenoscopy, focally enhanced gastritis, and granuloma on histological evaluation were not actually confirmed.
Thus, a final diagnosis should be comprehensively made based on physical symptoms, medical histories, clinical findings, and culture, imaging, and pathological tests. Even if the characteristic endoscopic findings of specific enteritis are detected, differential diagnosis based only on these findings will be difficult because the characteristic findings of endoscopy do not always correspond to the specific disease. Some enteric diseases might show similar endoscopic appearances, whereas the same disease might demonstrate various phenotypes depending on the time course and severity.
Unfortunately, no successful treatment for CAEBV has yet been established, and further research is needed to improve the outcome in the future [16, 17]. Therefore, it is crucial for clinicians to definitely diagnose CAEBV as quickly as possible.
In conclusion, we diagnosed a rare case of CAEBV, with refractory enteritis as the main clinical symptom and without manifestation of a typical IM feature. Diagnosing CAEBV by ulcer morphology is difficult, even with CE and routine histopathological examination only; thus, clinicians should consider CAEBV as a differential diagnosis of refractory enteritis in younger patients and eagerly check blood EBV-DNA and EBER expression levels by ISH.
Patient perspective
The patient's mother kindly told the authors that the patient had decided to fight her disease, though she had well realized the features and general prognosis of CAEBV.
Supplementary Information
Additional file 1: Supplementary Table S1. Results of her blood test on the first admission.
Additional file 2: Supplementary Table S2. Clinical features of the reported CAEBV cases.
Additional file 3: Figure S1. Endoscopic findings of each digestive organ before treatment. (a) Esophagus, (b) stomach, (c) duodenum, (d) terminal ileum, (e) colon, and (f) rectum. Arrow indicates an ulcerative lesion on the terminal ileum.
Abbreviations
CAEBVChronic active Epstein–Barr virus infection
EBVEpstein–Barr virus
CDCrohn’s disease
IBDInflammatory bowel disease
IMInfectious mononucleosis
CECapsule endoscopy
ADAAdalimumab
USKUstekinumab
EBEREBV-encoded small mRNA
ISHIn situ hybridization
HLHHemophagocytic lymphohistiocytosis
Publisher's Note
Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
Supplementary Information
The online version contains supplementary material available at 10.1186/s12876-020-01589-1.
Acknowledgements
The authors deeply appreciate the mercy of the patient and her parents for accepting the autopsy and publication of this report on her illness.
Authors’ contributions
Writing: YA and KM. Editing: KM. Figure preparation: NS, SN, SK, MU, HM, EI, and H Yagi. Supervision: TN, H Yoshiji, and EK. All authors have read and approved the final version of this manuscript.
Funding
There is nothing to declare.
Availability of data and materials
Data on this case not reported in the manuscript are available from the corresponding author upon reasonable request.
Ethics approval and consent to participate
Ethics committee approval is not required for a single presentation retrospectively. In accordance with the “Patient Rights Regulation” (Date: 01.08.1998; Issue: 23420), which was prepared in accordance with international standards, verbal and wet signed written consent was obtained from the patient under the title of “Consent to publish” to publish patient information and support public health.
Consent for publication
The parents of the patient provided written consent for reporting her case in an international published medical journal, including clinical details and images.
Competing interests
The authors confirm that there are no conflicts of interest to declare. | ADALIMUMAB, ASPARAGINASE, CYCLOPHOSPHAMIDE, CYCLOSPORINE, CYTARABINE, DOXORUBICIN, ETOPOSIDE, MESALAMINE, METHYLPREDNISOLONE, PREDNISOLONE, VINCRISTINE | DrugsGivenReaction | CC BY | 33407170 | 19,246,748 | 2021-01-06 |
Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Haemophagocytic lymphohistiocytosis'. | Chronic active EBV infection in refractory enteritis with longitudinal ulcers with a cobblestone appearance: an autopsied case report.
BACKGROUND
Chronic active Epstein-Barr virus infection (CAEBV) is defined as Epstein-Barr virus (EBV)-positive T/NK cell-related neoplasia, and its major clinical symptom is systemic inflammation presenting as infectious mononucleocytosis, whereas enteritis and diarrhea are minor clinical symptoms. The complex mixture of tumorigenic processes of EBV-positive cells and physical symptoms of systemic inflammatory disease constitutes the varied phenotypes of CAEBV. Herein, we describe a case of CAEBV that was initially diagnosed as Crohn's disease (CD) based on ileal ulcers and clinical symptoms of enteritis.
METHODS
A 19-year-old woman complained of abdominal pain and fever. Blood examination showed normal blood cell counts without atypical lymphocyte but detected modest inflammation, hypoalbuminemia, slight liver dysfunction, and evidence of past EBV infection. The esophagogastroduodenoscopic findings were normal. However, colonoscopy revealed a few small ulcers in the terminal ileum. The jejunum and ileum also exhibited various forms of ulcers, exhibiting a cobblestone appearance, on capsule endoscopy. Based on these clinical findings, she was strongly suspected with CD. In the course of treatment by steroid and biologics for refractory enteritis, skin ulcers appeared about 50 months after her initial hospital visit. Immunohistology of her skin biopsy revealed proliferation of EBV-encoded small RNA (EBER)-positive atypical lymphocytes. We retrospectively assessed her previous ileal ulcer biopsy before treatment and found many EBER-positive lymphocytes. Blood EBV DNA was also positive. Therefore, she was diagnosed with extranodal NK/T-cell lymphoma with CAEBV-related enteritis rather than CD. She was treated with cyclosporine and prednisolone combination therapy for CAEBV-related systemic inflammation and chemotherapy for malignant lymphoma. Unfortunately, her disease continued to progress, leading to multiple organ failure and death at the age of 23 years.
CONCLUSIONS
Clinicians need to remember the possibility of CAEBV as a differential diagnosis of refractory enteritis. Enteritis with intestinal ulcer is a rare symptom of CAEBV, and it is impossible to acquire a definitive diagnosis by ulcer morphology only. In cases where the possibility of CAEBV remains, tissue EBVR expression should be checked by in situ hybridization and blood EBV DNA.
Background
Enteritis is an inflammatory disease of the small intestine caused by some factors, such as bacterial or viral infections, ischemia, vasculitis, chemical or radiological tissue damage, and immune disorders including inflammatory bowel disease (IBD), with phenotype variation [1]. In fact, few cases of chronic active Epstein–Barr virus (CAEBV) reveal enteritis [2–4]. Previously, CAEBV was thought to be a rare child disease limitedly occurring in the East Asia. However, CAEBV has been recently found to occur worldwide with no relation to patient’s age [5]. Although CAEBV is a phenotype of EBV-lymphoproliferative disorders, its major clinical symptom is systemic inflammation presenting as infectious mononucleosis (IM) and enteritis as well as diarrhea are minor clinical symptoms. The complex mixture of tumorigenic processes associated with EBV-positive cells and the physical symptoms of inflammatory systemic disease constitute the varied phenotypes of CAEBV. The median period between the first visit and the definite diagnosis of CAEBV was 20 months. This extended duration was mainly due to the need to first exclude other diseases or cases where patients were diagnosed with unknown fever [6]. Although CAEBV generally presents with IM-like symptoms, we recently experienced a case of a young woman with CAEBV that appeared with refractory enteritis and was indistinguishable from Crohn’s disease (CD). This report of an autopsied CAEBV case will be of educational help, given the difficulty in acquiring a definite diagnosis.
Case presentation
A 19-year-old woman was referred to our hospital for intermittent abdominal pain and continuous fever which had persisted for a month. She had no obvious medical or familial history. Physical examination revealed no morbid lymph node swelling or skin abnormalities. Blood examination showed normal blood cell counts and no presence of atypical lymphocytes. Biochemical or immunoserum analysis revealed modest inflammation, hypoalbuminemia, slight liver dysfunction, and evidence of past EBV infection (Additional file 1: Table S1). Although esophagogastroduodenoscopy revealed normal findings, colonoscopy revealed a few small ulcers in the terminal ileum (Additional file 3: Fig. 1). Enhanced computed tomography showed obvious wall thickness of the small intestine, whereas no significant finding was detected by balloon intestinal endoscopy in the distal ileum. However, various types of ulcers surrounded by completely normal mucosa were found on the jejunum and proximal ileum by capsule endoscopy (CE) (Fig. 1). Additionally, multiple aphthous and some linear ulcers were observed on the jejunum, whereas circular ulcers and longitudinal ulcers with a cobblestone appearance were detected on the ileum. The possibility of intestinal tuberculosis and infectious gastroenteritis were serologically and culturally excluded. Although there were no histological findings of noncaseating granuloma on her digestive organs, she was strongly suspected with CD based on her age, clinical symptoms, and the morphology of the characteristic ulcers (Fig. 2). Consequently, the patient was treated with an elemental diet, mesalamine, and prednisolone for induction therapy. Although this treatment seemed to be partially effective, her symptoms recurred according to the tapering of prednisolone, and she was subsequently switched to adalimumab (ADA). Her clinical symptoms tended to be gradually modest, and the maintenance ADA therapy was effective for some time. The second CE revealed a definite improvement of the intestinal ulcers (Fig. 3a, b); however, 21 months after the initiation of treatment, her intermittent fever and repeated abdominal pain recurred, and re-induction therapy with prednisolone was restarted (Fig. 2). She remained stable for 9 months, before complaining of slight abdominal pain. We set a dose escalation of ADA with the addition of azathioprine; this seemed to be effective, and almost all of the ulcers disappeared, except for a few small erosions on the intestine (Fig. 3c, d). She next relapsed approximately 10 months later, and ADA was switched to ustekinumab (USK). However, this treatment was not sufficient, and prednisolone was added to USK for clinical improvement. Unfortunately, disease management was difficult regardless of these treatments, and skin ulcers appeared about 50 months after her initial hospital visit (Fig. 4a). Immunohistology of her skin biopsy revealed proliferation of EBV-encoded small RNA (EBER)-positive atypical lymphocytes (Fig. 4b, c). Retrospective assessments of the previous ileal ulcer biopsy before treatment demonstrated many EBER-positive lymphocytes, indicating that she had been in a continuously active EBV infection state (Fig. 4d, e). The blood level of EBV-DNA was also clearly positive (1.5 × 104 copy/WBC × 106). Consequently, she was diagnosed with extranodal NK/T-cell lymphoma (nasal type) related to CAEBV. Advanced-stage malignant lymphoma invading the skin was seen. Then, she was treated with a combination of cyclosporine A and prednisolone for her systemic inflammation related to CAEBV and followed by a systemic chemotherapy for malignant lymphoma. After completing the CHOP chemotherapy (cyclophosphamide, doxorubicin, vincristine, and prednisolone), she gradually showed intermediate liver injury as well as cholestasis, based on which she was diagnosed with secondary hemophagocytic lymphohistiocytosis (HLH) caused by CAEBV. Though etoposide and methylprednisolone combination therapy transiently improved her liver injury and jaundice, CHOP insufficiently controlled the progression of CAEBV. Hence, the combination therapy of etoposide, cytosine arabinoside, l-asparaginase, methylprednisolone, and prednisolone (ESCAP) was preferred over the CHOP therapy. However, her liver injury and jaundice related to HLH rapidly worsened during the recovery period after the first ESCAP therapy. Unfortunately, her disease progression could not be regulated at all and she finally fell into the stage of multiple organ failure; she died at the age of 23 years, 55 months after her first hospital visit. An autopsy was performed with the consent from her parents. Macroscopic findings showed no evidence of ulcer or stenotic changes on her digestive organs, including the small intestine (Fig. 5a). Microscopic findings showed no evidence of noncaseating granuloma on digestive organs and a remarkable proliferation of lymphocytes in the intra-mucosal/submucosal space of the small intestine (Fig. 5b, c).Fig. 1 Various forms of ulcers on digestive organs detected by capsule endoscopy prior to treatment. The surrounding mucosa was free from inflammation. a Multiple aphthous ulcers on the jejunum. b Liner ulcers on the jejunum. c Longitudinal ulcers with a cobblestone appearance on the ileum. d Circular ulcers on ileum
Fig. 2 Entire clinical course of the present case
Fig. 3 Findings of the second capsule endoscopic examination. a, b Ulcer scars on the jejunum and ileum (18 months after the first treatment). c, d Small recurrent erosions on the jejunum and ileum (42 months after the first treatment)
Fig. 4 Histological findings of extranodal NK/T-cell lymphoma (nasal type) associated with continuously activated EBV infection. a Macroscopic finding of skin ulcer on the patient’s thigh, which occurred more than 4 years after the initiation of medical treatment. b Microscopic finding of H&E staining of the skin ulcer. c Microscopic findings revealed high proliferation of EBER-positive atypical lymphocytes in the diseased skin. d Microscopic finding of H&E staining in the intestinal ulcer. e Microscopic immunohistological findings of ileal ulcerative lesions revealed moderate infiltration of many EBER-positive lymphocytes, which demonstrated continuously active EBV infection
Fig. 5 Histological findings of the autopsied small intestine. a Macroscopic observation revealed neither ulcerative changes nor stenotic changes in the small intestine. b Microscopic finding of H&E staining of the intestinal tissue. c Microscopic observation revealed mild lymphocyte proliferation with no atrophy of the intestinal villi (large magnification of H&E staining)
Discussion and conclusion
Chachu and Osterman concluded that "Thoughtful consideration and evaluation of these other potential etiologies through patient history and physical examination, laboratory tests, endoscopic evaluation with targeted biopsies of lesions, and cross-sectional imaging is required to evaluate any patient presenting with symptoms consistent with IBD" [7]. However, it is difficult to completely distinguish CAEBV enteritis from IBD by endoscopic findings only, and it is important to comprehend the clinical features of each disease. To appropriately diagnose CAEBV, it is important to remember the possibility of CAEBV as a differential diagnosis of systemic inflammation [8]. When CAEBV is suspected, the EBV-DNA level in peripheral blood should be checked, even in immunologically denied cases of acute EBV infection. Identification of EBV-infected T and NK cells should be performed for definite diagnosis of CAEBV. Moreover, in situ hybridization (ISH) of EBER by pathological examination and EBV-DNA analysis by flow cytometry should be performed. More details are described in the latest diagnostic criteria of CAEBV [5, 9].
To our knowledge, the first report of a case with gastrointestinal tract complications of CAEBV had serious colorectal bleeding [10]. Later, in the 2000s, there were several reports of CAEBV with gastrointestinal tract complications, which had initially been misdiagnosed as IBD [2–4]. Approximately 6% CAEBV-related deaths originated from intestinal bleeding or perforation [6]. As summarized in the Additional file 2: Table S2, the ulcer morphology of “cobblestone appearance” characteristic of CD [11] was first found in our current case, but this was not observed in all 27 previously reported CAEBV-related enteritis cases [2–4, 10, 12, 13]. According to the endoscopic features of these 28 cases, the diseased lesion was located in the colon (13 cases), small intestine (five cases), concomitant colon and small intestine (five cases), concomitant colon and ileocecal junction (one case), concomitant colon and stomach (one case), ileocecal junction (one case), and unknown location (two cases). Ulcer morphologies have generally been reported as small, shallow, irregular-shaped, and scattered, with the exception of eight cases of huge and profound ulcers. There was also a previous case in which the entire intestinal mucosa displayed lymphangiectasia [3]. In our case, many small aphthous ulcers were found in the whole intestine, and a cobblestone appearance was observed, especially in the ileum, whereas no ulcer was found in the colon. These aphthous ulcers remained after intensive treatment with steroids and biologics. Based on these findings, CAEBV-related enteritis might present various ulcer morphologies depending on the reaction of each therapeutic treatment and/or time course. To detect intestinal lesions, we adopted CE, which has been increasingly used worldwide since its establishment in 2000 [14]. With the advent of CE, various diseases have been clearly visualized, resulting in a paradigm shift in the diagnosis and treatment of small bowel disease. According to a nationwide study in Japan, the frequent findings of CE in patients with CD include cobblestone appearance (occurrence rate: 33%), longitudinal ulcer (78%), irregular ulcer (84%), liner erosion (90%), irregular erosion (89%), circumferential alignment of diminutive lesions (75%), and longitudinal alignment of diminutive lesions (56%) [15]. In this previous study, Esaki et al. observed that the endoscopic diagnosis varied in endoscopist’s clinical knowledge and proficiency; hence, this issue should be overcome. In this case, CD was most probable because ulcers with a cobblestone appearance were detected in the ileum. However, other characteristic findings, such as the bamboo joint-like appearance of the gastric mucosa in esophagogastroduodenoscopy, focally enhanced gastritis, and granuloma on histological evaluation were not actually confirmed.
Thus, a final diagnosis should be comprehensively made based on physical symptoms, medical histories, clinical findings, and culture, imaging, and pathological tests. Even if the characteristic endoscopic findings of specific enteritis are detected, differential diagnosis based only on these findings will be difficult because the characteristic findings of endoscopy do not always correspond to the specific disease. Some enteric diseases might show similar endoscopic appearances, whereas the same disease might demonstrate various phenotypes depending on the time course and severity.
Unfortunately, no successful treatment for CAEBV has yet been established, and further research is needed to improve the outcome in the future [16, 17]. Therefore, it is crucial for clinicians to definitely diagnose CAEBV as quickly as possible.
In conclusion, we diagnosed a rare case of CAEBV, with refractory enteritis as the main clinical symptom and without manifestation of a typical IM feature. Diagnosing CAEBV by ulcer morphology is difficult, even with CE and routine histopathological examination only; thus, clinicians should consider CAEBV as a differential diagnosis of refractory enteritis in younger patients and eagerly check blood EBV-DNA and EBER expression levels by ISH.
Patient perspective
The patient's mother kindly told the authors that the patient had decided to fight her disease, though she had well realized the features and general prognosis of CAEBV.
Supplementary Information
Additional file 1: Supplementary Table S1. Results of her blood test on the first admission.
Additional file 2: Supplementary Table S2. Clinical features of the reported CAEBV cases.
Additional file 3: Figure S1. Endoscopic findings of each digestive organ before treatment. (a) Esophagus, (b) stomach, (c) duodenum, (d) terminal ileum, (e) colon, and (f) rectum. Arrow indicates an ulcerative lesion on the terminal ileum.
Abbreviations
CAEBVChronic active Epstein–Barr virus infection
EBVEpstein–Barr virus
CDCrohn’s disease
IBDInflammatory bowel disease
IMInfectious mononucleosis
CECapsule endoscopy
ADAAdalimumab
USKUstekinumab
EBEREBV-encoded small mRNA
ISHIn situ hybridization
HLHHemophagocytic lymphohistiocytosis
Publisher's Note
Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
Supplementary Information
The online version contains supplementary material available at 10.1186/s12876-020-01589-1.
Acknowledgements
The authors deeply appreciate the mercy of the patient and her parents for accepting the autopsy and publication of this report on her illness.
Authors’ contributions
Writing: YA and KM. Editing: KM. Figure preparation: NS, SN, SK, MU, HM, EI, and H Yagi. Supervision: TN, H Yoshiji, and EK. All authors have read and approved the final version of this manuscript.
Funding
There is nothing to declare.
Availability of data and materials
Data on this case not reported in the manuscript are available from the corresponding author upon reasonable request.
Ethics approval and consent to participate
Ethics committee approval is not required for a single presentation retrospectively. In accordance with the “Patient Rights Regulation” (Date: 01.08.1998; Issue: 23420), which was prepared in accordance with international standards, verbal and wet signed written consent was obtained from the patient under the title of “Consent to publish” to publish patient information and support public health.
Consent for publication
The parents of the patient provided written consent for reporting her case in an international published medical journal, including clinical details and images.
Competing interests
The authors confirm that there are no conflicts of interest to declare. | ADALIMUMAB, ASPARAGINASE, CYCLOPHOSPHAMIDE, CYCLOSPORINE, CYTARABINE, DOXORUBICIN, ETOPOSIDE, MESALAMINE, METHYLPREDNISOLONE, PREDNISOLONE, VINCRISTINE | DrugsGivenReaction | CC BY | 33407170 | 19,246,748 | 2021-01-06 |
Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Multiple organ dysfunction syndrome'. | Chronic active EBV infection in refractory enteritis with longitudinal ulcers with a cobblestone appearance: an autopsied case report.
BACKGROUND
Chronic active Epstein-Barr virus infection (CAEBV) is defined as Epstein-Barr virus (EBV)-positive T/NK cell-related neoplasia, and its major clinical symptom is systemic inflammation presenting as infectious mononucleocytosis, whereas enteritis and diarrhea are minor clinical symptoms. The complex mixture of tumorigenic processes of EBV-positive cells and physical symptoms of systemic inflammatory disease constitutes the varied phenotypes of CAEBV. Herein, we describe a case of CAEBV that was initially diagnosed as Crohn's disease (CD) based on ileal ulcers and clinical symptoms of enteritis.
METHODS
A 19-year-old woman complained of abdominal pain and fever. Blood examination showed normal blood cell counts without atypical lymphocyte but detected modest inflammation, hypoalbuminemia, slight liver dysfunction, and evidence of past EBV infection. The esophagogastroduodenoscopic findings were normal. However, colonoscopy revealed a few small ulcers in the terminal ileum. The jejunum and ileum also exhibited various forms of ulcers, exhibiting a cobblestone appearance, on capsule endoscopy. Based on these clinical findings, she was strongly suspected with CD. In the course of treatment by steroid and biologics for refractory enteritis, skin ulcers appeared about 50 months after her initial hospital visit. Immunohistology of her skin biopsy revealed proliferation of EBV-encoded small RNA (EBER)-positive atypical lymphocytes. We retrospectively assessed her previous ileal ulcer biopsy before treatment and found many EBER-positive lymphocytes. Blood EBV DNA was also positive. Therefore, she was diagnosed with extranodal NK/T-cell lymphoma with CAEBV-related enteritis rather than CD. She was treated with cyclosporine and prednisolone combination therapy for CAEBV-related systemic inflammation and chemotherapy for malignant lymphoma. Unfortunately, her disease continued to progress, leading to multiple organ failure and death at the age of 23 years.
CONCLUSIONS
Clinicians need to remember the possibility of CAEBV as a differential diagnosis of refractory enteritis. Enteritis with intestinal ulcer is a rare symptom of CAEBV, and it is impossible to acquire a definitive diagnosis by ulcer morphology only. In cases where the possibility of CAEBV remains, tissue EBVR expression should be checked by in situ hybridization and blood EBV DNA.
Background
Enteritis is an inflammatory disease of the small intestine caused by some factors, such as bacterial or viral infections, ischemia, vasculitis, chemical or radiological tissue damage, and immune disorders including inflammatory bowel disease (IBD), with phenotype variation [1]. In fact, few cases of chronic active Epstein–Barr virus (CAEBV) reveal enteritis [2–4]. Previously, CAEBV was thought to be a rare child disease limitedly occurring in the East Asia. However, CAEBV has been recently found to occur worldwide with no relation to patient’s age [5]. Although CAEBV is a phenotype of EBV-lymphoproliferative disorders, its major clinical symptom is systemic inflammation presenting as infectious mononucleosis (IM) and enteritis as well as diarrhea are minor clinical symptoms. The complex mixture of tumorigenic processes associated with EBV-positive cells and the physical symptoms of inflammatory systemic disease constitute the varied phenotypes of CAEBV. The median period between the first visit and the definite diagnosis of CAEBV was 20 months. This extended duration was mainly due to the need to first exclude other diseases or cases where patients were diagnosed with unknown fever [6]. Although CAEBV generally presents with IM-like symptoms, we recently experienced a case of a young woman with CAEBV that appeared with refractory enteritis and was indistinguishable from Crohn’s disease (CD). This report of an autopsied CAEBV case will be of educational help, given the difficulty in acquiring a definite diagnosis.
Case presentation
A 19-year-old woman was referred to our hospital for intermittent abdominal pain and continuous fever which had persisted for a month. She had no obvious medical or familial history. Physical examination revealed no morbid lymph node swelling or skin abnormalities. Blood examination showed normal blood cell counts and no presence of atypical lymphocytes. Biochemical or immunoserum analysis revealed modest inflammation, hypoalbuminemia, slight liver dysfunction, and evidence of past EBV infection (Additional file 1: Table S1). Although esophagogastroduodenoscopy revealed normal findings, colonoscopy revealed a few small ulcers in the terminal ileum (Additional file 3: Fig. 1). Enhanced computed tomography showed obvious wall thickness of the small intestine, whereas no significant finding was detected by balloon intestinal endoscopy in the distal ileum. However, various types of ulcers surrounded by completely normal mucosa were found on the jejunum and proximal ileum by capsule endoscopy (CE) (Fig. 1). Additionally, multiple aphthous and some linear ulcers were observed on the jejunum, whereas circular ulcers and longitudinal ulcers with a cobblestone appearance were detected on the ileum. The possibility of intestinal tuberculosis and infectious gastroenteritis were serologically and culturally excluded. Although there were no histological findings of noncaseating granuloma on her digestive organs, she was strongly suspected with CD based on her age, clinical symptoms, and the morphology of the characteristic ulcers (Fig. 2). Consequently, the patient was treated with an elemental diet, mesalamine, and prednisolone for induction therapy. Although this treatment seemed to be partially effective, her symptoms recurred according to the tapering of prednisolone, and she was subsequently switched to adalimumab (ADA). Her clinical symptoms tended to be gradually modest, and the maintenance ADA therapy was effective for some time. The second CE revealed a definite improvement of the intestinal ulcers (Fig. 3a, b); however, 21 months after the initiation of treatment, her intermittent fever and repeated abdominal pain recurred, and re-induction therapy with prednisolone was restarted (Fig. 2). She remained stable for 9 months, before complaining of slight abdominal pain. We set a dose escalation of ADA with the addition of azathioprine; this seemed to be effective, and almost all of the ulcers disappeared, except for a few small erosions on the intestine (Fig. 3c, d). She next relapsed approximately 10 months later, and ADA was switched to ustekinumab (USK). However, this treatment was not sufficient, and prednisolone was added to USK for clinical improvement. Unfortunately, disease management was difficult regardless of these treatments, and skin ulcers appeared about 50 months after her initial hospital visit (Fig. 4a). Immunohistology of her skin biopsy revealed proliferation of EBV-encoded small RNA (EBER)-positive atypical lymphocytes (Fig. 4b, c). Retrospective assessments of the previous ileal ulcer biopsy before treatment demonstrated many EBER-positive lymphocytes, indicating that she had been in a continuously active EBV infection state (Fig. 4d, e). The blood level of EBV-DNA was also clearly positive (1.5 × 104 copy/WBC × 106). Consequently, she was diagnosed with extranodal NK/T-cell lymphoma (nasal type) related to CAEBV. Advanced-stage malignant lymphoma invading the skin was seen. Then, she was treated with a combination of cyclosporine A and prednisolone for her systemic inflammation related to CAEBV and followed by a systemic chemotherapy for malignant lymphoma. After completing the CHOP chemotherapy (cyclophosphamide, doxorubicin, vincristine, and prednisolone), she gradually showed intermediate liver injury as well as cholestasis, based on which she was diagnosed with secondary hemophagocytic lymphohistiocytosis (HLH) caused by CAEBV. Though etoposide and methylprednisolone combination therapy transiently improved her liver injury and jaundice, CHOP insufficiently controlled the progression of CAEBV. Hence, the combination therapy of etoposide, cytosine arabinoside, l-asparaginase, methylprednisolone, and prednisolone (ESCAP) was preferred over the CHOP therapy. However, her liver injury and jaundice related to HLH rapidly worsened during the recovery period after the first ESCAP therapy. Unfortunately, her disease progression could not be regulated at all and she finally fell into the stage of multiple organ failure; she died at the age of 23 years, 55 months after her first hospital visit. An autopsy was performed with the consent from her parents. Macroscopic findings showed no evidence of ulcer or stenotic changes on her digestive organs, including the small intestine (Fig. 5a). Microscopic findings showed no evidence of noncaseating granuloma on digestive organs and a remarkable proliferation of lymphocytes in the intra-mucosal/submucosal space of the small intestine (Fig. 5b, c).Fig. 1 Various forms of ulcers on digestive organs detected by capsule endoscopy prior to treatment. The surrounding mucosa was free from inflammation. a Multiple aphthous ulcers on the jejunum. b Liner ulcers on the jejunum. c Longitudinal ulcers with a cobblestone appearance on the ileum. d Circular ulcers on ileum
Fig. 2 Entire clinical course of the present case
Fig. 3 Findings of the second capsule endoscopic examination. a, b Ulcer scars on the jejunum and ileum (18 months after the first treatment). c, d Small recurrent erosions on the jejunum and ileum (42 months after the first treatment)
Fig. 4 Histological findings of extranodal NK/T-cell lymphoma (nasal type) associated with continuously activated EBV infection. a Macroscopic finding of skin ulcer on the patient’s thigh, which occurred more than 4 years after the initiation of medical treatment. b Microscopic finding of H&E staining of the skin ulcer. c Microscopic findings revealed high proliferation of EBER-positive atypical lymphocytes in the diseased skin. d Microscopic finding of H&E staining in the intestinal ulcer. e Microscopic immunohistological findings of ileal ulcerative lesions revealed moderate infiltration of many EBER-positive lymphocytes, which demonstrated continuously active EBV infection
Fig. 5 Histological findings of the autopsied small intestine. a Macroscopic observation revealed neither ulcerative changes nor stenotic changes in the small intestine. b Microscopic finding of H&E staining of the intestinal tissue. c Microscopic observation revealed mild lymphocyte proliferation with no atrophy of the intestinal villi (large magnification of H&E staining)
Discussion and conclusion
Chachu and Osterman concluded that "Thoughtful consideration and evaluation of these other potential etiologies through patient history and physical examination, laboratory tests, endoscopic evaluation with targeted biopsies of lesions, and cross-sectional imaging is required to evaluate any patient presenting with symptoms consistent with IBD" [7]. However, it is difficult to completely distinguish CAEBV enteritis from IBD by endoscopic findings only, and it is important to comprehend the clinical features of each disease. To appropriately diagnose CAEBV, it is important to remember the possibility of CAEBV as a differential diagnosis of systemic inflammation [8]. When CAEBV is suspected, the EBV-DNA level in peripheral blood should be checked, even in immunologically denied cases of acute EBV infection. Identification of EBV-infected T and NK cells should be performed for definite diagnosis of CAEBV. Moreover, in situ hybridization (ISH) of EBER by pathological examination and EBV-DNA analysis by flow cytometry should be performed. More details are described in the latest diagnostic criteria of CAEBV [5, 9].
To our knowledge, the first report of a case with gastrointestinal tract complications of CAEBV had serious colorectal bleeding [10]. Later, in the 2000s, there were several reports of CAEBV with gastrointestinal tract complications, which had initially been misdiagnosed as IBD [2–4]. Approximately 6% CAEBV-related deaths originated from intestinal bleeding or perforation [6]. As summarized in the Additional file 2: Table S2, the ulcer morphology of “cobblestone appearance” characteristic of CD [11] was first found in our current case, but this was not observed in all 27 previously reported CAEBV-related enteritis cases [2–4, 10, 12, 13]. According to the endoscopic features of these 28 cases, the diseased lesion was located in the colon (13 cases), small intestine (five cases), concomitant colon and small intestine (five cases), concomitant colon and ileocecal junction (one case), concomitant colon and stomach (one case), ileocecal junction (one case), and unknown location (two cases). Ulcer morphologies have generally been reported as small, shallow, irregular-shaped, and scattered, with the exception of eight cases of huge and profound ulcers. There was also a previous case in which the entire intestinal mucosa displayed lymphangiectasia [3]. In our case, many small aphthous ulcers were found in the whole intestine, and a cobblestone appearance was observed, especially in the ileum, whereas no ulcer was found in the colon. These aphthous ulcers remained after intensive treatment with steroids and biologics. Based on these findings, CAEBV-related enteritis might present various ulcer morphologies depending on the reaction of each therapeutic treatment and/or time course. To detect intestinal lesions, we adopted CE, which has been increasingly used worldwide since its establishment in 2000 [14]. With the advent of CE, various diseases have been clearly visualized, resulting in a paradigm shift in the diagnosis and treatment of small bowel disease. According to a nationwide study in Japan, the frequent findings of CE in patients with CD include cobblestone appearance (occurrence rate: 33%), longitudinal ulcer (78%), irregular ulcer (84%), liner erosion (90%), irregular erosion (89%), circumferential alignment of diminutive lesions (75%), and longitudinal alignment of diminutive lesions (56%) [15]. In this previous study, Esaki et al. observed that the endoscopic diagnosis varied in endoscopist’s clinical knowledge and proficiency; hence, this issue should be overcome. In this case, CD was most probable because ulcers with a cobblestone appearance were detected in the ileum. However, other characteristic findings, such as the bamboo joint-like appearance of the gastric mucosa in esophagogastroduodenoscopy, focally enhanced gastritis, and granuloma on histological evaluation were not actually confirmed.
Thus, a final diagnosis should be comprehensively made based on physical symptoms, medical histories, clinical findings, and culture, imaging, and pathological tests. Even if the characteristic endoscopic findings of specific enteritis are detected, differential diagnosis based only on these findings will be difficult because the characteristic findings of endoscopy do not always correspond to the specific disease. Some enteric diseases might show similar endoscopic appearances, whereas the same disease might demonstrate various phenotypes depending on the time course and severity.
Unfortunately, no successful treatment for CAEBV has yet been established, and further research is needed to improve the outcome in the future [16, 17]. Therefore, it is crucial for clinicians to definitely diagnose CAEBV as quickly as possible.
In conclusion, we diagnosed a rare case of CAEBV, with refractory enteritis as the main clinical symptom and without manifestation of a typical IM feature. Diagnosing CAEBV by ulcer morphology is difficult, even with CE and routine histopathological examination only; thus, clinicians should consider CAEBV as a differential diagnosis of refractory enteritis in younger patients and eagerly check blood EBV-DNA and EBER expression levels by ISH.
Patient perspective
The patient's mother kindly told the authors that the patient had decided to fight her disease, though she had well realized the features and general prognosis of CAEBV.
Supplementary Information
Additional file 1: Supplementary Table S1. Results of her blood test on the first admission.
Additional file 2: Supplementary Table S2. Clinical features of the reported CAEBV cases.
Additional file 3: Figure S1. Endoscopic findings of each digestive organ before treatment. (a) Esophagus, (b) stomach, (c) duodenum, (d) terminal ileum, (e) colon, and (f) rectum. Arrow indicates an ulcerative lesion on the terminal ileum.
Abbreviations
CAEBVChronic active Epstein–Barr virus infection
EBVEpstein–Barr virus
CDCrohn’s disease
IBDInflammatory bowel disease
IMInfectious mononucleosis
CECapsule endoscopy
ADAAdalimumab
USKUstekinumab
EBEREBV-encoded small mRNA
ISHIn situ hybridization
HLHHemophagocytic lymphohistiocytosis
Publisher's Note
Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
Supplementary Information
The online version contains supplementary material available at 10.1186/s12876-020-01589-1.
Acknowledgements
The authors deeply appreciate the mercy of the patient and her parents for accepting the autopsy and publication of this report on her illness.
Authors’ contributions
Writing: YA and KM. Editing: KM. Figure preparation: NS, SN, SK, MU, HM, EI, and H Yagi. Supervision: TN, H Yoshiji, and EK. All authors have read and approved the final version of this manuscript.
Funding
There is nothing to declare.
Availability of data and materials
Data on this case not reported in the manuscript are available from the corresponding author upon reasonable request.
Ethics approval and consent to participate
Ethics committee approval is not required for a single presentation retrospectively. In accordance with the “Patient Rights Regulation” (Date: 01.08.1998; Issue: 23420), which was prepared in accordance with international standards, verbal and wet signed written consent was obtained from the patient under the title of “Consent to publish” to publish patient information and support public health.
Consent for publication
The parents of the patient provided written consent for reporting her case in an international published medical journal, including clinical details and images.
Competing interests
The authors confirm that there are no conflicts of interest to declare. | ADALIMUMAB, ASPARAGINASE, CYCLOPHOSPHAMIDE, CYCLOSPORINE, CYTARABINE, DOXORUBICIN, ETOPOSIDE, MESALAMINE, METHYLPREDNISOLONE, PREDNISOLONE, VINCRISTINE | DrugsGivenReaction | CC BY | 33407170 | 19,246,748 | 2021-01-06 |
Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Off label use'. | Chronic active EBV infection in refractory enteritis with longitudinal ulcers with a cobblestone appearance: an autopsied case report.
BACKGROUND
Chronic active Epstein-Barr virus infection (CAEBV) is defined as Epstein-Barr virus (EBV)-positive T/NK cell-related neoplasia, and its major clinical symptom is systemic inflammation presenting as infectious mononucleocytosis, whereas enteritis and diarrhea are minor clinical symptoms. The complex mixture of tumorigenic processes of EBV-positive cells and physical symptoms of systemic inflammatory disease constitutes the varied phenotypes of CAEBV. Herein, we describe a case of CAEBV that was initially diagnosed as Crohn's disease (CD) based on ileal ulcers and clinical symptoms of enteritis.
METHODS
A 19-year-old woman complained of abdominal pain and fever. Blood examination showed normal blood cell counts without atypical lymphocyte but detected modest inflammation, hypoalbuminemia, slight liver dysfunction, and evidence of past EBV infection. The esophagogastroduodenoscopic findings were normal. However, colonoscopy revealed a few small ulcers in the terminal ileum. The jejunum and ileum also exhibited various forms of ulcers, exhibiting a cobblestone appearance, on capsule endoscopy. Based on these clinical findings, she was strongly suspected with CD. In the course of treatment by steroid and biologics for refractory enteritis, skin ulcers appeared about 50 months after her initial hospital visit. Immunohistology of her skin biopsy revealed proliferation of EBV-encoded small RNA (EBER)-positive atypical lymphocytes. We retrospectively assessed her previous ileal ulcer biopsy before treatment and found many EBER-positive lymphocytes. Blood EBV DNA was also positive. Therefore, she was diagnosed with extranodal NK/T-cell lymphoma with CAEBV-related enteritis rather than CD. She was treated with cyclosporine and prednisolone combination therapy for CAEBV-related systemic inflammation and chemotherapy for malignant lymphoma. Unfortunately, her disease continued to progress, leading to multiple organ failure and death at the age of 23 years.
CONCLUSIONS
Clinicians need to remember the possibility of CAEBV as a differential diagnosis of refractory enteritis. Enteritis with intestinal ulcer is a rare symptom of CAEBV, and it is impossible to acquire a definitive diagnosis by ulcer morphology only. In cases where the possibility of CAEBV remains, tissue EBVR expression should be checked by in situ hybridization and blood EBV DNA.
Background
Enteritis is an inflammatory disease of the small intestine caused by some factors, such as bacterial or viral infections, ischemia, vasculitis, chemical or radiological tissue damage, and immune disorders including inflammatory bowel disease (IBD), with phenotype variation [1]. In fact, few cases of chronic active Epstein–Barr virus (CAEBV) reveal enteritis [2–4]. Previously, CAEBV was thought to be a rare child disease limitedly occurring in the East Asia. However, CAEBV has been recently found to occur worldwide with no relation to patient’s age [5]. Although CAEBV is a phenotype of EBV-lymphoproliferative disorders, its major clinical symptom is systemic inflammation presenting as infectious mononucleosis (IM) and enteritis as well as diarrhea are minor clinical symptoms. The complex mixture of tumorigenic processes associated with EBV-positive cells and the physical symptoms of inflammatory systemic disease constitute the varied phenotypes of CAEBV. The median period between the first visit and the definite diagnosis of CAEBV was 20 months. This extended duration was mainly due to the need to first exclude other diseases or cases where patients were diagnosed with unknown fever [6]. Although CAEBV generally presents with IM-like symptoms, we recently experienced a case of a young woman with CAEBV that appeared with refractory enteritis and was indistinguishable from Crohn’s disease (CD). This report of an autopsied CAEBV case will be of educational help, given the difficulty in acquiring a definite diagnosis.
Case presentation
A 19-year-old woman was referred to our hospital for intermittent abdominal pain and continuous fever which had persisted for a month. She had no obvious medical or familial history. Physical examination revealed no morbid lymph node swelling or skin abnormalities. Blood examination showed normal blood cell counts and no presence of atypical lymphocytes. Biochemical or immunoserum analysis revealed modest inflammation, hypoalbuminemia, slight liver dysfunction, and evidence of past EBV infection (Additional file 1: Table S1). Although esophagogastroduodenoscopy revealed normal findings, colonoscopy revealed a few small ulcers in the terminal ileum (Additional file 3: Fig. 1). Enhanced computed tomography showed obvious wall thickness of the small intestine, whereas no significant finding was detected by balloon intestinal endoscopy in the distal ileum. However, various types of ulcers surrounded by completely normal mucosa were found on the jejunum and proximal ileum by capsule endoscopy (CE) (Fig. 1). Additionally, multiple aphthous and some linear ulcers were observed on the jejunum, whereas circular ulcers and longitudinal ulcers with a cobblestone appearance were detected on the ileum. The possibility of intestinal tuberculosis and infectious gastroenteritis were serologically and culturally excluded. Although there were no histological findings of noncaseating granuloma on her digestive organs, she was strongly suspected with CD based on her age, clinical symptoms, and the morphology of the characteristic ulcers (Fig. 2). Consequently, the patient was treated with an elemental diet, mesalamine, and prednisolone for induction therapy. Although this treatment seemed to be partially effective, her symptoms recurred according to the tapering of prednisolone, and she was subsequently switched to adalimumab (ADA). Her clinical symptoms tended to be gradually modest, and the maintenance ADA therapy was effective for some time. The second CE revealed a definite improvement of the intestinal ulcers (Fig. 3a, b); however, 21 months after the initiation of treatment, her intermittent fever and repeated abdominal pain recurred, and re-induction therapy with prednisolone was restarted (Fig. 2). She remained stable for 9 months, before complaining of slight abdominal pain. We set a dose escalation of ADA with the addition of azathioprine; this seemed to be effective, and almost all of the ulcers disappeared, except for a few small erosions on the intestine (Fig. 3c, d). She next relapsed approximately 10 months later, and ADA was switched to ustekinumab (USK). However, this treatment was not sufficient, and prednisolone was added to USK for clinical improvement. Unfortunately, disease management was difficult regardless of these treatments, and skin ulcers appeared about 50 months after her initial hospital visit (Fig. 4a). Immunohistology of her skin biopsy revealed proliferation of EBV-encoded small RNA (EBER)-positive atypical lymphocytes (Fig. 4b, c). Retrospective assessments of the previous ileal ulcer biopsy before treatment demonstrated many EBER-positive lymphocytes, indicating that she had been in a continuously active EBV infection state (Fig. 4d, e). The blood level of EBV-DNA was also clearly positive (1.5 × 104 copy/WBC × 106). Consequently, she was diagnosed with extranodal NK/T-cell lymphoma (nasal type) related to CAEBV. Advanced-stage malignant lymphoma invading the skin was seen. Then, she was treated with a combination of cyclosporine A and prednisolone for her systemic inflammation related to CAEBV and followed by a systemic chemotherapy for malignant lymphoma. After completing the CHOP chemotherapy (cyclophosphamide, doxorubicin, vincristine, and prednisolone), she gradually showed intermediate liver injury as well as cholestasis, based on which she was diagnosed with secondary hemophagocytic lymphohistiocytosis (HLH) caused by CAEBV. Though etoposide and methylprednisolone combination therapy transiently improved her liver injury and jaundice, CHOP insufficiently controlled the progression of CAEBV. Hence, the combination therapy of etoposide, cytosine arabinoside, l-asparaginase, methylprednisolone, and prednisolone (ESCAP) was preferred over the CHOP therapy. However, her liver injury and jaundice related to HLH rapidly worsened during the recovery period after the first ESCAP therapy. Unfortunately, her disease progression could not be regulated at all and she finally fell into the stage of multiple organ failure; she died at the age of 23 years, 55 months after her first hospital visit. An autopsy was performed with the consent from her parents. Macroscopic findings showed no evidence of ulcer or stenotic changes on her digestive organs, including the small intestine (Fig. 5a). Microscopic findings showed no evidence of noncaseating granuloma on digestive organs and a remarkable proliferation of lymphocytes in the intra-mucosal/submucosal space of the small intestine (Fig. 5b, c).Fig. 1 Various forms of ulcers on digestive organs detected by capsule endoscopy prior to treatment. The surrounding mucosa was free from inflammation. a Multiple aphthous ulcers on the jejunum. b Liner ulcers on the jejunum. c Longitudinal ulcers with a cobblestone appearance on the ileum. d Circular ulcers on ileum
Fig. 2 Entire clinical course of the present case
Fig. 3 Findings of the second capsule endoscopic examination. a, b Ulcer scars on the jejunum and ileum (18 months after the first treatment). c, d Small recurrent erosions on the jejunum and ileum (42 months after the first treatment)
Fig. 4 Histological findings of extranodal NK/T-cell lymphoma (nasal type) associated with continuously activated EBV infection. a Macroscopic finding of skin ulcer on the patient’s thigh, which occurred more than 4 years after the initiation of medical treatment. b Microscopic finding of H&E staining of the skin ulcer. c Microscopic findings revealed high proliferation of EBER-positive atypical lymphocytes in the diseased skin. d Microscopic finding of H&E staining in the intestinal ulcer. e Microscopic immunohistological findings of ileal ulcerative lesions revealed moderate infiltration of many EBER-positive lymphocytes, which demonstrated continuously active EBV infection
Fig. 5 Histological findings of the autopsied small intestine. a Macroscopic observation revealed neither ulcerative changes nor stenotic changes in the small intestine. b Microscopic finding of H&E staining of the intestinal tissue. c Microscopic observation revealed mild lymphocyte proliferation with no atrophy of the intestinal villi (large magnification of H&E staining)
Discussion and conclusion
Chachu and Osterman concluded that "Thoughtful consideration and evaluation of these other potential etiologies through patient history and physical examination, laboratory tests, endoscopic evaluation with targeted biopsies of lesions, and cross-sectional imaging is required to evaluate any patient presenting with symptoms consistent with IBD" [7]. However, it is difficult to completely distinguish CAEBV enteritis from IBD by endoscopic findings only, and it is important to comprehend the clinical features of each disease. To appropriately diagnose CAEBV, it is important to remember the possibility of CAEBV as a differential diagnosis of systemic inflammation [8]. When CAEBV is suspected, the EBV-DNA level in peripheral blood should be checked, even in immunologically denied cases of acute EBV infection. Identification of EBV-infected T and NK cells should be performed for definite diagnosis of CAEBV. Moreover, in situ hybridization (ISH) of EBER by pathological examination and EBV-DNA analysis by flow cytometry should be performed. More details are described in the latest diagnostic criteria of CAEBV [5, 9].
To our knowledge, the first report of a case with gastrointestinal tract complications of CAEBV had serious colorectal bleeding [10]. Later, in the 2000s, there were several reports of CAEBV with gastrointestinal tract complications, which had initially been misdiagnosed as IBD [2–4]. Approximately 6% CAEBV-related deaths originated from intestinal bleeding or perforation [6]. As summarized in the Additional file 2: Table S2, the ulcer morphology of “cobblestone appearance” characteristic of CD [11] was first found in our current case, but this was not observed in all 27 previously reported CAEBV-related enteritis cases [2–4, 10, 12, 13]. According to the endoscopic features of these 28 cases, the diseased lesion was located in the colon (13 cases), small intestine (five cases), concomitant colon and small intestine (five cases), concomitant colon and ileocecal junction (one case), concomitant colon and stomach (one case), ileocecal junction (one case), and unknown location (two cases). Ulcer morphologies have generally been reported as small, shallow, irregular-shaped, and scattered, with the exception of eight cases of huge and profound ulcers. There was also a previous case in which the entire intestinal mucosa displayed lymphangiectasia [3]. In our case, many small aphthous ulcers were found in the whole intestine, and a cobblestone appearance was observed, especially in the ileum, whereas no ulcer was found in the colon. These aphthous ulcers remained after intensive treatment with steroids and biologics. Based on these findings, CAEBV-related enteritis might present various ulcer morphologies depending on the reaction of each therapeutic treatment and/or time course. To detect intestinal lesions, we adopted CE, which has been increasingly used worldwide since its establishment in 2000 [14]. With the advent of CE, various diseases have been clearly visualized, resulting in a paradigm shift in the diagnosis and treatment of small bowel disease. According to a nationwide study in Japan, the frequent findings of CE in patients with CD include cobblestone appearance (occurrence rate: 33%), longitudinal ulcer (78%), irregular ulcer (84%), liner erosion (90%), irregular erosion (89%), circumferential alignment of diminutive lesions (75%), and longitudinal alignment of diminutive lesions (56%) [15]. In this previous study, Esaki et al. observed that the endoscopic diagnosis varied in endoscopist’s clinical knowledge and proficiency; hence, this issue should be overcome. In this case, CD was most probable because ulcers with a cobblestone appearance were detected in the ileum. However, other characteristic findings, such as the bamboo joint-like appearance of the gastric mucosa in esophagogastroduodenoscopy, focally enhanced gastritis, and granuloma on histological evaluation were not actually confirmed.
Thus, a final diagnosis should be comprehensively made based on physical symptoms, medical histories, clinical findings, and culture, imaging, and pathological tests. Even if the characteristic endoscopic findings of specific enteritis are detected, differential diagnosis based only on these findings will be difficult because the characteristic findings of endoscopy do not always correspond to the specific disease. Some enteric diseases might show similar endoscopic appearances, whereas the same disease might demonstrate various phenotypes depending on the time course and severity.
Unfortunately, no successful treatment for CAEBV has yet been established, and further research is needed to improve the outcome in the future [16, 17]. Therefore, it is crucial for clinicians to definitely diagnose CAEBV as quickly as possible.
In conclusion, we diagnosed a rare case of CAEBV, with refractory enteritis as the main clinical symptom and without manifestation of a typical IM feature. Diagnosing CAEBV by ulcer morphology is difficult, even with CE and routine histopathological examination only; thus, clinicians should consider CAEBV as a differential diagnosis of refractory enteritis in younger patients and eagerly check blood EBV-DNA and EBER expression levels by ISH.
Patient perspective
The patient's mother kindly told the authors that the patient had decided to fight her disease, though she had well realized the features and general prognosis of CAEBV.
Supplementary Information
Additional file 1: Supplementary Table S1. Results of her blood test on the first admission.
Additional file 2: Supplementary Table S2. Clinical features of the reported CAEBV cases.
Additional file 3: Figure S1. Endoscopic findings of each digestive organ before treatment. (a) Esophagus, (b) stomach, (c) duodenum, (d) terminal ileum, (e) colon, and (f) rectum. Arrow indicates an ulcerative lesion on the terminal ileum.
Abbreviations
CAEBVChronic active Epstein–Barr virus infection
EBVEpstein–Barr virus
CDCrohn’s disease
IBDInflammatory bowel disease
IMInfectious mononucleosis
CECapsule endoscopy
ADAAdalimumab
USKUstekinumab
EBEREBV-encoded small mRNA
ISHIn situ hybridization
HLHHemophagocytic lymphohistiocytosis
Publisher's Note
Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
Supplementary Information
The online version contains supplementary material available at 10.1186/s12876-020-01589-1.
Acknowledgements
The authors deeply appreciate the mercy of the patient and her parents for accepting the autopsy and publication of this report on her illness.
Authors’ contributions
Writing: YA and KM. Editing: KM. Figure preparation: NS, SN, SK, MU, HM, EI, and H Yagi. Supervision: TN, H Yoshiji, and EK. All authors have read and approved the final version of this manuscript.
Funding
There is nothing to declare.
Availability of data and materials
Data on this case not reported in the manuscript are available from the corresponding author upon reasonable request.
Ethics approval and consent to participate
Ethics committee approval is not required for a single presentation retrospectively. In accordance with the “Patient Rights Regulation” (Date: 01.08.1998; Issue: 23420), which was prepared in accordance with international standards, verbal and wet signed written consent was obtained from the patient under the title of “Consent to publish” to publish patient information and support public health.
Consent for publication
The parents of the patient provided written consent for reporting her case in an international published medical journal, including clinical details and images.
Competing interests
The authors confirm that there are no conflicts of interest to declare. | ADALIMUMAB, ASPARAGINASE, CYCLOPHOSPHAMIDE, CYCLOSPORINE, CYTARABINE, DOXORUBICIN, ETOPOSIDE, MESALAMINE, METHYLPREDNISOLONE, PREDNISOLONE, VINCRISTINE | DrugsGivenReaction | CC BY | 33407170 | 19,246,748 | 2021-01-06 |
What was the administration route of drug 'ADALIMUMAB'? | Chronic active EBV infection in refractory enteritis with longitudinal ulcers with a cobblestone appearance: an autopsied case report.
BACKGROUND
Chronic active Epstein-Barr virus infection (CAEBV) is defined as Epstein-Barr virus (EBV)-positive T/NK cell-related neoplasia, and its major clinical symptom is systemic inflammation presenting as infectious mononucleocytosis, whereas enteritis and diarrhea are minor clinical symptoms. The complex mixture of tumorigenic processes of EBV-positive cells and physical symptoms of systemic inflammatory disease constitutes the varied phenotypes of CAEBV. Herein, we describe a case of CAEBV that was initially diagnosed as Crohn's disease (CD) based on ileal ulcers and clinical symptoms of enteritis.
METHODS
A 19-year-old woman complained of abdominal pain and fever. Blood examination showed normal blood cell counts without atypical lymphocyte but detected modest inflammation, hypoalbuminemia, slight liver dysfunction, and evidence of past EBV infection. The esophagogastroduodenoscopic findings were normal. However, colonoscopy revealed a few small ulcers in the terminal ileum. The jejunum and ileum also exhibited various forms of ulcers, exhibiting a cobblestone appearance, on capsule endoscopy. Based on these clinical findings, she was strongly suspected with CD. In the course of treatment by steroid and biologics for refractory enteritis, skin ulcers appeared about 50 months after her initial hospital visit. Immunohistology of her skin biopsy revealed proliferation of EBV-encoded small RNA (EBER)-positive atypical lymphocytes. We retrospectively assessed her previous ileal ulcer biopsy before treatment and found many EBER-positive lymphocytes. Blood EBV DNA was also positive. Therefore, she was diagnosed with extranodal NK/T-cell lymphoma with CAEBV-related enteritis rather than CD. She was treated with cyclosporine and prednisolone combination therapy for CAEBV-related systemic inflammation and chemotherapy for malignant lymphoma. Unfortunately, her disease continued to progress, leading to multiple organ failure and death at the age of 23 years.
CONCLUSIONS
Clinicians need to remember the possibility of CAEBV as a differential diagnosis of refractory enteritis. Enteritis with intestinal ulcer is a rare symptom of CAEBV, and it is impossible to acquire a definitive diagnosis by ulcer morphology only. In cases where the possibility of CAEBV remains, tissue EBVR expression should be checked by in situ hybridization and blood EBV DNA.
Background
Enteritis is an inflammatory disease of the small intestine caused by some factors, such as bacterial or viral infections, ischemia, vasculitis, chemical or radiological tissue damage, and immune disorders including inflammatory bowel disease (IBD), with phenotype variation [1]. In fact, few cases of chronic active Epstein–Barr virus (CAEBV) reveal enteritis [2–4]. Previously, CAEBV was thought to be a rare child disease limitedly occurring in the East Asia. However, CAEBV has been recently found to occur worldwide with no relation to patient’s age [5]. Although CAEBV is a phenotype of EBV-lymphoproliferative disorders, its major clinical symptom is systemic inflammation presenting as infectious mononucleosis (IM) and enteritis as well as diarrhea are minor clinical symptoms. The complex mixture of tumorigenic processes associated with EBV-positive cells and the physical symptoms of inflammatory systemic disease constitute the varied phenotypes of CAEBV. The median period between the first visit and the definite diagnosis of CAEBV was 20 months. This extended duration was mainly due to the need to first exclude other diseases or cases where patients were diagnosed with unknown fever [6]. Although CAEBV generally presents with IM-like symptoms, we recently experienced a case of a young woman with CAEBV that appeared with refractory enteritis and was indistinguishable from Crohn’s disease (CD). This report of an autopsied CAEBV case will be of educational help, given the difficulty in acquiring a definite diagnosis.
Case presentation
A 19-year-old woman was referred to our hospital for intermittent abdominal pain and continuous fever which had persisted for a month. She had no obvious medical or familial history. Physical examination revealed no morbid lymph node swelling or skin abnormalities. Blood examination showed normal blood cell counts and no presence of atypical lymphocytes. Biochemical or immunoserum analysis revealed modest inflammation, hypoalbuminemia, slight liver dysfunction, and evidence of past EBV infection (Additional file 1: Table S1). Although esophagogastroduodenoscopy revealed normal findings, colonoscopy revealed a few small ulcers in the terminal ileum (Additional file 3: Fig. 1). Enhanced computed tomography showed obvious wall thickness of the small intestine, whereas no significant finding was detected by balloon intestinal endoscopy in the distal ileum. However, various types of ulcers surrounded by completely normal mucosa were found on the jejunum and proximal ileum by capsule endoscopy (CE) (Fig. 1). Additionally, multiple aphthous and some linear ulcers were observed on the jejunum, whereas circular ulcers and longitudinal ulcers with a cobblestone appearance were detected on the ileum. The possibility of intestinal tuberculosis and infectious gastroenteritis were serologically and culturally excluded. Although there were no histological findings of noncaseating granuloma on her digestive organs, she was strongly suspected with CD based on her age, clinical symptoms, and the morphology of the characteristic ulcers (Fig. 2). Consequently, the patient was treated with an elemental diet, mesalamine, and prednisolone for induction therapy. Although this treatment seemed to be partially effective, her symptoms recurred according to the tapering of prednisolone, and she was subsequently switched to adalimumab (ADA). Her clinical symptoms tended to be gradually modest, and the maintenance ADA therapy was effective for some time. The second CE revealed a definite improvement of the intestinal ulcers (Fig. 3a, b); however, 21 months after the initiation of treatment, her intermittent fever and repeated abdominal pain recurred, and re-induction therapy with prednisolone was restarted (Fig. 2). She remained stable for 9 months, before complaining of slight abdominal pain. We set a dose escalation of ADA with the addition of azathioprine; this seemed to be effective, and almost all of the ulcers disappeared, except for a few small erosions on the intestine (Fig. 3c, d). She next relapsed approximately 10 months later, and ADA was switched to ustekinumab (USK). However, this treatment was not sufficient, and prednisolone was added to USK for clinical improvement. Unfortunately, disease management was difficult regardless of these treatments, and skin ulcers appeared about 50 months after her initial hospital visit (Fig. 4a). Immunohistology of her skin biopsy revealed proliferation of EBV-encoded small RNA (EBER)-positive atypical lymphocytes (Fig. 4b, c). Retrospective assessments of the previous ileal ulcer biopsy before treatment demonstrated many EBER-positive lymphocytes, indicating that she had been in a continuously active EBV infection state (Fig. 4d, e). The blood level of EBV-DNA was also clearly positive (1.5 × 104 copy/WBC × 106). Consequently, she was diagnosed with extranodal NK/T-cell lymphoma (nasal type) related to CAEBV. Advanced-stage malignant lymphoma invading the skin was seen. Then, she was treated with a combination of cyclosporine A and prednisolone for her systemic inflammation related to CAEBV and followed by a systemic chemotherapy for malignant lymphoma. After completing the CHOP chemotherapy (cyclophosphamide, doxorubicin, vincristine, and prednisolone), she gradually showed intermediate liver injury as well as cholestasis, based on which she was diagnosed with secondary hemophagocytic lymphohistiocytosis (HLH) caused by CAEBV. Though etoposide and methylprednisolone combination therapy transiently improved her liver injury and jaundice, CHOP insufficiently controlled the progression of CAEBV. Hence, the combination therapy of etoposide, cytosine arabinoside, l-asparaginase, methylprednisolone, and prednisolone (ESCAP) was preferred over the CHOP therapy. However, her liver injury and jaundice related to HLH rapidly worsened during the recovery period after the first ESCAP therapy. Unfortunately, her disease progression could not be regulated at all and she finally fell into the stage of multiple organ failure; she died at the age of 23 years, 55 months after her first hospital visit. An autopsy was performed with the consent from her parents. Macroscopic findings showed no evidence of ulcer or stenotic changes on her digestive organs, including the small intestine (Fig. 5a). Microscopic findings showed no evidence of noncaseating granuloma on digestive organs and a remarkable proliferation of lymphocytes in the intra-mucosal/submucosal space of the small intestine (Fig. 5b, c).Fig. 1 Various forms of ulcers on digestive organs detected by capsule endoscopy prior to treatment. The surrounding mucosa was free from inflammation. a Multiple aphthous ulcers on the jejunum. b Liner ulcers on the jejunum. c Longitudinal ulcers with a cobblestone appearance on the ileum. d Circular ulcers on ileum
Fig. 2 Entire clinical course of the present case
Fig. 3 Findings of the second capsule endoscopic examination. a, b Ulcer scars on the jejunum and ileum (18 months after the first treatment). c, d Small recurrent erosions on the jejunum and ileum (42 months after the first treatment)
Fig. 4 Histological findings of extranodal NK/T-cell lymphoma (nasal type) associated with continuously activated EBV infection. a Macroscopic finding of skin ulcer on the patient’s thigh, which occurred more than 4 years after the initiation of medical treatment. b Microscopic finding of H&E staining of the skin ulcer. c Microscopic findings revealed high proliferation of EBER-positive atypical lymphocytes in the diseased skin. d Microscopic finding of H&E staining in the intestinal ulcer. e Microscopic immunohistological findings of ileal ulcerative lesions revealed moderate infiltration of many EBER-positive lymphocytes, which demonstrated continuously active EBV infection
Fig. 5 Histological findings of the autopsied small intestine. a Macroscopic observation revealed neither ulcerative changes nor stenotic changes in the small intestine. b Microscopic finding of H&E staining of the intestinal tissue. c Microscopic observation revealed mild lymphocyte proliferation with no atrophy of the intestinal villi (large magnification of H&E staining)
Discussion and conclusion
Chachu and Osterman concluded that "Thoughtful consideration and evaluation of these other potential etiologies through patient history and physical examination, laboratory tests, endoscopic evaluation with targeted biopsies of lesions, and cross-sectional imaging is required to evaluate any patient presenting with symptoms consistent with IBD" [7]. However, it is difficult to completely distinguish CAEBV enteritis from IBD by endoscopic findings only, and it is important to comprehend the clinical features of each disease. To appropriately diagnose CAEBV, it is important to remember the possibility of CAEBV as a differential diagnosis of systemic inflammation [8]. When CAEBV is suspected, the EBV-DNA level in peripheral blood should be checked, even in immunologically denied cases of acute EBV infection. Identification of EBV-infected T and NK cells should be performed for definite diagnosis of CAEBV. Moreover, in situ hybridization (ISH) of EBER by pathological examination and EBV-DNA analysis by flow cytometry should be performed. More details are described in the latest diagnostic criteria of CAEBV [5, 9].
To our knowledge, the first report of a case with gastrointestinal tract complications of CAEBV had serious colorectal bleeding [10]. Later, in the 2000s, there were several reports of CAEBV with gastrointestinal tract complications, which had initially been misdiagnosed as IBD [2–4]. Approximately 6% CAEBV-related deaths originated from intestinal bleeding or perforation [6]. As summarized in the Additional file 2: Table S2, the ulcer morphology of “cobblestone appearance” characteristic of CD [11] was first found in our current case, but this was not observed in all 27 previously reported CAEBV-related enteritis cases [2–4, 10, 12, 13]. According to the endoscopic features of these 28 cases, the diseased lesion was located in the colon (13 cases), small intestine (five cases), concomitant colon and small intestine (five cases), concomitant colon and ileocecal junction (one case), concomitant colon and stomach (one case), ileocecal junction (one case), and unknown location (two cases). Ulcer morphologies have generally been reported as small, shallow, irregular-shaped, and scattered, with the exception of eight cases of huge and profound ulcers. There was also a previous case in which the entire intestinal mucosa displayed lymphangiectasia [3]. In our case, many small aphthous ulcers were found in the whole intestine, and a cobblestone appearance was observed, especially in the ileum, whereas no ulcer was found in the colon. These aphthous ulcers remained after intensive treatment with steroids and biologics. Based on these findings, CAEBV-related enteritis might present various ulcer morphologies depending on the reaction of each therapeutic treatment and/or time course. To detect intestinal lesions, we adopted CE, which has been increasingly used worldwide since its establishment in 2000 [14]. With the advent of CE, various diseases have been clearly visualized, resulting in a paradigm shift in the diagnosis and treatment of small bowel disease. According to a nationwide study in Japan, the frequent findings of CE in patients with CD include cobblestone appearance (occurrence rate: 33%), longitudinal ulcer (78%), irregular ulcer (84%), liner erosion (90%), irregular erosion (89%), circumferential alignment of diminutive lesions (75%), and longitudinal alignment of diminutive lesions (56%) [15]. In this previous study, Esaki et al. observed that the endoscopic diagnosis varied in endoscopist’s clinical knowledge and proficiency; hence, this issue should be overcome. In this case, CD was most probable because ulcers with a cobblestone appearance were detected in the ileum. However, other characteristic findings, such as the bamboo joint-like appearance of the gastric mucosa in esophagogastroduodenoscopy, focally enhanced gastritis, and granuloma on histological evaluation were not actually confirmed.
Thus, a final diagnosis should be comprehensively made based on physical symptoms, medical histories, clinical findings, and culture, imaging, and pathological tests. Even if the characteristic endoscopic findings of specific enteritis are detected, differential diagnosis based only on these findings will be difficult because the characteristic findings of endoscopy do not always correspond to the specific disease. Some enteric diseases might show similar endoscopic appearances, whereas the same disease might demonstrate various phenotypes depending on the time course and severity.
Unfortunately, no successful treatment for CAEBV has yet been established, and further research is needed to improve the outcome in the future [16, 17]. Therefore, it is crucial for clinicians to definitely diagnose CAEBV as quickly as possible.
In conclusion, we diagnosed a rare case of CAEBV, with refractory enteritis as the main clinical symptom and without manifestation of a typical IM feature. Diagnosing CAEBV by ulcer morphology is difficult, even with CE and routine histopathological examination only; thus, clinicians should consider CAEBV as a differential diagnosis of refractory enteritis in younger patients and eagerly check blood EBV-DNA and EBER expression levels by ISH.
Patient perspective
The patient's mother kindly told the authors that the patient had decided to fight her disease, though she had well realized the features and general prognosis of CAEBV.
Supplementary Information
Additional file 1: Supplementary Table S1. Results of her blood test on the first admission.
Additional file 2: Supplementary Table S2. Clinical features of the reported CAEBV cases.
Additional file 3: Figure S1. Endoscopic findings of each digestive organ before treatment. (a) Esophagus, (b) stomach, (c) duodenum, (d) terminal ileum, (e) colon, and (f) rectum. Arrow indicates an ulcerative lesion on the terminal ileum.
Abbreviations
CAEBVChronic active Epstein–Barr virus infection
EBVEpstein–Barr virus
CDCrohn’s disease
IBDInflammatory bowel disease
IMInfectious mononucleosis
CECapsule endoscopy
ADAAdalimumab
USKUstekinumab
EBEREBV-encoded small mRNA
ISHIn situ hybridization
HLHHemophagocytic lymphohistiocytosis
Publisher's Note
Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
Supplementary Information
The online version contains supplementary material available at 10.1186/s12876-020-01589-1.
Acknowledgements
The authors deeply appreciate the mercy of the patient and her parents for accepting the autopsy and publication of this report on her illness.
Authors’ contributions
Writing: YA and KM. Editing: KM. Figure preparation: NS, SN, SK, MU, HM, EI, and H Yagi. Supervision: TN, H Yoshiji, and EK. All authors have read and approved the final version of this manuscript.
Funding
There is nothing to declare.
Availability of data and materials
Data on this case not reported in the manuscript are available from the corresponding author upon reasonable request.
Ethics approval and consent to participate
Ethics committee approval is not required for a single presentation retrospectively. In accordance with the “Patient Rights Regulation” (Date: 01.08.1998; Issue: 23420), which was prepared in accordance with international standards, verbal and wet signed written consent was obtained from the patient under the title of “Consent to publish” to publish patient information and support public health.
Consent for publication
The parents of the patient provided written consent for reporting her case in an international published medical journal, including clinical details and images.
Competing interests
The authors confirm that there are no conflicts of interest to declare. | Subcutaneous | DrugAdministrationRoute | CC BY | 33407170 | 19,233,908 | 2021-01-06 |
What was the dosage of drug 'AZATHIOPRINE'? | Chronic active EBV infection in refractory enteritis with longitudinal ulcers with a cobblestone appearance: an autopsied case report.
BACKGROUND
Chronic active Epstein-Barr virus infection (CAEBV) is defined as Epstein-Barr virus (EBV)-positive T/NK cell-related neoplasia, and its major clinical symptom is systemic inflammation presenting as infectious mononucleocytosis, whereas enteritis and diarrhea are minor clinical symptoms. The complex mixture of tumorigenic processes of EBV-positive cells and physical symptoms of systemic inflammatory disease constitutes the varied phenotypes of CAEBV. Herein, we describe a case of CAEBV that was initially diagnosed as Crohn's disease (CD) based on ileal ulcers and clinical symptoms of enteritis.
METHODS
A 19-year-old woman complained of abdominal pain and fever. Blood examination showed normal blood cell counts without atypical lymphocyte but detected modest inflammation, hypoalbuminemia, slight liver dysfunction, and evidence of past EBV infection. The esophagogastroduodenoscopic findings were normal. However, colonoscopy revealed a few small ulcers in the terminal ileum. The jejunum and ileum also exhibited various forms of ulcers, exhibiting a cobblestone appearance, on capsule endoscopy. Based on these clinical findings, she was strongly suspected with CD. In the course of treatment by steroid and biologics for refractory enteritis, skin ulcers appeared about 50 months after her initial hospital visit. Immunohistology of her skin biopsy revealed proliferation of EBV-encoded small RNA (EBER)-positive atypical lymphocytes. We retrospectively assessed her previous ileal ulcer biopsy before treatment and found many EBER-positive lymphocytes. Blood EBV DNA was also positive. Therefore, she was diagnosed with extranodal NK/T-cell lymphoma with CAEBV-related enteritis rather than CD. She was treated with cyclosporine and prednisolone combination therapy for CAEBV-related systemic inflammation and chemotherapy for malignant lymphoma. Unfortunately, her disease continued to progress, leading to multiple organ failure and death at the age of 23 years.
CONCLUSIONS
Clinicians need to remember the possibility of CAEBV as a differential diagnosis of refractory enteritis. Enteritis with intestinal ulcer is a rare symptom of CAEBV, and it is impossible to acquire a definitive diagnosis by ulcer morphology only. In cases where the possibility of CAEBV remains, tissue EBVR expression should be checked by in situ hybridization and blood EBV DNA.
Background
Enteritis is an inflammatory disease of the small intestine caused by some factors, such as bacterial or viral infections, ischemia, vasculitis, chemical or radiological tissue damage, and immune disorders including inflammatory bowel disease (IBD), with phenotype variation [1]. In fact, few cases of chronic active Epstein–Barr virus (CAEBV) reveal enteritis [2–4]. Previously, CAEBV was thought to be a rare child disease limitedly occurring in the East Asia. However, CAEBV has been recently found to occur worldwide with no relation to patient’s age [5]. Although CAEBV is a phenotype of EBV-lymphoproliferative disorders, its major clinical symptom is systemic inflammation presenting as infectious mononucleosis (IM) and enteritis as well as diarrhea are minor clinical symptoms. The complex mixture of tumorigenic processes associated with EBV-positive cells and the physical symptoms of inflammatory systemic disease constitute the varied phenotypes of CAEBV. The median period between the first visit and the definite diagnosis of CAEBV was 20 months. This extended duration was mainly due to the need to first exclude other diseases or cases where patients were diagnosed with unknown fever [6]. Although CAEBV generally presents with IM-like symptoms, we recently experienced a case of a young woman with CAEBV that appeared with refractory enteritis and was indistinguishable from Crohn’s disease (CD). This report of an autopsied CAEBV case will be of educational help, given the difficulty in acquiring a definite diagnosis.
Case presentation
A 19-year-old woman was referred to our hospital for intermittent abdominal pain and continuous fever which had persisted for a month. She had no obvious medical or familial history. Physical examination revealed no morbid lymph node swelling or skin abnormalities. Blood examination showed normal blood cell counts and no presence of atypical lymphocytes. Biochemical or immunoserum analysis revealed modest inflammation, hypoalbuminemia, slight liver dysfunction, and evidence of past EBV infection (Additional file 1: Table S1). Although esophagogastroduodenoscopy revealed normal findings, colonoscopy revealed a few small ulcers in the terminal ileum (Additional file 3: Fig. 1). Enhanced computed tomography showed obvious wall thickness of the small intestine, whereas no significant finding was detected by balloon intestinal endoscopy in the distal ileum. However, various types of ulcers surrounded by completely normal mucosa were found on the jejunum and proximal ileum by capsule endoscopy (CE) (Fig. 1). Additionally, multiple aphthous and some linear ulcers were observed on the jejunum, whereas circular ulcers and longitudinal ulcers with a cobblestone appearance were detected on the ileum. The possibility of intestinal tuberculosis and infectious gastroenteritis were serologically and culturally excluded. Although there were no histological findings of noncaseating granuloma on her digestive organs, she was strongly suspected with CD based on her age, clinical symptoms, and the morphology of the characteristic ulcers (Fig. 2). Consequently, the patient was treated with an elemental diet, mesalamine, and prednisolone for induction therapy. Although this treatment seemed to be partially effective, her symptoms recurred according to the tapering of prednisolone, and she was subsequently switched to adalimumab (ADA). Her clinical symptoms tended to be gradually modest, and the maintenance ADA therapy was effective for some time. The second CE revealed a definite improvement of the intestinal ulcers (Fig. 3a, b); however, 21 months after the initiation of treatment, her intermittent fever and repeated abdominal pain recurred, and re-induction therapy with prednisolone was restarted (Fig. 2). She remained stable for 9 months, before complaining of slight abdominal pain. We set a dose escalation of ADA with the addition of azathioprine; this seemed to be effective, and almost all of the ulcers disappeared, except for a few small erosions on the intestine (Fig. 3c, d). She next relapsed approximately 10 months later, and ADA was switched to ustekinumab (USK). However, this treatment was not sufficient, and prednisolone was added to USK for clinical improvement. Unfortunately, disease management was difficult regardless of these treatments, and skin ulcers appeared about 50 months after her initial hospital visit (Fig. 4a). Immunohistology of her skin biopsy revealed proliferation of EBV-encoded small RNA (EBER)-positive atypical lymphocytes (Fig. 4b, c). Retrospective assessments of the previous ileal ulcer biopsy before treatment demonstrated many EBER-positive lymphocytes, indicating that she had been in a continuously active EBV infection state (Fig. 4d, e). The blood level of EBV-DNA was also clearly positive (1.5 × 104 copy/WBC × 106). Consequently, she was diagnosed with extranodal NK/T-cell lymphoma (nasal type) related to CAEBV. Advanced-stage malignant lymphoma invading the skin was seen. Then, she was treated with a combination of cyclosporine A and prednisolone for her systemic inflammation related to CAEBV and followed by a systemic chemotherapy for malignant lymphoma. After completing the CHOP chemotherapy (cyclophosphamide, doxorubicin, vincristine, and prednisolone), she gradually showed intermediate liver injury as well as cholestasis, based on which she was diagnosed with secondary hemophagocytic lymphohistiocytosis (HLH) caused by CAEBV. Though etoposide and methylprednisolone combination therapy transiently improved her liver injury and jaundice, CHOP insufficiently controlled the progression of CAEBV. Hence, the combination therapy of etoposide, cytosine arabinoside, l-asparaginase, methylprednisolone, and prednisolone (ESCAP) was preferred over the CHOP therapy. However, her liver injury and jaundice related to HLH rapidly worsened during the recovery period after the first ESCAP therapy. Unfortunately, her disease progression could not be regulated at all and she finally fell into the stage of multiple organ failure; she died at the age of 23 years, 55 months after her first hospital visit. An autopsy was performed with the consent from her parents. Macroscopic findings showed no evidence of ulcer or stenotic changes on her digestive organs, including the small intestine (Fig. 5a). Microscopic findings showed no evidence of noncaseating granuloma on digestive organs and a remarkable proliferation of lymphocytes in the intra-mucosal/submucosal space of the small intestine (Fig. 5b, c).Fig. 1 Various forms of ulcers on digestive organs detected by capsule endoscopy prior to treatment. The surrounding mucosa was free from inflammation. a Multiple aphthous ulcers on the jejunum. b Liner ulcers on the jejunum. c Longitudinal ulcers with a cobblestone appearance on the ileum. d Circular ulcers on ileum
Fig. 2 Entire clinical course of the present case
Fig. 3 Findings of the second capsule endoscopic examination. a, b Ulcer scars on the jejunum and ileum (18 months after the first treatment). c, d Small recurrent erosions on the jejunum and ileum (42 months after the first treatment)
Fig. 4 Histological findings of extranodal NK/T-cell lymphoma (nasal type) associated with continuously activated EBV infection. a Macroscopic finding of skin ulcer on the patient’s thigh, which occurred more than 4 years after the initiation of medical treatment. b Microscopic finding of H&E staining of the skin ulcer. c Microscopic findings revealed high proliferation of EBER-positive atypical lymphocytes in the diseased skin. d Microscopic finding of H&E staining in the intestinal ulcer. e Microscopic immunohistological findings of ileal ulcerative lesions revealed moderate infiltration of many EBER-positive lymphocytes, which demonstrated continuously active EBV infection
Fig. 5 Histological findings of the autopsied small intestine. a Macroscopic observation revealed neither ulcerative changes nor stenotic changes in the small intestine. b Microscopic finding of H&E staining of the intestinal tissue. c Microscopic observation revealed mild lymphocyte proliferation with no atrophy of the intestinal villi (large magnification of H&E staining)
Discussion and conclusion
Chachu and Osterman concluded that "Thoughtful consideration and evaluation of these other potential etiologies through patient history and physical examination, laboratory tests, endoscopic evaluation with targeted biopsies of lesions, and cross-sectional imaging is required to evaluate any patient presenting with symptoms consistent with IBD" [7]. However, it is difficult to completely distinguish CAEBV enteritis from IBD by endoscopic findings only, and it is important to comprehend the clinical features of each disease. To appropriately diagnose CAEBV, it is important to remember the possibility of CAEBV as a differential diagnosis of systemic inflammation [8]. When CAEBV is suspected, the EBV-DNA level in peripheral blood should be checked, even in immunologically denied cases of acute EBV infection. Identification of EBV-infected T and NK cells should be performed for definite diagnosis of CAEBV. Moreover, in situ hybridization (ISH) of EBER by pathological examination and EBV-DNA analysis by flow cytometry should be performed. More details are described in the latest diagnostic criteria of CAEBV [5, 9].
To our knowledge, the first report of a case with gastrointestinal tract complications of CAEBV had serious colorectal bleeding [10]. Later, in the 2000s, there were several reports of CAEBV with gastrointestinal tract complications, which had initially been misdiagnosed as IBD [2–4]. Approximately 6% CAEBV-related deaths originated from intestinal bleeding or perforation [6]. As summarized in the Additional file 2: Table S2, the ulcer morphology of “cobblestone appearance” characteristic of CD [11] was first found in our current case, but this was not observed in all 27 previously reported CAEBV-related enteritis cases [2–4, 10, 12, 13]. According to the endoscopic features of these 28 cases, the diseased lesion was located in the colon (13 cases), small intestine (five cases), concomitant colon and small intestine (five cases), concomitant colon and ileocecal junction (one case), concomitant colon and stomach (one case), ileocecal junction (one case), and unknown location (two cases). Ulcer morphologies have generally been reported as small, shallow, irregular-shaped, and scattered, with the exception of eight cases of huge and profound ulcers. There was also a previous case in which the entire intestinal mucosa displayed lymphangiectasia [3]. In our case, many small aphthous ulcers were found in the whole intestine, and a cobblestone appearance was observed, especially in the ileum, whereas no ulcer was found in the colon. These aphthous ulcers remained after intensive treatment with steroids and biologics. Based on these findings, CAEBV-related enteritis might present various ulcer morphologies depending on the reaction of each therapeutic treatment and/or time course. To detect intestinal lesions, we adopted CE, which has been increasingly used worldwide since its establishment in 2000 [14]. With the advent of CE, various diseases have been clearly visualized, resulting in a paradigm shift in the diagnosis and treatment of small bowel disease. According to a nationwide study in Japan, the frequent findings of CE in patients with CD include cobblestone appearance (occurrence rate: 33%), longitudinal ulcer (78%), irregular ulcer (84%), liner erosion (90%), irregular erosion (89%), circumferential alignment of diminutive lesions (75%), and longitudinal alignment of diminutive lesions (56%) [15]. In this previous study, Esaki et al. observed that the endoscopic diagnosis varied in endoscopist’s clinical knowledge and proficiency; hence, this issue should be overcome. In this case, CD was most probable because ulcers with a cobblestone appearance were detected in the ileum. However, other characteristic findings, such as the bamboo joint-like appearance of the gastric mucosa in esophagogastroduodenoscopy, focally enhanced gastritis, and granuloma on histological evaluation were not actually confirmed.
Thus, a final diagnosis should be comprehensively made based on physical symptoms, medical histories, clinical findings, and culture, imaging, and pathological tests. Even if the characteristic endoscopic findings of specific enteritis are detected, differential diagnosis based only on these findings will be difficult because the characteristic findings of endoscopy do not always correspond to the specific disease. Some enteric diseases might show similar endoscopic appearances, whereas the same disease might demonstrate various phenotypes depending on the time course and severity.
Unfortunately, no successful treatment for CAEBV has yet been established, and further research is needed to improve the outcome in the future [16, 17]. Therefore, it is crucial for clinicians to definitely diagnose CAEBV as quickly as possible.
In conclusion, we diagnosed a rare case of CAEBV, with refractory enteritis as the main clinical symptom and without manifestation of a typical IM feature. Diagnosing CAEBV by ulcer morphology is difficult, even with CE and routine histopathological examination only; thus, clinicians should consider CAEBV as a differential diagnosis of refractory enteritis in younger patients and eagerly check blood EBV-DNA and EBER expression levels by ISH.
Patient perspective
The patient's mother kindly told the authors that the patient had decided to fight her disease, though she had well realized the features and general prognosis of CAEBV.
Supplementary Information
Additional file 1: Supplementary Table S1. Results of her blood test on the first admission.
Additional file 2: Supplementary Table S2. Clinical features of the reported CAEBV cases.
Additional file 3: Figure S1. Endoscopic findings of each digestive organ before treatment. (a) Esophagus, (b) stomach, (c) duodenum, (d) terminal ileum, (e) colon, and (f) rectum. Arrow indicates an ulcerative lesion on the terminal ileum.
Abbreviations
CAEBVChronic active Epstein–Barr virus infection
EBVEpstein–Barr virus
CDCrohn’s disease
IBDInflammatory bowel disease
IMInfectious mononucleosis
CECapsule endoscopy
ADAAdalimumab
USKUstekinumab
EBEREBV-encoded small mRNA
ISHIn situ hybridization
HLHHemophagocytic lymphohistiocytosis
Publisher's Note
Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
Supplementary Information
The online version contains supplementary material available at 10.1186/s12876-020-01589-1.
Acknowledgements
The authors deeply appreciate the mercy of the patient and her parents for accepting the autopsy and publication of this report on her illness.
Authors’ contributions
Writing: YA and KM. Editing: KM. Figure preparation: NS, SN, SK, MU, HM, EI, and H Yagi. Supervision: TN, H Yoshiji, and EK. All authors have read and approved the final version of this manuscript.
Funding
There is nothing to declare.
Availability of data and materials
Data on this case not reported in the manuscript are available from the corresponding author upon reasonable request.
Ethics approval and consent to participate
Ethics committee approval is not required for a single presentation retrospectively. In accordance with the “Patient Rights Regulation” (Date: 01.08.1998; Issue: 23420), which was prepared in accordance with international standards, verbal and wet signed written consent was obtained from the patient under the title of “Consent to publish” to publish patient information and support public health.
Consent for publication
The parents of the patient provided written consent for reporting her case in an international published medical journal, including clinical details and images.
Competing interests
The authors confirm that there are no conflicts of interest to declare. | 100 mg (milligrams). | DrugDosage | CC BY | 33407170 | 19,233,908 | 2021-01-06 |
What was the outcome of reaction 'Condition aggravated'? | Chronic active EBV infection in refractory enteritis with longitudinal ulcers with a cobblestone appearance: an autopsied case report.
BACKGROUND
Chronic active Epstein-Barr virus infection (CAEBV) is defined as Epstein-Barr virus (EBV)-positive T/NK cell-related neoplasia, and its major clinical symptom is systemic inflammation presenting as infectious mononucleocytosis, whereas enteritis and diarrhea are minor clinical symptoms. The complex mixture of tumorigenic processes of EBV-positive cells and physical symptoms of systemic inflammatory disease constitutes the varied phenotypes of CAEBV. Herein, we describe a case of CAEBV that was initially diagnosed as Crohn's disease (CD) based on ileal ulcers and clinical symptoms of enteritis.
METHODS
A 19-year-old woman complained of abdominal pain and fever. Blood examination showed normal blood cell counts without atypical lymphocyte but detected modest inflammation, hypoalbuminemia, slight liver dysfunction, and evidence of past EBV infection. The esophagogastroduodenoscopic findings were normal. However, colonoscopy revealed a few small ulcers in the terminal ileum. The jejunum and ileum also exhibited various forms of ulcers, exhibiting a cobblestone appearance, on capsule endoscopy. Based on these clinical findings, she was strongly suspected with CD. In the course of treatment by steroid and biologics for refractory enteritis, skin ulcers appeared about 50 months after her initial hospital visit. Immunohistology of her skin biopsy revealed proliferation of EBV-encoded small RNA (EBER)-positive atypical lymphocytes. We retrospectively assessed her previous ileal ulcer biopsy before treatment and found many EBER-positive lymphocytes. Blood EBV DNA was also positive. Therefore, she was diagnosed with extranodal NK/T-cell lymphoma with CAEBV-related enteritis rather than CD. She was treated with cyclosporine and prednisolone combination therapy for CAEBV-related systemic inflammation and chemotherapy for malignant lymphoma. Unfortunately, her disease continued to progress, leading to multiple organ failure and death at the age of 23 years.
CONCLUSIONS
Clinicians need to remember the possibility of CAEBV as a differential diagnosis of refractory enteritis. Enteritis with intestinal ulcer is a rare symptom of CAEBV, and it is impossible to acquire a definitive diagnosis by ulcer morphology only. In cases where the possibility of CAEBV remains, tissue EBVR expression should be checked by in situ hybridization and blood EBV DNA.
Background
Enteritis is an inflammatory disease of the small intestine caused by some factors, such as bacterial or viral infections, ischemia, vasculitis, chemical or radiological tissue damage, and immune disorders including inflammatory bowel disease (IBD), with phenotype variation [1]. In fact, few cases of chronic active Epstein–Barr virus (CAEBV) reveal enteritis [2–4]. Previously, CAEBV was thought to be a rare child disease limitedly occurring in the East Asia. However, CAEBV has been recently found to occur worldwide with no relation to patient’s age [5]. Although CAEBV is a phenotype of EBV-lymphoproliferative disorders, its major clinical symptom is systemic inflammation presenting as infectious mononucleosis (IM) and enteritis as well as diarrhea are minor clinical symptoms. The complex mixture of tumorigenic processes associated with EBV-positive cells and the physical symptoms of inflammatory systemic disease constitute the varied phenotypes of CAEBV. The median period between the first visit and the definite diagnosis of CAEBV was 20 months. This extended duration was mainly due to the need to first exclude other diseases or cases where patients were diagnosed with unknown fever [6]. Although CAEBV generally presents with IM-like symptoms, we recently experienced a case of a young woman with CAEBV that appeared with refractory enteritis and was indistinguishable from Crohn’s disease (CD). This report of an autopsied CAEBV case will be of educational help, given the difficulty in acquiring a definite diagnosis.
Case presentation
A 19-year-old woman was referred to our hospital for intermittent abdominal pain and continuous fever which had persisted for a month. She had no obvious medical or familial history. Physical examination revealed no morbid lymph node swelling or skin abnormalities. Blood examination showed normal blood cell counts and no presence of atypical lymphocytes. Biochemical or immunoserum analysis revealed modest inflammation, hypoalbuminemia, slight liver dysfunction, and evidence of past EBV infection (Additional file 1: Table S1). Although esophagogastroduodenoscopy revealed normal findings, colonoscopy revealed a few small ulcers in the terminal ileum (Additional file 3: Fig. 1). Enhanced computed tomography showed obvious wall thickness of the small intestine, whereas no significant finding was detected by balloon intestinal endoscopy in the distal ileum. However, various types of ulcers surrounded by completely normal mucosa were found on the jejunum and proximal ileum by capsule endoscopy (CE) (Fig. 1). Additionally, multiple aphthous and some linear ulcers were observed on the jejunum, whereas circular ulcers and longitudinal ulcers with a cobblestone appearance were detected on the ileum. The possibility of intestinal tuberculosis and infectious gastroenteritis were serologically and culturally excluded. Although there were no histological findings of noncaseating granuloma on her digestive organs, she was strongly suspected with CD based on her age, clinical symptoms, and the morphology of the characteristic ulcers (Fig. 2). Consequently, the patient was treated with an elemental diet, mesalamine, and prednisolone for induction therapy. Although this treatment seemed to be partially effective, her symptoms recurred according to the tapering of prednisolone, and she was subsequently switched to adalimumab (ADA). Her clinical symptoms tended to be gradually modest, and the maintenance ADA therapy was effective for some time. The second CE revealed a definite improvement of the intestinal ulcers (Fig. 3a, b); however, 21 months after the initiation of treatment, her intermittent fever and repeated abdominal pain recurred, and re-induction therapy with prednisolone was restarted (Fig. 2). She remained stable for 9 months, before complaining of slight abdominal pain. We set a dose escalation of ADA with the addition of azathioprine; this seemed to be effective, and almost all of the ulcers disappeared, except for a few small erosions on the intestine (Fig. 3c, d). She next relapsed approximately 10 months later, and ADA was switched to ustekinumab (USK). However, this treatment was not sufficient, and prednisolone was added to USK for clinical improvement. Unfortunately, disease management was difficult regardless of these treatments, and skin ulcers appeared about 50 months after her initial hospital visit (Fig. 4a). Immunohistology of her skin biopsy revealed proliferation of EBV-encoded small RNA (EBER)-positive atypical lymphocytes (Fig. 4b, c). Retrospective assessments of the previous ileal ulcer biopsy before treatment demonstrated many EBER-positive lymphocytes, indicating that she had been in a continuously active EBV infection state (Fig. 4d, e). The blood level of EBV-DNA was also clearly positive (1.5 × 104 copy/WBC × 106). Consequently, she was diagnosed with extranodal NK/T-cell lymphoma (nasal type) related to CAEBV. Advanced-stage malignant lymphoma invading the skin was seen. Then, she was treated with a combination of cyclosporine A and prednisolone for her systemic inflammation related to CAEBV and followed by a systemic chemotherapy for malignant lymphoma. After completing the CHOP chemotherapy (cyclophosphamide, doxorubicin, vincristine, and prednisolone), she gradually showed intermediate liver injury as well as cholestasis, based on which she was diagnosed with secondary hemophagocytic lymphohistiocytosis (HLH) caused by CAEBV. Though etoposide and methylprednisolone combination therapy transiently improved her liver injury and jaundice, CHOP insufficiently controlled the progression of CAEBV. Hence, the combination therapy of etoposide, cytosine arabinoside, l-asparaginase, methylprednisolone, and prednisolone (ESCAP) was preferred over the CHOP therapy. However, her liver injury and jaundice related to HLH rapidly worsened during the recovery period after the first ESCAP therapy. Unfortunately, her disease progression could not be regulated at all and she finally fell into the stage of multiple organ failure; she died at the age of 23 years, 55 months after her first hospital visit. An autopsy was performed with the consent from her parents. Macroscopic findings showed no evidence of ulcer or stenotic changes on her digestive organs, including the small intestine (Fig. 5a). Microscopic findings showed no evidence of noncaseating granuloma on digestive organs and a remarkable proliferation of lymphocytes in the intra-mucosal/submucosal space of the small intestine (Fig. 5b, c).Fig. 1 Various forms of ulcers on digestive organs detected by capsule endoscopy prior to treatment. The surrounding mucosa was free from inflammation. a Multiple aphthous ulcers on the jejunum. b Liner ulcers on the jejunum. c Longitudinal ulcers with a cobblestone appearance on the ileum. d Circular ulcers on ileum
Fig. 2 Entire clinical course of the present case
Fig. 3 Findings of the second capsule endoscopic examination. a, b Ulcer scars on the jejunum and ileum (18 months after the first treatment). c, d Small recurrent erosions on the jejunum and ileum (42 months after the first treatment)
Fig. 4 Histological findings of extranodal NK/T-cell lymphoma (nasal type) associated with continuously activated EBV infection. a Macroscopic finding of skin ulcer on the patient’s thigh, which occurred more than 4 years after the initiation of medical treatment. b Microscopic finding of H&E staining of the skin ulcer. c Microscopic findings revealed high proliferation of EBER-positive atypical lymphocytes in the diseased skin. d Microscopic finding of H&E staining in the intestinal ulcer. e Microscopic immunohistological findings of ileal ulcerative lesions revealed moderate infiltration of many EBER-positive lymphocytes, which demonstrated continuously active EBV infection
Fig. 5 Histological findings of the autopsied small intestine. a Macroscopic observation revealed neither ulcerative changes nor stenotic changes in the small intestine. b Microscopic finding of H&E staining of the intestinal tissue. c Microscopic observation revealed mild lymphocyte proliferation with no atrophy of the intestinal villi (large magnification of H&E staining)
Discussion and conclusion
Chachu and Osterman concluded that "Thoughtful consideration and evaluation of these other potential etiologies through patient history and physical examination, laboratory tests, endoscopic evaluation with targeted biopsies of lesions, and cross-sectional imaging is required to evaluate any patient presenting with symptoms consistent with IBD" [7]. However, it is difficult to completely distinguish CAEBV enteritis from IBD by endoscopic findings only, and it is important to comprehend the clinical features of each disease. To appropriately diagnose CAEBV, it is important to remember the possibility of CAEBV as a differential diagnosis of systemic inflammation [8]. When CAEBV is suspected, the EBV-DNA level in peripheral blood should be checked, even in immunologically denied cases of acute EBV infection. Identification of EBV-infected T and NK cells should be performed for definite diagnosis of CAEBV. Moreover, in situ hybridization (ISH) of EBER by pathological examination and EBV-DNA analysis by flow cytometry should be performed. More details are described in the latest diagnostic criteria of CAEBV [5, 9].
To our knowledge, the first report of a case with gastrointestinal tract complications of CAEBV had serious colorectal bleeding [10]. Later, in the 2000s, there were several reports of CAEBV with gastrointestinal tract complications, which had initially been misdiagnosed as IBD [2–4]. Approximately 6% CAEBV-related deaths originated from intestinal bleeding or perforation [6]. As summarized in the Additional file 2: Table S2, the ulcer morphology of “cobblestone appearance” characteristic of CD [11] was first found in our current case, but this was not observed in all 27 previously reported CAEBV-related enteritis cases [2–4, 10, 12, 13]. According to the endoscopic features of these 28 cases, the diseased lesion was located in the colon (13 cases), small intestine (five cases), concomitant colon and small intestine (five cases), concomitant colon and ileocecal junction (one case), concomitant colon and stomach (one case), ileocecal junction (one case), and unknown location (two cases). Ulcer morphologies have generally been reported as small, shallow, irregular-shaped, and scattered, with the exception of eight cases of huge and profound ulcers. There was also a previous case in which the entire intestinal mucosa displayed lymphangiectasia [3]. In our case, many small aphthous ulcers were found in the whole intestine, and a cobblestone appearance was observed, especially in the ileum, whereas no ulcer was found in the colon. These aphthous ulcers remained after intensive treatment with steroids and biologics. Based on these findings, CAEBV-related enteritis might present various ulcer morphologies depending on the reaction of each therapeutic treatment and/or time course. To detect intestinal lesions, we adopted CE, which has been increasingly used worldwide since its establishment in 2000 [14]. With the advent of CE, various diseases have been clearly visualized, resulting in a paradigm shift in the diagnosis and treatment of small bowel disease. According to a nationwide study in Japan, the frequent findings of CE in patients with CD include cobblestone appearance (occurrence rate: 33%), longitudinal ulcer (78%), irregular ulcer (84%), liner erosion (90%), irregular erosion (89%), circumferential alignment of diminutive lesions (75%), and longitudinal alignment of diminutive lesions (56%) [15]. In this previous study, Esaki et al. observed that the endoscopic diagnosis varied in endoscopist’s clinical knowledge and proficiency; hence, this issue should be overcome. In this case, CD was most probable because ulcers with a cobblestone appearance were detected in the ileum. However, other characteristic findings, such as the bamboo joint-like appearance of the gastric mucosa in esophagogastroduodenoscopy, focally enhanced gastritis, and granuloma on histological evaluation were not actually confirmed.
Thus, a final diagnosis should be comprehensively made based on physical symptoms, medical histories, clinical findings, and culture, imaging, and pathological tests. Even if the characteristic endoscopic findings of specific enteritis are detected, differential diagnosis based only on these findings will be difficult because the characteristic findings of endoscopy do not always correspond to the specific disease. Some enteric diseases might show similar endoscopic appearances, whereas the same disease might demonstrate various phenotypes depending on the time course and severity.
Unfortunately, no successful treatment for CAEBV has yet been established, and further research is needed to improve the outcome in the future [16, 17]. Therefore, it is crucial for clinicians to definitely diagnose CAEBV as quickly as possible.
In conclusion, we diagnosed a rare case of CAEBV, with refractory enteritis as the main clinical symptom and without manifestation of a typical IM feature. Diagnosing CAEBV by ulcer morphology is difficult, even with CE and routine histopathological examination only; thus, clinicians should consider CAEBV as a differential diagnosis of refractory enteritis in younger patients and eagerly check blood EBV-DNA and EBER expression levels by ISH.
Patient perspective
The patient's mother kindly told the authors that the patient had decided to fight her disease, though she had well realized the features and general prognosis of CAEBV.
Supplementary Information
Additional file 1: Supplementary Table S1. Results of her blood test on the first admission.
Additional file 2: Supplementary Table S2. Clinical features of the reported CAEBV cases.
Additional file 3: Figure S1. Endoscopic findings of each digestive organ before treatment. (a) Esophagus, (b) stomach, (c) duodenum, (d) terminal ileum, (e) colon, and (f) rectum. Arrow indicates an ulcerative lesion on the terminal ileum.
Abbreviations
CAEBVChronic active Epstein–Barr virus infection
EBVEpstein–Barr virus
CDCrohn’s disease
IBDInflammatory bowel disease
IMInfectious mononucleosis
CECapsule endoscopy
ADAAdalimumab
USKUstekinumab
EBEREBV-encoded small mRNA
ISHIn situ hybridization
HLHHemophagocytic lymphohistiocytosis
Publisher's Note
Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
Supplementary Information
The online version contains supplementary material available at 10.1186/s12876-020-01589-1.
Acknowledgements
The authors deeply appreciate the mercy of the patient and her parents for accepting the autopsy and publication of this report on her illness.
Authors’ contributions
Writing: YA and KM. Editing: KM. Figure preparation: NS, SN, SK, MU, HM, EI, and H Yagi. Supervision: TN, H Yoshiji, and EK. All authors have read and approved the final version of this manuscript.
Funding
There is nothing to declare.
Availability of data and materials
Data on this case not reported in the manuscript are available from the corresponding author upon reasonable request.
Ethics approval and consent to participate
Ethics committee approval is not required for a single presentation retrospectively. In accordance with the “Patient Rights Regulation” (Date: 01.08.1998; Issue: 23420), which was prepared in accordance with international standards, verbal and wet signed written consent was obtained from the patient under the title of “Consent to publish” to publish patient information and support public health.
Consent for publication
The parents of the patient provided written consent for reporting her case in an international published medical journal, including clinical details and images.
Competing interests
The authors confirm that there are no conflicts of interest to declare. | Fatal | ReactionOutcome | CC BY | 33407170 | 19,246,748 | 2021-01-06 |
What was the outcome of reaction 'Haemophagocytic lymphohistiocytosis'? | Chronic active EBV infection in refractory enteritis with longitudinal ulcers with a cobblestone appearance: an autopsied case report.
BACKGROUND
Chronic active Epstein-Barr virus infection (CAEBV) is defined as Epstein-Barr virus (EBV)-positive T/NK cell-related neoplasia, and its major clinical symptom is systemic inflammation presenting as infectious mononucleocytosis, whereas enteritis and diarrhea are minor clinical symptoms. The complex mixture of tumorigenic processes of EBV-positive cells and physical symptoms of systemic inflammatory disease constitutes the varied phenotypes of CAEBV. Herein, we describe a case of CAEBV that was initially diagnosed as Crohn's disease (CD) based on ileal ulcers and clinical symptoms of enteritis.
METHODS
A 19-year-old woman complained of abdominal pain and fever. Blood examination showed normal blood cell counts without atypical lymphocyte but detected modest inflammation, hypoalbuminemia, slight liver dysfunction, and evidence of past EBV infection. The esophagogastroduodenoscopic findings were normal. However, colonoscopy revealed a few small ulcers in the terminal ileum. The jejunum and ileum also exhibited various forms of ulcers, exhibiting a cobblestone appearance, on capsule endoscopy. Based on these clinical findings, she was strongly suspected with CD. In the course of treatment by steroid and biologics for refractory enteritis, skin ulcers appeared about 50 months after her initial hospital visit. Immunohistology of her skin biopsy revealed proliferation of EBV-encoded small RNA (EBER)-positive atypical lymphocytes. We retrospectively assessed her previous ileal ulcer biopsy before treatment and found many EBER-positive lymphocytes. Blood EBV DNA was also positive. Therefore, she was diagnosed with extranodal NK/T-cell lymphoma with CAEBV-related enteritis rather than CD. She was treated with cyclosporine and prednisolone combination therapy for CAEBV-related systemic inflammation and chemotherapy for malignant lymphoma. Unfortunately, her disease continued to progress, leading to multiple organ failure and death at the age of 23 years.
CONCLUSIONS
Clinicians need to remember the possibility of CAEBV as a differential diagnosis of refractory enteritis. Enteritis with intestinal ulcer is a rare symptom of CAEBV, and it is impossible to acquire a definitive diagnosis by ulcer morphology only. In cases where the possibility of CAEBV remains, tissue EBVR expression should be checked by in situ hybridization and blood EBV DNA.
Background
Enteritis is an inflammatory disease of the small intestine caused by some factors, such as bacterial or viral infections, ischemia, vasculitis, chemical or radiological tissue damage, and immune disorders including inflammatory bowel disease (IBD), with phenotype variation [1]. In fact, few cases of chronic active Epstein–Barr virus (CAEBV) reveal enteritis [2–4]. Previously, CAEBV was thought to be a rare child disease limitedly occurring in the East Asia. However, CAEBV has been recently found to occur worldwide with no relation to patient’s age [5]. Although CAEBV is a phenotype of EBV-lymphoproliferative disorders, its major clinical symptom is systemic inflammation presenting as infectious mononucleosis (IM) and enteritis as well as diarrhea are minor clinical symptoms. The complex mixture of tumorigenic processes associated with EBV-positive cells and the physical symptoms of inflammatory systemic disease constitute the varied phenotypes of CAEBV. The median period between the first visit and the definite diagnosis of CAEBV was 20 months. This extended duration was mainly due to the need to first exclude other diseases or cases where patients were diagnosed with unknown fever [6]. Although CAEBV generally presents with IM-like symptoms, we recently experienced a case of a young woman with CAEBV that appeared with refractory enteritis and was indistinguishable from Crohn’s disease (CD). This report of an autopsied CAEBV case will be of educational help, given the difficulty in acquiring a definite diagnosis.
Case presentation
A 19-year-old woman was referred to our hospital for intermittent abdominal pain and continuous fever which had persisted for a month. She had no obvious medical or familial history. Physical examination revealed no morbid lymph node swelling or skin abnormalities. Blood examination showed normal blood cell counts and no presence of atypical lymphocytes. Biochemical or immunoserum analysis revealed modest inflammation, hypoalbuminemia, slight liver dysfunction, and evidence of past EBV infection (Additional file 1: Table S1). Although esophagogastroduodenoscopy revealed normal findings, colonoscopy revealed a few small ulcers in the terminal ileum (Additional file 3: Fig. 1). Enhanced computed tomography showed obvious wall thickness of the small intestine, whereas no significant finding was detected by balloon intestinal endoscopy in the distal ileum. However, various types of ulcers surrounded by completely normal mucosa were found on the jejunum and proximal ileum by capsule endoscopy (CE) (Fig. 1). Additionally, multiple aphthous and some linear ulcers were observed on the jejunum, whereas circular ulcers and longitudinal ulcers with a cobblestone appearance were detected on the ileum. The possibility of intestinal tuberculosis and infectious gastroenteritis were serologically and culturally excluded. Although there were no histological findings of noncaseating granuloma on her digestive organs, she was strongly suspected with CD based on her age, clinical symptoms, and the morphology of the characteristic ulcers (Fig. 2). Consequently, the patient was treated with an elemental diet, mesalamine, and prednisolone for induction therapy. Although this treatment seemed to be partially effective, her symptoms recurred according to the tapering of prednisolone, and she was subsequently switched to adalimumab (ADA). Her clinical symptoms tended to be gradually modest, and the maintenance ADA therapy was effective for some time. The second CE revealed a definite improvement of the intestinal ulcers (Fig. 3a, b); however, 21 months after the initiation of treatment, her intermittent fever and repeated abdominal pain recurred, and re-induction therapy with prednisolone was restarted (Fig. 2). She remained stable for 9 months, before complaining of slight abdominal pain. We set a dose escalation of ADA with the addition of azathioprine; this seemed to be effective, and almost all of the ulcers disappeared, except for a few small erosions on the intestine (Fig. 3c, d). She next relapsed approximately 10 months later, and ADA was switched to ustekinumab (USK). However, this treatment was not sufficient, and prednisolone was added to USK for clinical improvement. Unfortunately, disease management was difficult regardless of these treatments, and skin ulcers appeared about 50 months after her initial hospital visit (Fig. 4a). Immunohistology of her skin biopsy revealed proliferation of EBV-encoded small RNA (EBER)-positive atypical lymphocytes (Fig. 4b, c). Retrospective assessments of the previous ileal ulcer biopsy before treatment demonstrated many EBER-positive lymphocytes, indicating that she had been in a continuously active EBV infection state (Fig. 4d, e). The blood level of EBV-DNA was also clearly positive (1.5 × 104 copy/WBC × 106). Consequently, she was diagnosed with extranodal NK/T-cell lymphoma (nasal type) related to CAEBV. Advanced-stage malignant lymphoma invading the skin was seen. Then, she was treated with a combination of cyclosporine A and prednisolone for her systemic inflammation related to CAEBV and followed by a systemic chemotherapy for malignant lymphoma. After completing the CHOP chemotherapy (cyclophosphamide, doxorubicin, vincristine, and prednisolone), she gradually showed intermediate liver injury as well as cholestasis, based on which she was diagnosed with secondary hemophagocytic lymphohistiocytosis (HLH) caused by CAEBV. Though etoposide and methylprednisolone combination therapy transiently improved her liver injury and jaundice, CHOP insufficiently controlled the progression of CAEBV. Hence, the combination therapy of etoposide, cytosine arabinoside, l-asparaginase, methylprednisolone, and prednisolone (ESCAP) was preferred over the CHOP therapy. However, her liver injury and jaundice related to HLH rapidly worsened during the recovery period after the first ESCAP therapy. Unfortunately, her disease progression could not be regulated at all and she finally fell into the stage of multiple organ failure; she died at the age of 23 years, 55 months after her first hospital visit. An autopsy was performed with the consent from her parents. Macroscopic findings showed no evidence of ulcer or stenotic changes on her digestive organs, including the small intestine (Fig. 5a). Microscopic findings showed no evidence of noncaseating granuloma on digestive organs and a remarkable proliferation of lymphocytes in the intra-mucosal/submucosal space of the small intestine (Fig. 5b, c).Fig. 1 Various forms of ulcers on digestive organs detected by capsule endoscopy prior to treatment. The surrounding mucosa was free from inflammation. a Multiple aphthous ulcers on the jejunum. b Liner ulcers on the jejunum. c Longitudinal ulcers with a cobblestone appearance on the ileum. d Circular ulcers on ileum
Fig. 2 Entire clinical course of the present case
Fig. 3 Findings of the second capsule endoscopic examination. a, b Ulcer scars on the jejunum and ileum (18 months after the first treatment). c, d Small recurrent erosions on the jejunum and ileum (42 months after the first treatment)
Fig. 4 Histological findings of extranodal NK/T-cell lymphoma (nasal type) associated with continuously activated EBV infection. a Macroscopic finding of skin ulcer on the patient’s thigh, which occurred more than 4 years after the initiation of medical treatment. b Microscopic finding of H&E staining of the skin ulcer. c Microscopic findings revealed high proliferation of EBER-positive atypical lymphocytes in the diseased skin. d Microscopic finding of H&E staining in the intestinal ulcer. e Microscopic immunohistological findings of ileal ulcerative lesions revealed moderate infiltration of many EBER-positive lymphocytes, which demonstrated continuously active EBV infection
Fig. 5 Histological findings of the autopsied small intestine. a Macroscopic observation revealed neither ulcerative changes nor stenotic changes in the small intestine. b Microscopic finding of H&E staining of the intestinal tissue. c Microscopic observation revealed mild lymphocyte proliferation with no atrophy of the intestinal villi (large magnification of H&E staining)
Discussion and conclusion
Chachu and Osterman concluded that "Thoughtful consideration and evaluation of these other potential etiologies through patient history and physical examination, laboratory tests, endoscopic evaluation with targeted biopsies of lesions, and cross-sectional imaging is required to evaluate any patient presenting with symptoms consistent with IBD" [7]. However, it is difficult to completely distinguish CAEBV enteritis from IBD by endoscopic findings only, and it is important to comprehend the clinical features of each disease. To appropriately diagnose CAEBV, it is important to remember the possibility of CAEBV as a differential diagnosis of systemic inflammation [8]. When CAEBV is suspected, the EBV-DNA level in peripheral blood should be checked, even in immunologically denied cases of acute EBV infection. Identification of EBV-infected T and NK cells should be performed for definite diagnosis of CAEBV. Moreover, in situ hybridization (ISH) of EBER by pathological examination and EBV-DNA analysis by flow cytometry should be performed. More details are described in the latest diagnostic criteria of CAEBV [5, 9].
To our knowledge, the first report of a case with gastrointestinal tract complications of CAEBV had serious colorectal bleeding [10]. Later, in the 2000s, there were several reports of CAEBV with gastrointestinal tract complications, which had initially been misdiagnosed as IBD [2–4]. Approximately 6% CAEBV-related deaths originated from intestinal bleeding or perforation [6]. As summarized in the Additional file 2: Table S2, the ulcer morphology of “cobblestone appearance” characteristic of CD [11] was first found in our current case, but this was not observed in all 27 previously reported CAEBV-related enteritis cases [2–4, 10, 12, 13]. According to the endoscopic features of these 28 cases, the diseased lesion was located in the colon (13 cases), small intestine (five cases), concomitant colon and small intestine (five cases), concomitant colon and ileocecal junction (one case), concomitant colon and stomach (one case), ileocecal junction (one case), and unknown location (two cases). Ulcer morphologies have generally been reported as small, shallow, irregular-shaped, and scattered, with the exception of eight cases of huge and profound ulcers. There was also a previous case in which the entire intestinal mucosa displayed lymphangiectasia [3]. In our case, many small aphthous ulcers were found in the whole intestine, and a cobblestone appearance was observed, especially in the ileum, whereas no ulcer was found in the colon. These aphthous ulcers remained after intensive treatment with steroids and biologics. Based on these findings, CAEBV-related enteritis might present various ulcer morphologies depending on the reaction of each therapeutic treatment and/or time course. To detect intestinal lesions, we adopted CE, which has been increasingly used worldwide since its establishment in 2000 [14]. With the advent of CE, various diseases have been clearly visualized, resulting in a paradigm shift in the diagnosis and treatment of small bowel disease. According to a nationwide study in Japan, the frequent findings of CE in patients with CD include cobblestone appearance (occurrence rate: 33%), longitudinal ulcer (78%), irregular ulcer (84%), liner erosion (90%), irregular erosion (89%), circumferential alignment of diminutive lesions (75%), and longitudinal alignment of diminutive lesions (56%) [15]. In this previous study, Esaki et al. observed that the endoscopic diagnosis varied in endoscopist’s clinical knowledge and proficiency; hence, this issue should be overcome. In this case, CD was most probable because ulcers with a cobblestone appearance were detected in the ileum. However, other characteristic findings, such as the bamboo joint-like appearance of the gastric mucosa in esophagogastroduodenoscopy, focally enhanced gastritis, and granuloma on histological evaluation were not actually confirmed.
Thus, a final diagnosis should be comprehensively made based on physical symptoms, medical histories, clinical findings, and culture, imaging, and pathological tests. Even if the characteristic endoscopic findings of specific enteritis are detected, differential diagnosis based only on these findings will be difficult because the characteristic findings of endoscopy do not always correspond to the specific disease. Some enteric diseases might show similar endoscopic appearances, whereas the same disease might demonstrate various phenotypes depending on the time course and severity.
Unfortunately, no successful treatment for CAEBV has yet been established, and further research is needed to improve the outcome in the future [16, 17]. Therefore, it is crucial for clinicians to definitely diagnose CAEBV as quickly as possible.
In conclusion, we diagnosed a rare case of CAEBV, with refractory enteritis as the main clinical symptom and without manifestation of a typical IM feature. Diagnosing CAEBV by ulcer morphology is difficult, even with CE and routine histopathological examination only; thus, clinicians should consider CAEBV as a differential diagnosis of refractory enteritis in younger patients and eagerly check blood EBV-DNA and EBER expression levels by ISH.
Patient perspective
The patient's mother kindly told the authors that the patient had decided to fight her disease, though she had well realized the features and general prognosis of CAEBV.
Supplementary Information
Additional file 1: Supplementary Table S1. Results of her blood test on the first admission.
Additional file 2: Supplementary Table S2. Clinical features of the reported CAEBV cases.
Additional file 3: Figure S1. Endoscopic findings of each digestive organ before treatment. (a) Esophagus, (b) stomach, (c) duodenum, (d) terminal ileum, (e) colon, and (f) rectum. Arrow indicates an ulcerative lesion on the terminal ileum.
Abbreviations
CAEBVChronic active Epstein–Barr virus infection
EBVEpstein–Barr virus
CDCrohn’s disease
IBDInflammatory bowel disease
IMInfectious mononucleosis
CECapsule endoscopy
ADAAdalimumab
USKUstekinumab
EBEREBV-encoded small mRNA
ISHIn situ hybridization
HLHHemophagocytic lymphohistiocytosis
Publisher's Note
Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
Supplementary Information
The online version contains supplementary material available at 10.1186/s12876-020-01589-1.
Acknowledgements
The authors deeply appreciate the mercy of the patient and her parents for accepting the autopsy and publication of this report on her illness.
Authors’ contributions
Writing: YA and KM. Editing: KM. Figure preparation: NS, SN, SK, MU, HM, EI, and H Yagi. Supervision: TN, H Yoshiji, and EK. All authors have read and approved the final version of this manuscript.
Funding
There is nothing to declare.
Availability of data and materials
Data on this case not reported in the manuscript are available from the corresponding author upon reasonable request.
Ethics approval and consent to participate
Ethics committee approval is not required for a single presentation retrospectively. In accordance with the “Patient Rights Regulation” (Date: 01.08.1998; Issue: 23420), which was prepared in accordance with international standards, verbal and wet signed written consent was obtained from the patient under the title of “Consent to publish” to publish patient information and support public health.
Consent for publication
The parents of the patient provided written consent for reporting her case in an international published medical journal, including clinical details and images.
Competing interests
The authors confirm that there are no conflicts of interest to declare. | Fatal | ReactionOutcome | CC BY | 33407170 | 19,246,748 | 2021-01-06 |
What was the outcome of reaction 'Multiple organ dysfunction syndrome'? | Chronic active EBV infection in refractory enteritis with longitudinal ulcers with a cobblestone appearance: an autopsied case report.
BACKGROUND
Chronic active Epstein-Barr virus infection (CAEBV) is defined as Epstein-Barr virus (EBV)-positive T/NK cell-related neoplasia, and its major clinical symptom is systemic inflammation presenting as infectious mononucleocytosis, whereas enteritis and diarrhea are minor clinical symptoms. The complex mixture of tumorigenic processes of EBV-positive cells and physical symptoms of systemic inflammatory disease constitutes the varied phenotypes of CAEBV. Herein, we describe a case of CAEBV that was initially diagnosed as Crohn's disease (CD) based on ileal ulcers and clinical symptoms of enteritis.
METHODS
A 19-year-old woman complained of abdominal pain and fever. Blood examination showed normal blood cell counts without atypical lymphocyte but detected modest inflammation, hypoalbuminemia, slight liver dysfunction, and evidence of past EBV infection. The esophagogastroduodenoscopic findings were normal. However, colonoscopy revealed a few small ulcers in the terminal ileum. The jejunum and ileum also exhibited various forms of ulcers, exhibiting a cobblestone appearance, on capsule endoscopy. Based on these clinical findings, she was strongly suspected with CD. In the course of treatment by steroid and biologics for refractory enteritis, skin ulcers appeared about 50 months after her initial hospital visit. Immunohistology of her skin biopsy revealed proliferation of EBV-encoded small RNA (EBER)-positive atypical lymphocytes. We retrospectively assessed her previous ileal ulcer biopsy before treatment and found many EBER-positive lymphocytes. Blood EBV DNA was also positive. Therefore, she was diagnosed with extranodal NK/T-cell lymphoma with CAEBV-related enteritis rather than CD. She was treated with cyclosporine and prednisolone combination therapy for CAEBV-related systemic inflammation and chemotherapy for malignant lymphoma. Unfortunately, her disease continued to progress, leading to multiple organ failure and death at the age of 23 years.
CONCLUSIONS
Clinicians need to remember the possibility of CAEBV as a differential diagnosis of refractory enteritis. Enteritis with intestinal ulcer is a rare symptom of CAEBV, and it is impossible to acquire a definitive diagnosis by ulcer morphology only. In cases where the possibility of CAEBV remains, tissue EBVR expression should be checked by in situ hybridization and blood EBV DNA.
Background
Enteritis is an inflammatory disease of the small intestine caused by some factors, such as bacterial or viral infections, ischemia, vasculitis, chemical or radiological tissue damage, and immune disorders including inflammatory bowel disease (IBD), with phenotype variation [1]. In fact, few cases of chronic active Epstein–Barr virus (CAEBV) reveal enteritis [2–4]. Previously, CAEBV was thought to be a rare child disease limitedly occurring in the East Asia. However, CAEBV has been recently found to occur worldwide with no relation to patient’s age [5]. Although CAEBV is a phenotype of EBV-lymphoproliferative disorders, its major clinical symptom is systemic inflammation presenting as infectious mononucleosis (IM) and enteritis as well as diarrhea are minor clinical symptoms. The complex mixture of tumorigenic processes associated with EBV-positive cells and the physical symptoms of inflammatory systemic disease constitute the varied phenotypes of CAEBV. The median period between the first visit and the definite diagnosis of CAEBV was 20 months. This extended duration was mainly due to the need to first exclude other diseases or cases where patients were diagnosed with unknown fever [6]. Although CAEBV generally presents with IM-like symptoms, we recently experienced a case of a young woman with CAEBV that appeared with refractory enteritis and was indistinguishable from Crohn’s disease (CD). This report of an autopsied CAEBV case will be of educational help, given the difficulty in acquiring a definite diagnosis.
Case presentation
A 19-year-old woman was referred to our hospital for intermittent abdominal pain and continuous fever which had persisted for a month. She had no obvious medical or familial history. Physical examination revealed no morbid lymph node swelling or skin abnormalities. Blood examination showed normal blood cell counts and no presence of atypical lymphocytes. Biochemical or immunoserum analysis revealed modest inflammation, hypoalbuminemia, slight liver dysfunction, and evidence of past EBV infection (Additional file 1: Table S1). Although esophagogastroduodenoscopy revealed normal findings, colonoscopy revealed a few small ulcers in the terminal ileum (Additional file 3: Fig. 1). Enhanced computed tomography showed obvious wall thickness of the small intestine, whereas no significant finding was detected by balloon intestinal endoscopy in the distal ileum. However, various types of ulcers surrounded by completely normal mucosa were found on the jejunum and proximal ileum by capsule endoscopy (CE) (Fig. 1). Additionally, multiple aphthous and some linear ulcers were observed on the jejunum, whereas circular ulcers and longitudinal ulcers with a cobblestone appearance were detected on the ileum. The possibility of intestinal tuberculosis and infectious gastroenteritis were serologically and culturally excluded. Although there were no histological findings of noncaseating granuloma on her digestive organs, she was strongly suspected with CD based on her age, clinical symptoms, and the morphology of the characteristic ulcers (Fig. 2). Consequently, the patient was treated with an elemental diet, mesalamine, and prednisolone for induction therapy. Although this treatment seemed to be partially effective, her symptoms recurred according to the tapering of prednisolone, and she was subsequently switched to adalimumab (ADA). Her clinical symptoms tended to be gradually modest, and the maintenance ADA therapy was effective for some time. The second CE revealed a definite improvement of the intestinal ulcers (Fig. 3a, b); however, 21 months after the initiation of treatment, her intermittent fever and repeated abdominal pain recurred, and re-induction therapy with prednisolone was restarted (Fig. 2). She remained stable for 9 months, before complaining of slight abdominal pain. We set a dose escalation of ADA with the addition of azathioprine; this seemed to be effective, and almost all of the ulcers disappeared, except for a few small erosions on the intestine (Fig. 3c, d). She next relapsed approximately 10 months later, and ADA was switched to ustekinumab (USK). However, this treatment was not sufficient, and prednisolone was added to USK for clinical improvement. Unfortunately, disease management was difficult regardless of these treatments, and skin ulcers appeared about 50 months after her initial hospital visit (Fig. 4a). Immunohistology of her skin biopsy revealed proliferation of EBV-encoded small RNA (EBER)-positive atypical lymphocytes (Fig. 4b, c). Retrospective assessments of the previous ileal ulcer biopsy before treatment demonstrated many EBER-positive lymphocytes, indicating that she had been in a continuously active EBV infection state (Fig. 4d, e). The blood level of EBV-DNA was also clearly positive (1.5 × 104 copy/WBC × 106). Consequently, she was diagnosed with extranodal NK/T-cell lymphoma (nasal type) related to CAEBV. Advanced-stage malignant lymphoma invading the skin was seen. Then, she was treated with a combination of cyclosporine A and prednisolone for her systemic inflammation related to CAEBV and followed by a systemic chemotherapy for malignant lymphoma. After completing the CHOP chemotherapy (cyclophosphamide, doxorubicin, vincristine, and prednisolone), she gradually showed intermediate liver injury as well as cholestasis, based on which she was diagnosed with secondary hemophagocytic lymphohistiocytosis (HLH) caused by CAEBV. Though etoposide and methylprednisolone combination therapy transiently improved her liver injury and jaundice, CHOP insufficiently controlled the progression of CAEBV. Hence, the combination therapy of etoposide, cytosine arabinoside, l-asparaginase, methylprednisolone, and prednisolone (ESCAP) was preferred over the CHOP therapy. However, her liver injury and jaundice related to HLH rapidly worsened during the recovery period after the first ESCAP therapy. Unfortunately, her disease progression could not be regulated at all and she finally fell into the stage of multiple organ failure; she died at the age of 23 years, 55 months after her first hospital visit. An autopsy was performed with the consent from her parents. Macroscopic findings showed no evidence of ulcer or stenotic changes on her digestive organs, including the small intestine (Fig. 5a). Microscopic findings showed no evidence of noncaseating granuloma on digestive organs and a remarkable proliferation of lymphocytes in the intra-mucosal/submucosal space of the small intestine (Fig. 5b, c).Fig. 1 Various forms of ulcers on digestive organs detected by capsule endoscopy prior to treatment. The surrounding mucosa was free from inflammation. a Multiple aphthous ulcers on the jejunum. b Liner ulcers on the jejunum. c Longitudinal ulcers with a cobblestone appearance on the ileum. d Circular ulcers on ileum
Fig. 2 Entire clinical course of the present case
Fig. 3 Findings of the second capsule endoscopic examination. a, b Ulcer scars on the jejunum and ileum (18 months after the first treatment). c, d Small recurrent erosions on the jejunum and ileum (42 months after the first treatment)
Fig. 4 Histological findings of extranodal NK/T-cell lymphoma (nasal type) associated with continuously activated EBV infection. a Macroscopic finding of skin ulcer on the patient’s thigh, which occurred more than 4 years after the initiation of medical treatment. b Microscopic finding of H&E staining of the skin ulcer. c Microscopic findings revealed high proliferation of EBER-positive atypical lymphocytes in the diseased skin. d Microscopic finding of H&E staining in the intestinal ulcer. e Microscopic immunohistological findings of ileal ulcerative lesions revealed moderate infiltration of many EBER-positive lymphocytes, which demonstrated continuously active EBV infection
Fig. 5 Histological findings of the autopsied small intestine. a Macroscopic observation revealed neither ulcerative changes nor stenotic changes in the small intestine. b Microscopic finding of H&E staining of the intestinal tissue. c Microscopic observation revealed mild lymphocyte proliferation with no atrophy of the intestinal villi (large magnification of H&E staining)
Discussion and conclusion
Chachu and Osterman concluded that "Thoughtful consideration and evaluation of these other potential etiologies through patient history and physical examination, laboratory tests, endoscopic evaluation with targeted biopsies of lesions, and cross-sectional imaging is required to evaluate any patient presenting with symptoms consistent with IBD" [7]. However, it is difficult to completely distinguish CAEBV enteritis from IBD by endoscopic findings only, and it is important to comprehend the clinical features of each disease. To appropriately diagnose CAEBV, it is important to remember the possibility of CAEBV as a differential diagnosis of systemic inflammation [8]. When CAEBV is suspected, the EBV-DNA level in peripheral blood should be checked, even in immunologically denied cases of acute EBV infection. Identification of EBV-infected T and NK cells should be performed for definite diagnosis of CAEBV. Moreover, in situ hybridization (ISH) of EBER by pathological examination and EBV-DNA analysis by flow cytometry should be performed. More details are described in the latest diagnostic criteria of CAEBV [5, 9].
To our knowledge, the first report of a case with gastrointestinal tract complications of CAEBV had serious colorectal bleeding [10]. Later, in the 2000s, there were several reports of CAEBV with gastrointestinal tract complications, which had initially been misdiagnosed as IBD [2–4]. Approximately 6% CAEBV-related deaths originated from intestinal bleeding or perforation [6]. As summarized in the Additional file 2: Table S2, the ulcer morphology of “cobblestone appearance” characteristic of CD [11] was first found in our current case, but this was not observed in all 27 previously reported CAEBV-related enteritis cases [2–4, 10, 12, 13]. According to the endoscopic features of these 28 cases, the diseased lesion was located in the colon (13 cases), small intestine (five cases), concomitant colon and small intestine (five cases), concomitant colon and ileocecal junction (one case), concomitant colon and stomach (one case), ileocecal junction (one case), and unknown location (two cases). Ulcer morphologies have generally been reported as small, shallow, irregular-shaped, and scattered, with the exception of eight cases of huge and profound ulcers. There was also a previous case in which the entire intestinal mucosa displayed lymphangiectasia [3]. In our case, many small aphthous ulcers were found in the whole intestine, and a cobblestone appearance was observed, especially in the ileum, whereas no ulcer was found in the colon. These aphthous ulcers remained after intensive treatment with steroids and biologics. Based on these findings, CAEBV-related enteritis might present various ulcer morphologies depending on the reaction of each therapeutic treatment and/or time course. To detect intestinal lesions, we adopted CE, which has been increasingly used worldwide since its establishment in 2000 [14]. With the advent of CE, various diseases have been clearly visualized, resulting in a paradigm shift in the diagnosis and treatment of small bowel disease. According to a nationwide study in Japan, the frequent findings of CE in patients with CD include cobblestone appearance (occurrence rate: 33%), longitudinal ulcer (78%), irregular ulcer (84%), liner erosion (90%), irregular erosion (89%), circumferential alignment of diminutive lesions (75%), and longitudinal alignment of diminutive lesions (56%) [15]. In this previous study, Esaki et al. observed that the endoscopic diagnosis varied in endoscopist’s clinical knowledge and proficiency; hence, this issue should be overcome. In this case, CD was most probable because ulcers with a cobblestone appearance were detected in the ileum. However, other characteristic findings, such as the bamboo joint-like appearance of the gastric mucosa in esophagogastroduodenoscopy, focally enhanced gastritis, and granuloma on histological evaluation were not actually confirmed.
Thus, a final diagnosis should be comprehensively made based on physical symptoms, medical histories, clinical findings, and culture, imaging, and pathological tests. Even if the characteristic endoscopic findings of specific enteritis are detected, differential diagnosis based only on these findings will be difficult because the characteristic findings of endoscopy do not always correspond to the specific disease. Some enteric diseases might show similar endoscopic appearances, whereas the same disease might demonstrate various phenotypes depending on the time course and severity.
Unfortunately, no successful treatment for CAEBV has yet been established, and further research is needed to improve the outcome in the future [16, 17]. Therefore, it is crucial for clinicians to definitely diagnose CAEBV as quickly as possible.
In conclusion, we diagnosed a rare case of CAEBV, with refractory enteritis as the main clinical symptom and without manifestation of a typical IM feature. Diagnosing CAEBV by ulcer morphology is difficult, even with CE and routine histopathological examination only; thus, clinicians should consider CAEBV as a differential diagnosis of refractory enteritis in younger patients and eagerly check blood EBV-DNA and EBER expression levels by ISH.
Patient perspective
The patient's mother kindly told the authors that the patient had decided to fight her disease, though she had well realized the features and general prognosis of CAEBV.
Supplementary Information
Additional file 1: Supplementary Table S1. Results of her blood test on the first admission.
Additional file 2: Supplementary Table S2. Clinical features of the reported CAEBV cases.
Additional file 3: Figure S1. Endoscopic findings of each digestive organ before treatment. (a) Esophagus, (b) stomach, (c) duodenum, (d) terminal ileum, (e) colon, and (f) rectum. Arrow indicates an ulcerative lesion on the terminal ileum.
Abbreviations
CAEBVChronic active Epstein–Barr virus infection
EBVEpstein–Barr virus
CDCrohn’s disease
IBDInflammatory bowel disease
IMInfectious mononucleosis
CECapsule endoscopy
ADAAdalimumab
USKUstekinumab
EBEREBV-encoded small mRNA
ISHIn situ hybridization
HLHHemophagocytic lymphohistiocytosis
Publisher's Note
Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
Supplementary Information
The online version contains supplementary material available at 10.1186/s12876-020-01589-1.
Acknowledgements
The authors deeply appreciate the mercy of the patient and her parents for accepting the autopsy and publication of this report on her illness.
Authors’ contributions
Writing: YA and KM. Editing: KM. Figure preparation: NS, SN, SK, MU, HM, EI, and H Yagi. Supervision: TN, H Yoshiji, and EK. All authors have read and approved the final version of this manuscript.
Funding
There is nothing to declare.
Availability of data and materials
Data on this case not reported in the manuscript are available from the corresponding author upon reasonable request.
Ethics approval and consent to participate
Ethics committee approval is not required for a single presentation retrospectively. In accordance with the “Patient Rights Regulation” (Date: 01.08.1998; Issue: 23420), which was prepared in accordance with international standards, verbal and wet signed written consent was obtained from the patient under the title of “Consent to publish” to publish patient information and support public health.
Consent for publication
The parents of the patient provided written consent for reporting her case in an international published medical journal, including clinical details and images.
Competing interests
The authors confirm that there are no conflicts of interest to declare. | Fatal | ReactionOutcome | CC BY | 33407170 | 19,246,748 | 2021-01-06 |
Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Cardiac arrest'. | Klebsiella pneumoniae-related invasive liver abscess syndrome complicated by purulent meningitis: a review of the literature and description of three cases.
BACKGROUND
Klebsiella pneumoniae (K. pneumoniae) invasive liver abscess syndrome (ILAS) with purulent meningitis was rarely identified the mainland of China. Last winter, we received 3 cases of K. pneumoniae meningitis and all of them died in a short time. We report these cases in order to find the reason of high mortality and discuss effective effort to improve these patients' prognosis.
METHODS
Three patients with uncontrolled diabetes developed live abscess and purulent meningitis. Upon admission, the clinical manifestations, laboratory result of blood and cerebrospinal fluid (CSF) and imaging examinations were compatible with K. pneumoniae ILAS which had metastasis infection of meningitis. Even with timely adequate antibiotic therapy and strict glycemic control, all of the patients' condition deteriorated rapidly and died in a short time.
CONCLUSIONS
The reason of patients' poor prognosis might be the absence of liver abscess drainage, high level of CSF protein which indicates severe inflammation and unknown special but stronger virulence factors of K. pneumoniae the patients' living place Zhangjiakou. Strict glycemic control, early drainage of liver abscess and appropriate antibiotic application are recommended for treating this condition, further progress on the pathogenesis and treatment of K. pneumoniae meningitis may help patients gain a better prognosis.
Background
Over a century ago, bacterial meningitis was virtually 100% fatal [1]. Despite current antibiotics being able to clear bacteria from the cerebrospinal fluid (CSF), mortality remains approximately 25%, and, even among survivors, 21–28% of patients have chronic neurologic complications [2, 3]. Streptococcus pneumoniae is the most common bacterial cause of community-acquired meningitis in adults. The distribution of other pathogens, such as Neisseria meningitidis, group B Streptococcus, Haemophilus influenzae and Listeria monocytogenes, depends upon the age of the patient, their vaccination status and the regional epidemiological trends where the patient lives [4, 5]. Besides the more common organisms listed above, Klebsiella pneumoniae (K. pneumoniae) has been reported as a cause of community-acquired meningitis in Taiwan with a mortality rate of 30–40% in patients with liver abscesses [6, 7]. Diabetes and age > 65 years old were independent predictors of septic ocular or CNS complications in patients with liver abscesses [8]. Besides Taiwan, in South Korea, K. pneumoniae was the third most common cause of community-acquired bacterial meningitis [9]. However, K. pneumoniae meningitis is rarely identified in other regions, including mainland China. In 2018, our emergency department received three cases of K. pneumoniae meningitis. These three initially presented with fever and altered mental status, and all three died within two days after admission. We report these cases in order to illustrate the early signs of K. pneumoniae meningitis and discuss potentially effective strategies to improve the prognosis of these patients.
Case presentations
Case 1
At 07:23 on June 3, 2018, we received a 39-year-old male patient in our emergency room. He came from Zhangjiakou in Hebei province, China and presented with five days of fever and three hours of altered mental status. He had a history of poorly controlled diabetes mellitus. At the time of admission, his vital signs included a body temperature of 39 °C, a heart rate of 146 beats/min, blood pressure of 125/84 mmHg, respiratory rate of 42 breaths/min, and an oxygen saturation of 99% on room air. He had a Glasgow coma scale (GCS) of E1 + V1 + M3 with nuchal rigidity on an otherwise unremarkable physical examination.
White blood cell count was 25.73 × 109/L with an elevated neutrophil percentage of 84.9%. The concentration of C-reactive protein (CRP) was > 240 mg/L, glucose was 30 mmol/L, arterial blood gas (ABG) results were as follows (on 3 L/min of oxygen via nasal cannula): pH: 7.09, arterial pressure of CO2 (PaCO2): 9.7 mmHg, arterial pressure of oxygen (PaO2): 141 mmHg, HCO3: 2.8 mmol/L, lactic acid: 3.9 mmol/L, liver and renal function tests were within normal limits. Alb:39 g/L, PCT:2-10 ng/ml. Two sets of peripheral blood cultures were obtained (and were negative). Head and abdominal computed tomography (CT) scans demonstrated diffuse cerebral edema and possible brain and liver abscesses (see Fig. 1).
Fig. 1 a: Head CT scan showed diffuse cerebral edema; b: Abdominal CT scan demonstrating an area of abnormal attenuation measuring 24 mm × 19 mm in the right lobe of the liver, suggestive of a single abscess
The patient next underwent a lumbar puncture examination. The opening pressure was 150 mm H2O. CSF appeared yellow and purulent, revealing a 178,640 × 106/μL white blood cell count with a multinucleated cells percentage of 86.2%, protein 32.41 g/L and glucose 10.2 mmol/L. CSF was submitted for Gram staining and bacterial culture. The above findings led to the diagnoses of purulent meningitis, sepsis, diabetic ketoacidosis (DKA), as well as (possible) brain and liver abscesses. Meropenem 2 g every 8 h combined with vancomycin 1 g every 12 h were given intravenously. Due to the loss of spontaneous breathing, mechanical ventilation was started. Intensive care was begun and his DKA was treated. However, further invasive examinations (e.g. brain or liver abscess aspirations) were deemed too dangerous for him. At 11:41, the patient was transferred to the Emergency Department’s Intensive Care Unit (EICU).
By June 4, the patient’s condition had not improved. His body temperature fluctuated between 35.3 °C and 39.5 °C. His blood pressure dropped to 91/64 mmHg while the pulse rate rose to 142 beats/min. Norepinephrine was pumped venously to maintain a mean arterial pressure (MAP) > 65 mmHg. Pupils were bilaterally dilated at 3 mm’s with a slow light reflex, a GCS score of E1 + (Ventilated) + M1. Based on his worsening situation, emergency bedside lateral ventricular drainage was performed. During the operation, his cerebrospinal fluid was examined again, demonstrating a white blood cell count of 19,054 cells/μL with a multinucleated cells ratio of 78.9%, protein of 1.06 g/L and a glucose level of 0.1 mmol/L. After the operation, his intracranial pressure was consistently over 330mmH2O while undergoing continuous renal replacement therapy along with a maximal dose of mannitol.
K. pneumoniae was isolated from the patient’s cerebrospinal fluid and was found to be sensitive to all tested antibiotics including meropenem. However, the patient’s vital signs deteriorated, and he eventually died of cardiac arrest later on June 4.
Case 2
A 49-year-old woman was admitted to the emergency department of our hospital at 14:00 on July 3, 2018 because of fever and “twitching” for the past three days. She was born and currently lived in Zhangjiakou city of Hebei Province, she had a history of untreated diabetes mellitus and hypertension. At the time of admission, the patient was found to have intermittent convulsions and was unable to cooperate for a physical examination. Her temperature was 38 °C, pulse rate was 152 beats/min, respiratory rate 39 breaths/min, blood pressure was 158/88 mmHg, and her oxygen saturation was 92% on 3 L/min of oxygen via nasal cannula.
The patient’s white blood count was 24.87 × 109/L with an elevated neutrophil percentage of 91.4%, a hemoglobin of 148 g/L and a platelet count of 108 × 109/L. The CRP was 242 mg/L, glucose was 42.4 mmol/L. Arterial blood gas results were as follows (on 3 L/min oxygen via nasal cannula): pH of 7.09, PaCO2: 9.7 mmHg, PaO2: 141 mmHg, HCO3: 2.8 mmol/L, lactic acid: 3.9 mmol/L, creatinine 125 μmol/l, Urea 13.9 mmol/l, other liver and kidney function testing was normal. The patient’s procalcitonin level was > 10 ng/ml. Head CT scans revealed bilateral basal ganglia hemorrhages and a subarachnoid hemorrhage. Abdominal CT scan demonstrated a possible liver abscess (Fig. 2). Puncture examination showed the intracranial pressure was > 330 mm H2O. CSF was pale red and purulent, and revealed 4263 × 106/L white blood cells/μL with multinucleated cells ratio of 43.1%, protein 8.82 g/L and glucose 0.6 mmol/L.
Fig. 2 a and b: head CT scan showed bilateral basal ganglia hemorrhages and a subarachnoid hemorrhage; c: Abdominal CT scan demonstrating an area of abnormal attenuation measuring 18 mm × 14 mm in the right lobe of the liver
The patient was diagnosed with purulent meningitis, septic shock, cerebral hemorrhage, subarachnoid hemorrhage, DKA and a probable liver abscess. The patient was intubated for airway protection and mechanical ventilation was begun. Meropenem 2 g every 8 h was given intravenously, and lateral ventricular drainage was performed at 12:00. After the operation, the patient’s condition did not improve, and she died that afternoon due to cerebral herniation.
Two days later, blood, sputum and cerebrospinal fluid cultures all grew K. pneumoniae (sensitive to all the tested antibiotics including Meropenem).
Case 3
A 62-year-old male also from Zhangjiakou city of Hebei Province with a history of uncontrolled diabetes mellitus was admitted to the emergency department after he developed confusion for the past 11 h. Two days ago, the patient complained of a fever and vomiting. The patient was seen at a different local hospital, but his condition worsened. On arrival to our hospital, his initial vital signs were: body temperature, 37 °C, heart rate 119 beats/min, blood pressure, 159/126 mmHg, respiratory rate, 32 breaths/min, and oxygen saturation 92% on air. His physical examination was significant for a GCS of 5 (E1 + V1 + M3).
His white blood count was 12.39 × 109/L with an elevated neutrophil percentage of 92.8%, hemoglobin 165 g/L and a platelet count 25 × 109/L. ABG results were: pH 7.28, PaCO2: 24.1 mmHg, PaO2: 89.3 mmHg, HCO3: 10.9 mmol/L, lactic acid: 3.4 mmol/L, CRP was > 160 mg/L, procalcitonin > 100 ng/ml, blood glucose was 24.1 mmol/L, alanine transaminase was 139 U/L, total bilirubin/direct bilirubin were 62.0/31.4umol/L, creatinine was 274umol, and urea was 22.79 mmol/L. An abdominal CT scan demonstrated a single liver abscess (Fig. 3). A lumbar puncture was performed after the patient received a platelet transfusion. The opening pressure was too low to measure, and the CSF was a murky yellow and revealed 17,148 × 106/L white blood cells/μL with a multinucleated cells percentage of 84.3%, protein of 12.82 g/L and a glucose of < 0.1 mmol/L. The patient was diagnosed with purulent meningitis, septic shock and DKA. Meropenem 2 g every 8 h combined with vancomycin 1 g every 12 h were given intravenously and blood glucose (BG) was well controlled by insulin. However, the patient got worse and his relatives decided to withdraw care. A telephone follow-up revealed that the patient died on his way back home. Two days later, K. pneumoniae was isolated from his CSF and was sensitive to all available antibiotics.
Fig. 3 Abdominal CT scan demonstrating an area of abnormal attenuation measuring 25 mm × 19 mm in the right lobe of the liver
Discussion and conclusions
Cases of spontaneous K. pneumoniae meningitis are rare and commonly observed in hospitalized postoperative patients. Community-acquired K. pneumoniae meningitis could be associated with an invasive liver abscess syndrome (ILAS). In a study, two cases (2/15, 13.3%) were associated with K. pneumoniae liver abscess. In another study from South Korea, 4 (14.8%) of 27 patients with K. pneumoniae meningitis had a concomitant liver abscess [10]. But this situation is still rare, in a study, only 1 (0.9%) of 112 patients with K. pneumoniae liver abscess had CNS involvement [11]. We reviewed the case reports and related original articles about adult community-acquired K. pneumoniae meningitis and found that only two cases have been recorded in the mainland of China [12, 13]. As all three patients we received died relatively quickly, we summarized above the key points of their diagnosis and treatment and will now shift to analyzing the reasons for our patients’ unfortunate outcomes.
The three patients with community-acquired K. pneumoniae meningitis in this article had poorly controlled T2DM. Meningitis was preceded by an ILAS. Accordingly, when patients with T2DM present with fever, headache, coma and confusion, a high degree of suspicion should be held for ILAS besides meningitis, including possible K. pneumoniae infection [14]. However, sometimes community-acquired K. pneumoniae meningitis appears independently without a liver abscess [13, 15–17]. Besides T2DM, other risk factors may include alcohol-related chronic diseases, especially alcoholic cirrhosis, which is also related to ILAS [15, 16, 18]. The clinical manifestation and high leukocyte, high protein, and low glucose in each patients’ CSF are often found in cases of gram-negative bacilli meningitis [19]. So, the key points for diagnosing community-acquired K. pneumoniae meningitis are risk factors and pathogen culture.
Currently, there are no clear guidelines for the management of K. pneumoniae meningitis as a manifestation of ILAS. Besides strict glycemic control, a combination of early drainage of the abscess and appropriate antibiotic application is the standard treatment for this condition [20]. The selection of antibiotics should be based on in-vitro susceptibilities and clinical response. In view of the better penetration into the CSF, large doses of third-generation cephalosporins including cefotaxime (up to 2 g every four hours) and ceftriaxone (2 g twice a day) are the drugs of choice for K. pneumoniae meningitis. Imipenem and meropenem can be given to patients when strains containing extended-spectrum beta-lactamases are suspected [19]. As reported in the literature, surviving patients with K. pneumoniae meningitis were treated with ceftazidime, ceftriaxone, cefmetazole, cefotaxime, cefepime or meropenem [13, 16, 17, 21–27]. In our cases, K. pneumoniae cultured from the CSF were susceptible to all the remaining antibiotics tested, but meropenem was the antibiotic chosen for all three patients, and vancomycin was also used in two of them.
Unfortunately, each patient’s ending was still tragic. We noticed that the CSF protein levels in our patients (32.41 g/L, 8.82 g/L and 12.82 g/L, respectively) were extremely high. Previous studies of neonatal bacterial meningitis showed that high CSF protein levels, which with an optimal cutoff value of 1.88 g/L [28], were associated with poor prognosis [29–31]. The only reported case of K. pneumoniae meningitis who died mentioned a CSF protein of 2.34 g/L [12]. Another study into the clinical features of patients with adult bacterial meningitis showed the CSF protein levels in such patients with good or poor outcomes were 2.18 ± 1.47 g/L and 4.03 ± 4.19 g/L, respectively [32]. Additionally, white blood cells, immunoglobulins, and complements are normally absent in CSF, but the inflammatory response triggered by bacteria during meningitis results in increasing protein levels in the CSF which coincides with the intensity of the inflammatory response. Cytokines produced in inflammation may cause impairment of cell structure and organ function, thus increasing the risk of morbidity [28]. Overall then, the sky-high level of CSF protein in our patients may have foreshadowed their outcomes.
It is also noteworthy that all three patients came from Zhangjiakou city in Hebei Province. We suspect that the virulence of the K. pneumoniae species in this area may be particularly high. Five major virulence factors of K. pneumoniae are known to contribute to the pathogenesis of infection. These are the capsular serotype, hypermucoviscosity phenotype, lipopolysaccharide, siderophores, and pili. K [10, 33]. Based on previous study, we also know that severe manifestations such as comatose mental status, septic shock, and concomitant extra meningeal infections were more common in community- acquired K. pneumoniae meningitis patients compared with community-acquired Streptococcus pneumoniae meningitis, and the 28-day mortality (44.4% versus 10.7%; P = 0.001) and inhospitable mortality (51.9% versus 14.3%; P = 0.001) were much higher [9]. Besides the 100% mortality, all of the three patients had comatose mental status, septic shock, and live abscesses, the characters tallied with the reported study and may due to the high virulence of K. pneumoniae. What’s worse, multidrug-resistant and hypervirulent (MDR-HV) K. pneumoniae strains had spread in the community, 13 MDR-HV strains were identified from a total of 218 K. pneumoniae liver abscess episodes in a Taiwan Hospital [34]. Given the three cases in our study all occurred in one city in Hebei province, a future study might examine the particular virulence factors of this strain of K. pneumoniae.
Although liver abscess drainage has been recommended for a better clinical response [19] and hepatic resection is preferred for patients with Acute Physiology and Chronic Health Evaluation II (APACHE II) scores of ≥15 [28]. In our cases, liver abscesses were less than 5 cm, Percutaneous drainage for small liver abscess adjacent to the liver capsule can cause complications such as bleeding or peritonitis. The poor outcomes might have no business with the lack of liver abscess drainage.
In conclusion, K. pneumoniae meningitis is a rare cause of meningitis around the world. When patients with risk factors such as T2DM and alcoholic cirrhosis present to the emergency department with clinical features of meningitis, providers should maintain a high degree of suspicion for potential K. pneumoniae-related ILAS complicated by meningitis. Strict glycemic control, early drainage of liver abscesses and appropriate antibiotic application are all recommended for treating this condition. All three patients we received unfortunately died in short order, and it’s uncertain whether emergent liver abscess drainage would have helped at that point given the patients’ already high levels of CSF protein indicating severe inflammation. Potentially unknown virulence factors of K. pneumoniae in Zhangjiakou may also play a role in these patients’ poor outcomes. These cases were shared with the international medical community with the hope for timely diagnoses of K. pneumoniae meningitis in the future and to promote progress on learning more about this bacteria’s pathogenesis and treatment.
Abbreviations
APACHE IIAcute Physiology and Chronic Health Evaluation II
BGBlood glucose
CSFCerebrospinal fluid
CRPC-reactive protein
CTComputed tomography
DKADiabetic ketoacidosis
EDEmergency Department
EICUEmergency Department Intensive Care Unit
GCSGlasgow coma scale
ILASInvasive liver abscess syndrome
K. pneumoniaeKlebsiella pneumoniae bacteria
magAMucoid-associated gene A
rmpARegulator of mucoid phenotype gene A
T2DMType 2 diabetes mellitus
Publisher’s Note
Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
Acknowledgements
Not applicable.
Authors’ contributions
YC X and XZ Y contributed to the study conception and design. Case collection and description were performed by RX S, HZ1 and JX. The first draft of the manuscript was written by RX S and JX, HZ2 revised the study design and initial manuscript, and all authors commented on previous versions of the manuscript. All authors read and approved the final manuscript.
Funding
No funding.
Availability of data and materials
The datasets used and analyzed during the current study are available from the corresponding author on reasonable request.
Ethics approval and consent to participate
The Institutional Review Board (IRB) of Peking Union Medical College Hospital has reviewed the study and has determined that this is a retrospective study and the design is scientifically and is up to the ethics standards. The IRB thus approve the study.
Consent for publication
Consent for publication has been obtained from the patients reported in this article. And each patients next-of-kin have given written consent for their relative’s personal or clinical details along with any identifying images to be published in this study.
Competing interests
The authors declare that they have no conflicts of interests. | MEROPENEM, VANCOMYCIN | DrugsGivenReaction | CC BY | 33407192 | 19,395,094 | 2021-01-06 |
Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Treatment failure'. | Klebsiella pneumoniae-related invasive liver abscess syndrome complicated by purulent meningitis: a review of the literature and description of three cases.
BACKGROUND
Klebsiella pneumoniae (K. pneumoniae) invasive liver abscess syndrome (ILAS) with purulent meningitis was rarely identified the mainland of China. Last winter, we received 3 cases of K. pneumoniae meningitis and all of them died in a short time. We report these cases in order to find the reason of high mortality and discuss effective effort to improve these patients' prognosis.
METHODS
Three patients with uncontrolled diabetes developed live abscess and purulent meningitis. Upon admission, the clinical manifestations, laboratory result of blood and cerebrospinal fluid (CSF) and imaging examinations were compatible with K. pneumoniae ILAS which had metastasis infection of meningitis. Even with timely adequate antibiotic therapy and strict glycemic control, all of the patients' condition deteriorated rapidly and died in a short time.
CONCLUSIONS
The reason of patients' poor prognosis might be the absence of liver abscess drainage, high level of CSF protein which indicates severe inflammation and unknown special but stronger virulence factors of K. pneumoniae the patients' living place Zhangjiakou. Strict glycemic control, early drainage of liver abscess and appropriate antibiotic application are recommended for treating this condition, further progress on the pathogenesis and treatment of K. pneumoniae meningitis may help patients gain a better prognosis.
Background
Over a century ago, bacterial meningitis was virtually 100% fatal [1]. Despite current antibiotics being able to clear bacteria from the cerebrospinal fluid (CSF), mortality remains approximately 25%, and, even among survivors, 21–28% of patients have chronic neurologic complications [2, 3]. Streptococcus pneumoniae is the most common bacterial cause of community-acquired meningitis in adults. The distribution of other pathogens, such as Neisseria meningitidis, group B Streptococcus, Haemophilus influenzae and Listeria monocytogenes, depends upon the age of the patient, their vaccination status and the regional epidemiological trends where the patient lives [4, 5]. Besides the more common organisms listed above, Klebsiella pneumoniae (K. pneumoniae) has been reported as a cause of community-acquired meningitis in Taiwan with a mortality rate of 30–40% in patients with liver abscesses [6, 7]. Diabetes and age > 65 years old were independent predictors of septic ocular or CNS complications in patients with liver abscesses [8]. Besides Taiwan, in South Korea, K. pneumoniae was the third most common cause of community-acquired bacterial meningitis [9]. However, K. pneumoniae meningitis is rarely identified in other regions, including mainland China. In 2018, our emergency department received three cases of K. pneumoniae meningitis. These three initially presented with fever and altered mental status, and all three died within two days after admission. We report these cases in order to illustrate the early signs of K. pneumoniae meningitis and discuss potentially effective strategies to improve the prognosis of these patients.
Case presentations
Case 1
At 07:23 on June 3, 2018, we received a 39-year-old male patient in our emergency room. He came from Zhangjiakou in Hebei province, China and presented with five days of fever and three hours of altered mental status. He had a history of poorly controlled diabetes mellitus. At the time of admission, his vital signs included a body temperature of 39 °C, a heart rate of 146 beats/min, blood pressure of 125/84 mmHg, respiratory rate of 42 breaths/min, and an oxygen saturation of 99% on room air. He had a Glasgow coma scale (GCS) of E1 + V1 + M3 with nuchal rigidity on an otherwise unremarkable physical examination.
White blood cell count was 25.73 × 109/L with an elevated neutrophil percentage of 84.9%. The concentration of C-reactive protein (CRP) was > 240 mg/L, glucose was 30 mmol/L, arterial blood gas (ABG) results were as follows (on 3 L/min of oxygen via nasal cannula): pH: 7.09, arterial pressure of CO2 (PaCO2): 9.7 mmHg, arterial pressure of oxygen (PaO2): 141 mmHg, HCO3: 2.8 mmol/L, lactic acid: 3.9 mmol/L, liver and renal function tests were within normal limits. Alb:39 g/L, PCT:2-10 ng/ml. Two sets of peripheral blood cultures were obtained (and were negative). Head and abdominal computed tomography (CT) scans demonstrated diffuse cerebral edema and possible brain and liver abscesses (see Fig. 1).
Fig. 1 a: Head CT scan showed diffuse cerebral edema; b: Abdominal CT scan demonstrating an area of abnormal attenuation measuring 24 mm × 19 mm in the right lobe of the liver, suggestive of a single abscess
The patient next underwent a lumbar puncture examination. The opening pressure was 150 mm H2O. CSF appeared yellow and purulent, revealing a 178,640 × 106/μL white blood cell count with a multinucleated cells percentage of 86.2%, protein 32.41 g/L and glucose 10.2 mmol/L. CSF was submitted for Gram staining and bacterial culture. The above findings led to the diagnoses of purulent meningitis, sepsis, diabetic ketoacidosis (DKA), as well as (possible) brain and liver abscesses. Meropenem 2 g every 8 h combined with vancomycin 1 g every 12 h were given intravenously. Due to the loss of spontaneous breathing, mechanical ventilation was started. Intensive care was begun and his DKA was treated. However, further invasive examinations (e.g. brain or liver abscess aspirations) were deemed too dangerous for him. At 11:41, the patient was transferred to the Emergency Department’s Intensive Care Unit (EICU).
By June 4, the patient’s condition had not improved. His body temperature fluctuated between 35.3 °C and 39.5 °C. His blood pressure dropped to 91/64 mmHg while the pulse rate rose to 142 beats/min. Norepinephrine was pumped venously to maintain a mean arterial pressure (MAP) > 65 mmHg. Pupils were bilaterally dilated at 3 mm’s with a slow light reflex, a GCS score of E1 + (Ventilated) + M1. Based on his worsening situation, emergency bedside lateral ventricular drainage was performed. During the operation, his cerebrospinal fluid was examined again, demonstrating a white blood cell count of 19,054 cells/μL with a multinucleated cells ratio of 78.9%, protein of 1.06 g/L and a glucose level of 0.1 mmol/L. After the operation, his intracranial pressure was consistently over 330mmH2O while undergoing continuous renal replacement therapy along with a maximal dose of mannitol.
K. pneumoniae was isolated from the patient’s cerebrospinal fluid and was found to be sensitive to all tested antibiotics including meropenem. However, the patient’s vital signs deteriorated, and he eventually died of cardiac arrest later on June 4.
Case 2
A 49-year-old woman was admitted to the emergency department of our hospital at 14:00 on July 3, 2018 because of fever and “twitching” for the past three days. She was born and currently lived in Zhangjiakou city of Hebei Province, she had a history of untreated diabetes mellitus and hypertension. At the time of admission, the patient was found to have intermittent convulsions and was unable to cooperate for a physical examination. Her temperature was 38 °C, pulse rate was 152 beats/min, respiratory rate 39 breaths/min, blood pressure was 158/88 mmHg, and her oxygen saturation was 92% on 3 L/min of oxygen via nasal cannula.
The patient’s white blood count was 24.87 × 109/L with an elevated neutrophil percentage of 91.4%, a hemoglobin of 148 g/L and a platelet count of 108 × 109/L. The CRP was 242 mg/L, glucose was 42.4 mmol/L. Arterial blood gas results were as follows (on 3 L/min oxygen via nasal cannula): pH of 7.09, PaCO2: 9.7 mmHg, PaO2: 141 mmHg, HCO3: 2.8 mmol/L, lactic acid: 3.9 mmol/L, creatinine 125 μmol/l, Urea 13.9 mmol/l, other liver and kidney function testing was normal. The patient’s procalcitonin level was > 10 ng/ml. Head CT scans revealed bilateral basal ganglia hemorrhages and a subarachnoid hemorrhage. Abdominal CT scan demonstrated a possible liver abscess (Fig. 2). Puncture examination showed the intracranial pressure was > 330 mm H2O. CSF was pale red and purulent, and revealed 4263 × 106/L white blood cells/μL with multinucleated cells ratio of 43.1%, protein 8.82 g/L and glucose 0.6 mmol/L.
Fig. 2 a and b: head CT scan showed bilateral basal ganglia hemorrhages and a subarachnoid hemorrhage; c: Abdominal CT scan demonstrating an area of abnormal attenuation measuring 18 mm × 14 mm in the right lobe of the liver
The patient was diagnosed with purulent meningitis, septic shock, cerebral hemorrhage, subarachnoid hemorrhage, DKA and a probable liver abscess. The patient was intubated for airway protection and mechanical ventilation was begun. Meropenem 2 g every 8 h was given intravenously, and lateral ventricular drainage was performed at 12:00. After the operation, the patient’s condition did not improve, and she died that afternoon due to cerebral herniation.
Two days later, blood, sputum and cerebrospinal fluid cultures all grew K. pneumoniae (sensitive to all the tested antibiotics including Meropenem).
Case 3
A 62-year-old male also from Zhangjiakou city of Hebei Province with a history of uncontrolled diabetes mellitus was admitted to the emergency department after he developed confusion for the past 11 h. Two days ago, the patient complained of a fever and vomiting. The patient was seen at a different local hospital, but his condition worsened. On arrival to our hospital, his initial vital signs were: body temperature, 37 °C, heart rate 119 beats/min, blood pressure, 159/126 mmHg, respiratory rate, 32 breaths/min, and oxygen saturation 92% on air. His physical examination was significant for a GCS of 5 (E1 + V1 + M3).
His white blood count was 12.39 × 109/L with an elevated neutrophil percentage of 92.8%, hemoglobin 165 g/L and a platelet count 25 × 109/L. ABG results were: pH 7.28, PaCO2: 24.1 mmHg, PaO2: 89.3 mmHg, HCO3: 10.9 mmol/L, lactic acid: 3.4 mmol/L, CRP was > 160 mg/L, procalcitonin > 100 ng/ml, blood glucose was 24.1 mmol/L, alanine transaminase was 139 U/L, total bilirubin/direct bilirubin were 62.0/31.4umol/L, creatinine was 274umol, and urea was 22.79 mmol/L. An abdominal CT scan demonstrated a single liver abscess (Fig. 3). A lumbar puncture was performed after the patient received a platelet transfusion. The opening pressure was too low to measure, and the CSF was a murky yellow and revealed 17,148 × 106/L white blood cells/μL with a multinucleated cells percentage of 84.3%, protein of 12.82 g/L and a glucose of < 0.1 mmol/L. The patient was diagnosed with purulent meningitis, septic shock and DKA. Meropenem 2 g every 8 h combined with vancomycin 1 g every 12 h were given intravenously and blood glucose (BG) was well controlled by insulin. However, the patient got worse and his relatives decided to withdraw care. A telephone follow-up revealed that the patient died on his way back home. Two days later, K. pneumoniae was isolated from his CSF and was sensitive to all available antibiotics.
Fig. 3 Abdominal CT scan demonstrating an area of abnormal attenuation measuring 25 mm × 19 mm in the right lobe of the liver
Discussion and conclusions
Cases of spontaneous K. pneumoniae meningitis are rare and commonly observed in hospitalized postoperative patients. Community-acquired K. pneumoniae meningitis could be associated with an invasive liver abscess syndrome (ILAS). In a study, two cases (2/15, 13.3%) were associated with K. pneumoniae liver abscess. In another study from South Korea, 4 (14.8%) of 27 patients with K. pneumoniae meningitis had a concomitant liver abscess [10]. But this situation is still rare, in a study, only 1 (0.9%) of 112 patients with K. pneumoniae liver abscess had CNS involvement [11]. We reviewed the case reports and related original articles about adult community-acquired K. pneumoniae meningitis and found that only two cases have been recorded in the mainland of China [12, 13]. As all three patients we received died relatively quickly, we summarized above the key points of their diagnosis and treatment and will now shift to analyzing the reasons for our patients’ unfortunate outcomes.
The three patients with community-acquired K. pneumoniae meningitis in this article had poorly controlled T2DM. Meningitis was preceded by an ILAS. Accordingly, when patients with T2DM present with fever, headache, coma and confusion, a high degree of suspicion should be held for ILAS besides meningitis, including possible K. pneumoniae infection [14]. However, sometimes community-acquired K. pneumoniae meningitis appears independently without a liver abscess [13, 15–17]. Besides T2DM, other risk factors may include alcohol-related chronic diseases, especially alcoholic cirrhosis, which is also related to ILAS [15, 16, 18]. The clinical manifestation and high leukocyte, high protein, and low glucose in each patients’ CSF are often found in cases of gram-negative bacilli meningitis [19]. So, the key points for diagnosing community-acquired K. pneumoniae meningitis are risk factors and pathogen culture.
Currently, there are no clear guidelines for the management of K. pneumoniae meningitis as a manifestation of ILAS. Besides strict glycemic control, a combination of early drainage of the abscess and appropriate antibiotic application is the standard treatment for this condition [20]. The selection of antibiotics should be based on in-vitro susceptibilities and clinical response. In view of the better penetration into the CSF, large doses of third-generation cephalosporins including cefotaxime (up to 2 g every four hours) and ceftriaxone (2 g twice a day) are the drugs of choice for K. pneumoniae meningitis. Imipenem and meropenem can be given to patients when strains containing extended-spectrum beta-lactamases are suspected [19]. As reported in the literature, surviving patients with K. pneumoniae meningitis were treated with ceftazidime, ceftriaxone, cefmetazole, cefotaxime, cefepime or meropenem [13, 16, 17, 21–27]. In our cases, K. pneumoniae cultured from the CSF were susceptible to all the remaining antibiotics tested, but meropenem was the antibiotic chosen for all three patients, and vancomycin was also used in two of them.
Unfortunately, each patient’s ending was still tragic. We noticed that the CSF protein levels in our patients (32.41 g/L, 8.82 g/L and 12.82 g/L, respectively) were extremely high. Previous studies of neonatal bacterial meningitis showed that high CSF protein levels, which with an optimal cutoff value of 1.88 g/L [28], were associated with poor prognosis [29–31]. The only reported case of K. pneumoniae meningitis who died mentioned a CSF protein of 2.34 g/L [12]. Another study into the clinical features of patients with adult bacterial meningitis showed the CSF protein levels in such patients with good or poor outcomes were 2.18 ± 1.47 g/L and 4.03 ± 4.19 g/L, respectively [32]. Additionally, white blood cells, immunoglobulins, and complements are normally absent in CSF, but the inflammatory response triggered by bacteria during meningitis results in increasing protein levels in the CSF which coincides with the intensity of the inflammatory response. Cytokines produced in inflammation may cause impairment of cell structure and organ function, thus increasing the risk of morbidity [28]. Overall then, the sky-high level of CSF protein in our patients may have foreshadowed their outcomes.
It is also noteworthy that all three patients came from Zhangjiakou city in Hebei Province. We suspect that the virulence of the K. pneumoniae species in this area may be particularly high. Five major virulence factors of K. pneumoniae are known to contribute to the pathogenesis of infection. These are the capsular serotype, hypermucoviscosity phenotype, lipopolysaccharide, siderophores, and pili. K [10, 33]. Based on previous study, we also know that severe manifestations such as comatose mental status, septic shock, and concomitant extra meningeal infections were more common in community- acquired K. pneumoniae meningitis patients compared with community-acquired Streptococcus pneumoniae meningitis, and the 28-day mortality (44.4% versus 10.7%; P = 0.001) and inhospitable mortality (51.9% versus 14.3%; P = 0.001) were much higher [9]. Besides the 100% mortality, all of the three patients had comatose mental status, septic shock, and live abscesses, the characters tallied with the reported study and may due to the high virulence of K. pneumoniae. What’s worse, multidrug-resistant and hypervirulent (MDR-HV) K. pneumoniae strains had spread in the community, 13 MDR-HV strains were identified from a total of 218 K. pneumoniae liver abscess episodes in a Taiwan Hospital [34]. Given the three cases in our study all occurred in one city in Hebei province, a future study might examine the particular virulence factors of this strain of K. pneumoniae.
Although liver abscess drainage has been recommended for a better clinical response [19] and hepatic resection is preferred for patients with Acute Physiology and Chronic Health Evaluation II (APACHE II) scores of ≥15 [28]. In our cases, liver abscesses were less than 5 cm, Percutaneous drainage for small liver abscess adjacent to the liver capsule can cause complications such as bleeding or peritonitis. The poor outcomes might have no business with the lack of liver abscess drainage.
In conclusion, K. pneumoniae meningitis is a rare cause of meningitis around the world. When patients with risk factors such as T2DM and alcoholic cirrhosis present to the emergency department with clinical features of meningitis, providers should maintain a high degree of suspicion for potential K. pneumoniae-related ILAS complicated by meningitis. Strict glycemic control, early drainage of liver abscesses and appropriate antibiotic application are all recommended for treating this condition. All three patients we received unfortunately died in short order, and it’s uncertain whether emergent liver abscess drainage would have helped at that point given the patients’ already high levels of CSF protein indicating severe inflammation. Potentially unknown virulence factors of K. pneumoniae in Zhangjiakou may also play a role in these patients’ poor outcomes. These cases were shared with the international medical community with the hope for timely diagnoses of K. pneumoniae meningitis in the future and to promote progress on learning more about this bacteria’s pathogenesis and treatment.
Abbreviations
APACHE IIAcute Physiology and Chronic Health Evaluation II
BGBlood glucose
CSFCerebrospinal fluid
CRPC-reactive protein
CTComputed tomography
DKADiabetic ketoacidosis
EDEmergency Department
EICUEmergency Department Intensive Care Unit
GCSGlasgow coma scale
ILASInvasive liver abscess syndrome
K. pneumoniaeKlebsiella pneumoniae bacteria
magAMucoid-associated gene A
rmpARegulator of mucoid phenotype gene A
T2DMType 2 diabetes mellitus
Publisher’s Note
Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
Acknowledgements
Not applicable.
Authors’ contributions
YC X and XZ Y contributed to the study conception and design. Case collection and description were performed by RX S, HZ1 and JX. The first draft of the manuscript was written by RX S and JX, HZ2 revised the study design and initial manuscript, and all authors commented on previous versions of the manuscript. All authors read and approved the final manuscript.
Funding
No funding.
Availability of data and materials
The datasets used and analyzed during the current study are available from the corresponding author on reasonable request.
Ethics approval and consent to participate
The Institutional Review Board (IRB) of Peking Union Medical College Hospital has reviewed the study and has determined that this is a retrospective study and the design is scientifically and is up to the ethics standards. The IRB thus approve the study.
Consent for publication
Consent for publication has been obtained from the patients reported in this article. And each patients next-of-kin have given written consent for their relative’s personal or clinical details along with any identifying images to be published in this study.
Competing interests
The authors declare that they have no conflicts of interests. | MEROPENEM, VANCOMYCIN | DrugsGivenReaction | CC BY | 33407192 | 19,395,094 | 2021-01-06 |
What was the administration route of drug 'MEROPENEM'? | Klebsiella pneumoniae-related invasive liver abscess syndrome complicated by purulent meningitis: a review of the literature and description of three cases.
BACKGROUND
Klebsiella pneumoniae (K. pneumoniae) invasive liver abscess syndrome (ILAS) with purulent meningitis was rarely identified the mainland of China. Last winter, we received 3 cases of K. pneumoniae meningitis and all of them died in a short time. We report these cases in order to find the reason of high mortality and discuss effective effort to improve these patients' prognosis.
METHODS
Three patients with uncontrolled diabetes developed live abscess and purulent meningitis. Upon admission, the clinical manifestations, laboratory result of blood and cerebrospinal fluid (CSF) and imaging examinations were compatible with K. pneumoniae ILAS which had metastasis infection of meningitis. Even with timely adequate antibiotic therapy and strict glycemic control, all of the patients' condition deteriorated rapidly and died in a short time.
CONCLUSIONS
The reason of patients' poor prognosis might be the absence of liver abscess drainage, high level of CSF protein which indicates severe inflammation and unknown special but stronger virulence factors of K. pneumoniae the patients' living place Zhangjiakou. Strict glycemic control, early drainage of liver abscess and appropriate antibiotic application are recommended for treating this condition, further progress on the pathogenesis and treatment of K. pneumoniae meningitis may help patients gain a better prognosis.
Background
Over a century ago, bacterial meningitis was virtually 100% fatal [1]. Despite current antibiotics being able to clear bacteria from the cerebrospinal fluid (CSF), mortality remains approximately 25%, and, even among survivors, 21–28% of patients have chronic neurologic complications [2, 3]. Streptococcus pneumoniae is the most common bacterial cause of community-acquired meningitis in adults. The distribution of other pathogens, such as Neisseria meningitidis, group B Streptococcus, Haemophilus influenzae and Listeria monocytogenes, depends upon the age of the patient, their vaccination status and the regional epidemiological trends where the patient lives [4, 5]. Besides the more common organisms listed above, Klebsiella pneumoniae (K. pneumoniae) has been reported as a cause of community-acquired meningitis in Taiwan with a mortality rate of 30–40% in patients with liver abscesses [6, 7]. Diabetes and age > 65 years old were independent predictors of septic ocular or CNS complications in patients with liver abscesses [8]. Besides Taiwan, in South Korea, K. pneumoniae was the third most common cause of community-acquired bacterial meningitis [9]. However, K. pneumoniae meningitis is rarely identified in other regions, including mainland China. In 2018, our emergency department received three cases of K. pneumoniae meningitis. These three initially presented with fever and altered mental status, and all three died within two days after admission. We report these cases in order to illustrate the early signs of K. pneumoniae meningitis and discuss potentially effective strategies to improve the prognosis of these patients.
Case presentations
Case 1
At 07:23 on June 3, 2018, we received a 39-year-old male patient in our emergency room. He came from Zhangjiakou in Hebei province, China and presented with five days of fever and three hours of altered mental status. He had a history of poorly controlled diabetes mellitus. At the time of admission, his vital signs included a body temperature of 39 °C, a heart rate of 146 beats/min, blood pressure of 125/84 mmHg, respiratory rate of 42 breaths/min, and an oxygen saturation of 99% on room air. He had a Glasgow coma scale (GCS) of E1 + V1 + M3 with nuchal rigidity on an otherwise unremarkable physical examination.
White blood cell count was 25.73 × 109/L with an elevated neutrophil percentage of 84.9%. The concentration of C-reactive protein (CRP) was > 240 mg/L, glucose was 30 mmol/L, arterial blood gas (ABG) results were as follows (on 3 L/min of oxygen via nasal cannula): pH: 7.09, arterial pressure of CO2 (PaCO2): 9.7 mmHg, arterial pressure of oxygen (PaO2): 141 mmHg, HCO3: 2.8 mmol/L, lactic acid: 3.9 mmol/L, liver and renal function tests were within normal limits. Alb:39 g/L, PCT:2-10 ng/ml. Two sets of peripheral blood cultures were obtained (and were negative). Head and abdominal computed tomography (CT) scans demonstrated diffuse cerebral edema and possible brain and liver abscesses (see Fig. 1).
Fig. 1 a: Head CT scan showed diffuse cerebral edema; b: Abdominal CT scan demonstrating an area of abnormal attenuation measuring 24 mm × 19 mm in the right lobe of the liver, suggestive of a single abscess
The patient next underwent a lumbar puncture examination. The opening pressure was 150 mm H2O. CSF appeared yellow and purulent, revealing a 178,640 × 106/μL white blood cell count with a multinucleated cells percentage of 86.2%, protein 32.41 g/L and glucose 10.2 mmol/L. CSF was submitted for Gram staining and bacterial culture. The above findings led to the diagnoses of purulent meningitis, sepsis, diabetic ketoacidosis (DKA), as well as (possible) brain and liver abscesses. Meropenem 2 g every 8 h combined with vancomycin 1 g every 12 h were given intravenously. Due to the loss of spontaneous breathing, mechanical ventilation was started. Intensive care was begun and his DKA was treated. However, further invasive examinations (e.g. brain or liver abscess aspirations) were deemed too dangerous for him. At 11:41, the patient was transferred to the Emergency Department’s Intensive Care Unit (EICU).
By June 4, the patient’s condition had not improved. His body temperature fluctuated between 35.3 °C and 39.5 °C. His blood pressure dropped to 91/64 mmHg while the pulse rate rose to 142 beats/min. Norepinephrine was pumped venously to maintain a mean arterial pressure (MAP) > 65 mmHg. Pupils were bilaterally dilated at 3 mm’s with a slow light reflex, a GCS score of E1 + (Ventilated) + M1. Based on his worsening situation, emergency bedside lateral ventricular drainage was performed. During the operation, his cerebrospinal fluid was examined again, demonstrating a white blood cell count of 19,054 cells/μL with a multinucleated cells ratio of 78.9%, protein of 1.06 g/L and a glucose level of 0.1 mmol/L. After the operation, his intracranial pressure was consistently over 330mmH2O while undergoing continuous renal replacement therapy along with a maximal dose of mannitol.
K. pneumoniae was isolated from the patient’s cerebrospinal fluid and was found to be sensitive to all tested antibiotics including meropenem. However, the patient’s vital signs deteriorated, and he eventually died of cardiac arrest later on June 4.
Case 2
A 49-year-old woman was admitted to the emergency department of our hospital at 14:00 on July 3, 2018 because of fever and “twitching” for the past three days. She was born and currently lived in Zhangjiakou city of Hebei Province, she had a history of untreated diabetes mellitus and hypertension. At the time of admission, the patient was found to have intermittent convulsions and was unable to cooperate for a physical examination. Her temperature was 38 °C, pulse rate was 152 beats/min, respiratory rate 39 breaths/min, blood pressure was 158/88 mmHg, and her oxygen saturation was 92% on 3 L/min of oxygen via nasal cannula.
The patient’s white blood count was 24.87 × 109/L with an elevated neutrophil percentage of 91.4%, a hemoglobin of 148 g/L and a platelet count of 108 × 109/L. The CRP was 242 mg/L, glucose was 42.4 mmol/L. Arterial blood gas results were as follows (on 3 L/min oxygen via nasal cannula): pH of 7.09, PaCO2: 9.7 mmHg, PaO2: 141 mmHg, HCO3: 2.8 mmol/L, lactic acid: 3.9 mmol/L, creatinine 125 μmol/l, Urea 13.9 mmol/l, other liver and kidney function testing was normal. The patient’s procalcitonin level was > 10 ng/ml. Head CT scans revealed bilateral basal ganglia hemorrhages and a subarachnoid hemorrhage. Abdominal CT scan demonstrated a possible liver abscess (Fig. 2). Puncture examination showed the intracranial pressure was > 330 mm H2O. CSF was pale red and purulent, and revealed 4263 × 106/L white blood cells/μL with multinucleated cells ratio of 43.1%, protein 8.82 g/L and glucose 0.6 mmol/L.
Fig. 2 a and b: head CT scan showed bilateral basal ganglia hemorrhages and a subarachnoid hemorrhage; c: Abdominal CT scan demonstrating an area of abnormal attenuation measuring 18 mm × 14 mm in the right lobe of the liver
The patient was diagnosed with purulent meningitis, septic shock, cerebral hemorrhage, subarachnoid hemorrhage, DKA and a probable liver abscess. The patient was intubated for airway protection and mechanical ventilation was begun. Meropenem 2 g every 8 h was given intravenously, and lateral ventricular drainage was performed at 12:00. After the operation, the patient’s condition did not improve, and she died that afternoon due to cerebral herniation.
Two days later, blood, sputum and cerebrospinal fluid cultures all grew K. pneumoniae (sensitive to all the tested antibiotics including Meropenem).
Case 3
A 62-year-old male also from Zhangjiakou city of Hebei Province with a history of uncontrolled diabetes mellitus was admitted to the emergency department after he developed confusion for the past 11 h. Two days ago, the patient complained of a fever and vomiting. The patient was seen at a different local hospital, but his condition worsened. On arrival to our hospital, his initial vital signs were: body temperature, 37 °C, heart rate 119 beats/min, blood pressure, 159/126 mmHg, respiratory rate, 32 breaths/min, and oxygen saturation 92% on air. His physical examination was significant for a GCS of 5 (E1 + V1 + M3).
His white blood count was 12.39 × 109/L with an elevated neutrophil percentage of 92.8%, hemoglobin 165 g/L and a platelet count 25 × 109/L. ABG results were: pH 7.28, PaCO2: 24.1 mmHg, PaO2: 89.3 mmHg, HCO3: 10.9 mmol/L, lactic acid: 3.4 mmol/L, CRP was > 160 mg/L, procalcitonin > 100 ng/ml, blood glucose was 24.1 mmol/L, alanine transaminase was 139 U/L, total bilirubin/direct bilirubin were 62.0/31.4umol/L, creatinine was 274umol, and urea was 22.79 mmol/L. An abdominal CT scan demonstrated a single liver abscess (Fig. 3). A lumbar puncture was performed after the patient received a platelet transfusion. The opening pressure was too low to measure, and the CSF was a murky yellow and revealed 17,148 × 106/L white blood cells/μL with a multinucleated cells percentage of 84.3%, protein of 12.82 g/L and a glucose of < 0.1 mmol/L. The patient was diagnosed with purulent meningitis, septic shock and DKA. Meropenem 2 g every 8 h combined with vancomycin 1 g every 12 h were given intravenously and blood glucose (BG) was well controlled by insulin. However, the patient got worse and his relatives decided to withdraw care. A telephone follow-up revealed that the patient died on his way back home. Two days later, K. pneumoniae was isolated from his CSF and was sensitive to all available antibiotics.
Fig. 3 Abdominal CT scan demonstrating an area of abnormal attenuation measuring 25 mm × 19 mm in the right lobe of the liver
Discussion and conclusions
Cases of spontaneous K. pneumoniae meningitis are rare and commonly observed in hospitalized postoperative patients. Community-acquired K. pneumoniae meningitis could be associated with an invasive liver abscess syndrome (ILAS). In a study, two cases (2/15, 13.3%) were associated with K. pneumoniae liver abscess. In another study from South Korea, 4 (14.8%) of 27 patients with K. pneumoniae meningitis had a concomitant liver abscess [10]. But this situation is still rare, in a study, only 1 (0.9%) of 112 patients with K. pneumoniae liver abscess had CNS involvement [11]. We reviewed the case reports and related original articles about adult community-acquired K. pneumoniae meningitis and found that only two cases have been recorded in the mainland of China [12, 13]. As all three patients we received died relatively quickly, we summarized above the key points of their diagnosis and treatment and will now shift to analyzing the reasons for our patients’ unfortunate outcomes.
The three patients with community-acquired K. pneumoniae meningitis in this article had poorly controlled T2DM. Meningitis was preceded by an ILAS. Accordingly, when patients with T2DM present with fever, headache, coma and confusion, a high degree of suspicion should be held for ILAS besides meningitis, including possible K. pneumoniae infection [14]. However, sometimes community-acquired K. pneumoniae meningitis appears independently without a liver abscess [13, 15–17]. Besides T2DM, other risk factors may include alcohol-related chronic diseases, especially alcoholic cirrhosis, which is also related to ILAS [15, 16, 18]. The clinical manifestation and high leukocyte, high protein, and low glucose in each patients’ CSF are often found in cases of gram-negative bacilli meningitis [19]. So, the key points for diagnosing community-acquired K. pneumoniae meningitis are risk factors and pathogen culture.
Currently, there are no clear guidelines for the management of K. pneumoniae meningitis as a manifestation of ILAS. Besides strict glycemic control, a combination of early drainage of the abscess and appropriate antibiotic application is the standard treatment for this condition [20]. The selection of antibiotics should be based on in-vitro susceptibilities and clinical response. In view of the better penetration into the CSF, large doses of third-generation cephalosporins including cefotaxime (up to 2 g every four hours) and ceftriaxone (2 g twice a day) are the drugs of choice for K. pneumoniae meningitis. Imipenem and meropenem can be given to patients when strains containing extended-spectrum beta-lactamases are suspected [19]. As reported in the literature, surviving patients with K. pneumoniae meningitis were treated with ceftazidime, ceftriaxone, cefmetazole, cefotaxime, cefepime or meropenem [13, 16, 17, 21–27]. In our cases, K. pneumoniae cultured from the CSF were susceptible to all the remaining antibiotics tested, but meropenem was the antibiotic chosen for all three patients, and vancomycin was also used in two of them.
Unfortunately, each patient’s ending was still tragic. We noticed that the CSF protein levels in our patients (32.41 g/L, 8.82 g/L and 12.82 g/L, respectively) were extremely high. Previous studies of neonatal bacterial meningitis showed that high CSF protein levels, which with an optimal cutoff value of 1.88 g/L [28], were associated with poor prognosis [29–31]. The only reported case of K. pneumoniae meningitis who died mentioned a CSF protein of 2.34 g/L [12]. Another study into the clinical features of patients with adult bacterial meningitis showed the CSF protein levels in such patients with good or poor outcomes were 2.18 ± 1.47 g/L and 4.03 ± 4.19 g/L, respectively [32]. Additionally, white blood cells, immunoglobulins, and complements are normally absent in CSF, but the inflammatory response triggered by bacteria during meningitis results in increasing protein levels in the CSF which coincides with the intensity of the inflammatory response. Cytokines produced in inflammation may cause impairment of cell structure and organ function, thus increasing the risk of morbidity [28]. Overall then, the sky-high level of CSF protein in our patients may have foreshadowed their outcomes.
It is also noteworthy that all three patients came from Zhangjiakou city in Hebei Province. We suspect that the virulence of the K. pneumoniae species in this area may be particularly high. Five major virulence factors of K. pneumoniae are known to contribute to the pathogenesis of infection. These are the capsular serotype, hypermucoviscosity phenotype, lipopolysaccharide, siderophores, and pili. K [10, 33]. Based on previous study, we also know that severe manifestations such as comatose mental status, septic shock, and concomitant extra meningeal infections were more common in community- acquired K. pneumoniae meningitis patients compared with community-acquired Streptococcus pneumoniae meningitis, and the 28-day mortality (44.4% versus 10.7%; P = 0.001) and inhospitable mortality (51.9% versus 14.3%; P = 0.001) were much higher [9]. Besides the 100% mortality, all of the three patients had comatose mental status, septic shock, and live abscesses, the characters tallied with the reported study and may due to the high virulence of K. pneumoniae. What’s worse, multidrug-resistant and hypervirulent (MDR-HV) K. pneumoniae strains had spread in the community, 13 MDR-HV strains were identified from a total of 218 K. pneumoniae liver abscess episodes in a Taiwan Hospital [34]. Given the three cases in our study all occurred in one city in Hebei province, a future study might examine the particular virulence factors of this strain of K. pneumoniae.
Although liver abscess drainage has been recommended for a better clinical response [19] and hepatic resection is preferred for patients with Acute Physiology and Chronic Health Evaluation II (APACHE II) scores of ≥15 [28]. In our cases, liver abscesses were less than 5 cm, Percutaneous drainage for small liver abscess adjacent to the liver capsule can cause complications such as bleeding or peritonitis. The poor outcomes might have no business with the lack of liver abscess drainage.
In conclusion, K. pneumoniae meningitis is a rare cause of meningitis around the world. When patients with risk factors such as T2DM and alcoholic cirrhosis present to the emergency department with clinical features of meningitis, providers should maintain a high degree of suspicion for potential K. pneumoniae-related ILAS complicated by meningitis. Strict glycemic control, early drainage of liver abscesses and appropriate antibiotic application are all recommended for treating this condition. All three patients we received unfortunately died in short order, and it’s uncertain whether emergent liver abscess drainage would have helped at that point given the patients’ already high levels of CSF protein indicating severe inflammation. Potentially unknown virulence factors of K. pneumoniae in Zhangjiakou may also play a role in these patients’ poor outcomes. These cases were shared with the international medical community with the hope for timely diagnoses of K. pneumoniae meningitis in the future and to promote progress on learning more about this bacteria’s pathogenesis and treatment.
Abbreviations
APACHE IIAcute Physiology and Chronic Health Evaluation II
BGBlood glucose
CSFCerebrospinal fluid
CRPC-reactive protein
CTComputed tomography
DKADiabetic ketoacidosis
EDEmergency Department
EICUEmergency Department Intensive Care Unit
GCSGlasgow coma scale
ILASInvasive liver abscess syndrome
K. pneumoniaeKlebsiella pneumoniae bacteria
magAMucoid-associated gene A
rmpARegulator of mucoid phenotype gene A
T2DMType 2 diabetes mellitus
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Acknowledgements
Not applicable.
Authors’ contributions
YC X and XZ Y contributed to the study conception and design. Case collection and description were performed by RX S, HZ1 and JX. The first draft of the manuscript was written by RX S and JX, HZ2 revised the study design and initial manuscript, and all authors commented on previous versions of the manuscript. All authors read and approved the final manuscript.
Funding
No funding.
Availability of data and materials
The datasets used and analyzed during the current study are available from the corresponding author on reasonable request.
Ethics approval and consent to participate
The Institutional Review Board (IRB) of Peking Union Medical College Hospital has reviewed the study and has determined that this is a retrospective study and the design is scientifically and is up to the ethics standards. The IRB thus approve the study.
Consent for publication
Consent for publication has been obtained from the patients reported in this article. And each patients next-of-kin have given written consent for their relative’s personal or clinical details along with any identifying images to be published in this study.
Competing interests
The authors declare that they have no conflicts of interests. | Intravenous (not otherwise specified) | DrugAdministrationRoute | CC BY | 33407192 | 19,395,094 | 2021-01-06 |
What was the administration route of drug 'NOREPINEPHRINE'? | Klebsiella pneumoniae-related invasive liver abscess syndrome complicated by purulent meningitis: a review of the literature and description of three cases.
BACKGROUND
Klebsiella pneumoniae (K. pneumoniae) invasive liver abscess syndrome (ILAS) with purulent meningitis was rarely identified the mainland of China. Last winter, we received 3 cases of K. pneumoniae meningitis and all of them died in a short time. We report these cases in order to find the reason of high mortality and discuss effective effort to improve these patients' prognosis.
METHODS
Three patients with uncontrolled diabetes developed live abscess and purulent meningitis. Upon admission, the clinical manifestations, laboratory result of blood and cerebrospinal fluid (CSF) and imaging examinations were compatible with K. pneumoniae ILAS which had metastasis infection of meningitis. Even with timely adequate antibiotic therapy and strict glycemic control, all of the patients' condition deteriorated rapidly and died in a short time.
CONCLUSIONS
The reason of patients' poor prognosis might be the absence of liver abscess drainage, high level of CSF protein which indicates severe inflammation and unknown special but stronger virulence factors of K. pneumoniae the patients' living place Zhangjiakou. Strict glycemic control, early drainage of liver abscess and appropriate antibiotic application are recommended for treating this condition, further progress on the pathogenesis and treatment of K. pneumoniae meningitis may help patients gain a better prognosis.
Background
Over a century ago, bacterial meningitis was virtually 100% fatal [1]. Despite current antibiotics being able to clear bacteria from the cerebrospinal fluid (CSF), mortality remains approximately 25%, and, even among survivors, 21–28% of patients have chronic neurologic complications [2, 3]. Streptococcus pneumoniae is the most common bacterial cause of community-acquired meningitis in adults. The distribution of other pathogens, such as Neisseria meningitidis, group B Streptococcus, Haemophilus influenzae and Listeria monocytogenes, depends upon the age of the patient, their vaccination status and the regional epidemiological trends where the patient lives [4, 5]. Besides the more common organisms listed above, Klebsiella pneumoniae (K. pneumoniae) has been reported as a cause of community-acquired meningitis in Taiwan with a mortality rate of 30–40% in patients with liver abscesses [6, 7]. Diabetes and age > 65 years old were independent predictors of septic ocular or CNS complications in patients with liver abscesses [8]. Besides Taiwan, in South Korea, K. pneumoniae was the third most common cause of community-acquired bacterial meningitis [9]. However, K. pneumoniae meningitis is rarely identified in other regions, including mainland China. In 2018, our emergency department received three cases of K. pneumoniae meningitis. These three initially presented with fever and altered mental status, and all three died within two days after admission. We report these cases in order to illustrate the early signs of K. pneumoniae meningitis and discuss potentially effective strategies to improve the prognosis of these patients.
Case presentations
Case 1
At 07:23 on June 3, 2018, we received a 39-year-old male patient in our emergency room. He came from Zhangjiakou in Hebei province, China and presented with five days of fever and three hours of altered mental status. He had a history of poorly controlled diabetes mellitus. At the time of admission, his vital signs included a body temperature of 39 °C, a heart rate of 146 beats/min, blood pressure of 125/84 mmHg, respiratory rate of 42 breaths/min, and an oxygen saturation of 99% on room air. He had a Glasgow coma scale (GCS) of E1 + V1 + M3 with nuchal rigidity on an otherwise unremarkable physical examination.
White blood cell count was 25.73 × 109/L with an elevated neutrophil percentage of 84.9%. The concentration of C-reactive protein (CRP) was > 240 mg/L, glucose was 30 mmol/L, arterial blood gas (ABG) results were as follows (on 3 L/min of oxygen via nasal cannula): pH: 7.09, arterial pressure of CO2 (PaCO2): 9.7 mmHg, arterial pressure of oxygen (PaO2): 141 mmHg, HCO3: 2.8 mmol/L, lactic acid: 3.9 mmol/L, liver and renal function tests were within normal limits. Alb:39 g/L, PCT:2-10 ng/ml. Two sets of peripheral blood cultures were obtained (and were negative). Head and abdominal computed tomography (CT) scans demonstrated diffuse cerebral edema and possible brain and liver abscesses (see Fig. 1).
Fig. 1 a: Head CT scan showed diffuse cerebral edema; b: Abdominal CT scan demonstrating an area of abnormal attenuation measuring 24 mm × 19 mm in the right lobe of the liver, suggestive of a single abscess
The patient next underwent a lumbar puncture examination. The opening pressure was 150 mm H2O. CSF appeared yellow and purulent, revealing a 178,640 × 106/μL white blood cell count with a multinucleated cells percentage of 86.2%, protein 32.41 g/L and glucose 10.2 mmol/L. CSF was submitted for Gram staining and bacterial culture. The above findings led to the diagnoses of purulent meningitis, sepsis, diabetic ketoacidosis (DKA), as well as (possible) brain and liver abscesses. Meropenem 2 g every 8 h combined with vancomycin 1 g every 12 h were given intravenously. Due to the loss of spontaneous breathing, mechanical ventilation was started. Intensive care was begun and his DKA was treated. However, further invasive examinations (e.g. brain or liver abscess aspirations) were deemed too dangerous for him. At 11:41, the patient was transferred to the Emergency Department’s Intensive Care Unit (EICU).
By June 4, the patient’s condition had not improved. His body temperature fluctuated between 35.3 °C and 39.5 °C. His blood pressure dropped to 91/64 mmHg while the pulse rate rose to 142 beats/min. Norepinephrine was pumped venously to maintain a mean arterial pressure (MAP) > 65 mmHg. Pupils were bilaterally dilated at 3 mm’s with a slow light reflex, a GCS score of E1 + (Ventilated) + M1. Based on his worsening situation, emergency bedside lateral ventricular drainage was performed. During the operation, his cerebrospinal fluid was examined again, demonstrating a white blood cell count of 19,054 cells/μL with a multinucleated cells ratio of 78.9%, protein of 1.06 g/L and a glucose level of 0.1 mmol/L. After the operation, his intracranial pressure was consistently over 330mmH2O while undergoing continuous renal replacement therapy along with a maximal dose of mannitol.
K. pneumoniae was isolated from the patient’s cerebrospinal fluid and was found to be sensitive to all tested antibiotics including meropenem. However, the patient’s vital signs deteriorated, and he eventually died of cardiac arrest later on June 4.
Case 2
A 49-year-old woman was admitted to the emergency department of our hospital at 14:00 on July 3, 2018 because of fever and “twitching” for the past three days. She was born and currently lived in Zhangjiakou city of Hebei Province, she had a history of untreated diabetes mellitus and hypertension. At the time of admission, the patient was found to have intermittent convulsions and was unable to cooperate for a physical examination. Her temperature was 38 °C, pulse rate was 152 beats/min, respiratory rate 39 breaths/min, blood pressure was 158/88 mmHg, and her oxygen saturation was 92% on 3 L/min of oxygen via nasal cannula.
The patient’s white blood count was 24.87 × 109/L with an elevated neutrophil percentage of 91.4%, a hemoglobin of 148 g/L and a platelet count of 108 × 109/L. The CRP was 242 mg/L, glucose was 42.4 mmol/L. Arterial blood gas results were as follows (on 3 L/min oxygen via nasal cannula): pH of 7.09, PaCO2: 9.7 mmHg, PaO2: 141 mmHg, HCO3: 2.8 mmol/L, lactic acid: 3.9 mmol/L, creatinine 125 μmol/l, Urea 13.9 mmol/l, other liver and kidney function testing was normal. The patient’s procalcitonin level was > 10 ng/ml. Head CT scans revealed bilateral basal ganglia hemorrhages and a subarachnoid hemorrhage. Abdominal CT scan demonstrated a possible liver abscess (Fig. 2). Puncture examination showed the intracranial pressure was > 330 mm H2O. CSF was pale red and purulent, and revealed 4263 × 106/L white blood cells/μL with multinucleated cells ratio of 43.1%, protein 8.82 g/L and glucose 0.6 mmol/L.
Fig. 2 a and b: head CT scan showed bilateral basal ganglia hemorrhages and a subarachnoid hemorrhage; c: Abdominal CT scan demonstrating an area of abnormal attenuation measuring 18 mm × 14 mm in the right lobe of the liver
The patient was diagnosed with purulent meningitis, septic shock, cerebral hemorrhage, subarachnoid hemorrhage, DKA and a probable liver abscess. The patient was intubated for airway protection and mechanical ventilation was begun. Meropenem 2 g every 8 h was given intravenously, and lateral ventricular drainage was performed at 12:00. After the operation, the patient’s condition did not improve, and she died that afternoon due to cerebral herniation.
Two days later, blood, sputum and cerebrospinal fluid cultures all grew K. pneumoniae (sensitive to all the tested antibiotics including Meropenem).
Case 3
A 62-year-old male also from Zhangjiakou city of Hebei Province with a history of uncontrolled diabetes mellitus was admitted to the emergency department after he developed confusion for the past 11 h. Two days ago, the patient complained of a fever and vomiting. The patient was seen at a different local hospital, but his condition worsened. On arrival to our hospital, his initial vital signs were: body temperature, 37 °C, heart rate 119 beats/min, blood pressure, 159/126 mmHg, respiratory rate, 32 breaths/min, and oxygen saturation 92% on air. His physical examination was significant for a GCS of 5 (E1 + V1 + M3).
His white blood count was 12.39 × 109/L with an elevated neutrophil percentage of 92.8%, hemoglobin 165 g/L and a platelet count 25 × 109/L. ABG results were: pH 7.28, PaCO2: 24.1 mmHg, PaO2: 89.3 mmHg, HCO3: 10.9 mmol/L, lactic acid: 3.4 mmol/L, CRP was > 160 mg/L, procalcitonin > 100 ng/ml, blood glucose was 24.1 mmol/L, alanine transaminase was 139 U/L, total bilirubin/direct bilirubin were 62.0/31.4umol/L, creatinine was 274umol, and urea was 22.79 mmol/L. An abdominal CT scan demonstrated a single liver abscess (Fig. 3). A lumbar puncture was performed after the patient received a platelet transfusion. The opening pressure was too low to measure, and the CSF was a murky yellow and revealed 17,148 × 106/L white blood cells/μL with a multinucleated cells percentage of 84.3%, protein of 12.82 g/L and a glucose of < 0.1 mmol/L. The patient was diagnosed with purulent meningitis, septic shock and DKA. Meropenem 2 g every 8 h combined with vancomycin 1 g every 12 h were given intravenously and blood glucose (BG) was well controlled by insulin. However, the patient got worse and his relatives decided to withdraw care. A telephone follow-up revealed that the patient died on his way back home. Two days later, K. pneumoniae was isolated from his CSF and was sensitive to all available antibiotics.
Fig. 3 Abdominal CT scan demonstrating an area of abnormal attenuation measuring 25 mm × 19 mm in the right lobe of the liver
Discussion and conclusions
Cases of spontaneous K. pneumoniae meningitis are rare and commonly observed in hospitalized postoperative patients. Community-acquired K. pneumoniae meningitis could be associated with an invasive liver abscess syndrome (ILAS). In a study, two cases (2/15, 13.3%) were associated with K. pneumoniae liver abscess. In another study from South Korea, 4 (14.8%) of 27 patients with K. pneumoniae meningitis had a concomitant liver abscess [10]. But this situation is still rare, in a study, only 1 (0.9%) of 112 patients with K. pneumoniae liver abscess had CNS involvement [11]. We reviewed the case reports and related original articles about adult community-acquired K. pneumoniae meningitis and found that only two cases have been recorded in the mainland of China [12, 13]. As all three patients we received died relatively quickly, we summarized above the key points of their diagnosis and treatment and will now shift to analyzing the reasons for our patients’ unfortunate outcomes.
The three patients with community-acquired K. pneumoniae meningitis in this article had poorly controlled T2DM. Meningitis was preceded by an ILAS. Accordingly, when patients with T2DM present with fever, headache, coma and confusion, a high degree of suspicion should be held for ILAS besides meningitis, including possible K. pneumoniae infection [14]. However, sometimes community-acquired K. pneumoniae meningitis appears independently without a liver abscess [13, 15–17]. Besides T2DM, other risk factors may include alcohol-related chronic diseases, especially alcoholic cirrhosis, which is also related to ILAS [15, 16, 18]. The clinical manifestation and high leukocyte, high protein, and low glucose in each patients’ CSF are often found in cases of gram-negative bacilli meningitis [19]. So, the key points for diagnosing community-acquired K. pneumoniae meningitis are risk factors and pathogen culture.
Currently, there are no clear guidelines for the management of K. pneumoniae meningitis as a manifestation of ILAS. Besides strict glycemic control, a combination of early drainage of the abscess and appropriate antibiotic application is the standard treatment for this condition [20]. The selection of antibiotics should be based on in-vitro susceptibilities and clinical response. In view of the better penetration into the CSF, large doses of third-generation cephalosporins including cefotaxime (up to 2 g every four hours) and ceftriaxone (2 g twice a day) are the drugs of choice for K. pneumoniae meningitis. Imipenem and meropenem can be given to patients when strains containing extended-spectrum beta-lactamases are suspected [19]. As reported in the literature, surviving patients with K. pneumoniae meningitis were treated with ceftazidime, ceftriaxone, cefmetazole, cefotaxime, cefepime or meropenem [13, 16, 17, 21–27]. In our cases, K. pneumoniae cultured from the CSF were susceptible to all the remaining antibiotics tested, but meropenem was the antibiotic chosen for all three patients, and vancomycin was also used in two of them.
Unfortunately, each patient’s ending was still tragic. We noticed that the CSF protein levels in our patients (32.41 g/L, 8.82 g/L and 12.82 g/L, respectively) were extremely high. Previous studies of neonatal bacterial meningitis showed that high CSF protein levels, which with an optimal cutoff value of 1.88 g/L [28], were associated with poor prognosis [29–31]. The only reported case of K. pneumoniae meningitis who died mentioned a CSF protein of 2.34 g/L [12]. Another study into the clinical features of patients with adult bacterial meningitis showed the CSF protein levels in such patients with good or poor outcomes were 2.18 ± 1.47 g/L and 4.03 ± 4.19 g/L, respectively [32]. Additionally, white blood cells, immunoglobulins, and complements are normally absent in CSF, but the inflammatory response triggered by bacteria during meningitis results in increasing protein levels in the CSF which coincides with the intensity of the inflammatory response. Cytokines produced in inflammation may cause impairment of cell structure and organ function, thus increasing the risk of morbidity [28]. Overall then, the sky-high level of CSF protein in our patients may have foreshadowed their outcomes.
It is also noteworthy that all three patients came from Zhangjiakou city in Hebei Province. We suspect that the virulence of the K. pneumoniae species in this area may be particularly high. Five major virulence factors of K. pneumoniae are known to contribute to the pathogenesis of infection. These are the capsular serotype, hypermucoviscosity phenotype, lipopolysaccharide, siderophores, and pili. K [10, 33]. Based on previous study, we also know that severe manifestations such as comatose mental status, septic shock, and concomitant extra meningeal infections were more common in community- acquired K. pneumoniae meningitis patients compared with community-acquired Streptococcus pneumoniae meningitis, and the 28-day mortality (44.4% versus 10.7%; P = 0.001) and inhospitable mortality (51.9% versus 14.3%; P = 0.001) were much higher [9]. Besides the 100% mortality, all of the three patients had comatose mental status, septic shock, and live abscesses, the characters tallied with the reported study and may due to the high virulence of K. pneumoniae. What’s worse, multidrug-resistant and hypervirulent (MDR-HV) K. pneumoniae strains had spread in the community, 13 MDR-HV strains were identified from a total of 218 K. pneumoniae liver abscess episodes in a Taiwan Hospital [34]. Given the three cases in our study all occurred in one city in Hebei province, a future study might examine the particular virulence factors of this strain of K. pneumoniae.
Although liver abscess drainage has been recommended for a better clinical response [19] and hepatic resection is preferred for patients with Acute Physiology and Chronic Health Evaluation II (APACHE II) scores of ≥15 [28]. In our cases, liver abscesses were less than 5 cm, Percutaneous drainage for small liver abscess adjacent to the liver capsule can cause complications such as bleeding or peritonitis. The poor outcomes might have no business with the lack of liver abscess drainage.
In conclusion, K. pneumoniae meningitis is a rare cause of meningitis around the world. When patients with risk factors such as T2DM and alcoholic cirrhosis present to the emergency department with clinical features of meningitis, providers should maintain a high degree of suspicion for potential K. pneumoniae-related ILAS complicated by meningitis. Strict glycemic control, early drainage of liver abscesses and appropriate antibiotic application are all recommended for treating this condition. All three patients we received unfortunately died in short order, and it’s uncertain whether emergent liver abscess drainage would have helped at that point given the patients’ already high levels of CSF protein indicating severe inflammation. Potentially unknown virulence factors of K. pneumoniae in Zhangjiakou may also play a role in these patients’ poor outcomes. These cases were shared with the international medical community with the hope for timely diagnoses of K. pneumoniae meningitis in the future and to promote progress on learning more about this bacteria’s pathogenesis and treatment.
Abbreviations
APACHE IIAcute Physiology and Chronic Health Evaluation II
BGBlood glucose
CSFCerebrospinal fluid
CRPC-reactive protein
CTComputed tomography
DKADiabetic ketoacidosis
EDEmergency Department
EICUEmergency Department Intensive Care Unit
GCSGlasgow coma scale
ILASInvasive liver abscess syndrome
K. pneumoniaeKlebsiella pneumoniae bacteria
magAMucoid-associated gene A
rmpARegulator of mucoid phenotype gene A
T2DMType 2 diabetes mellitus
Publisher’s Note
Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
Acknowledgements
Not applicable.
Authors’ contributions
YC X and XZ Y contributed to the study conception and design. Case collection and description were performed by RX S, HZ1 and JX. The first draft of the manuscript was written by RX S and JX, HZ2 revised the study design and initial manuscript, and all authors commented on previous versions of the manuscript. All authors read and approved the final manuscript.
Funding
No funding.
Availability of data and materials
The datasets used and analyzed during the current study are available from the corresponding author on reasonable request.
Ethics approval and consent to participate
The Institutional Review Board (IRB) of Peking Union Medical College Hospital has reviewed the study and has determined that this is a retrospective study and the design is scientifically and is up to the ethics standards. The IRB thus approve the study.
Consent for publication
Consent for publication has been obtained from the patients reported in this article. And each patients next-of-kin have given written consent for their relative’s personal or clinical details along with any identifying images to be published in this study.
Competing interests
The authors declare that they have no conflicts of interests. | Intravenous (not otherwise specified) | DrugAdministrationRoute | CC BY | 33407192 | 19,512,215 | 2021-01-06 |
What was the administration route of drug 'VANCOMYCIN'? | Klebsiella pneumoniae-related invasive liver abscess syndrome complicated by purulent meningitis: a review of the literature and description of three cases.
BACKGROUND
Klebsiella pneumoniae (K. pneumoniae) invasive liver abscess syndrome (ILAS) with purulent meningitis was rarely identified the mainland of China. Last winter, we received 3 cases of K. pneumoniae meningitis and all of them died in a short time. We report these cases in order to find the reason of high mortality and discuss effective effort to improve these patients' prognosis.
METHODS
Three patients with uncontrolled diabetes developed live abscess and purulent meningitis. Upon admission, the clinical manifestations, laboratory result of blood and cerebrospinal fluid (CSF) and imaging examinations were compatible with K. pneumoniae ILAS which had metastasis infection of meningitis. Even with timely adequate antibiotic therapy and strict glycemic control, all of the patients' condition deteriorated rapidly and died in a short time.
CONCLUSIONS
The reason of patients' poor prognosis might be the absence of liver abscess drainage, high level of CSF protein which indicates severe inflammation and unknown special but stronger virulence factors of K. pneumoniae the patients' living place Zhangjiakou. Strict glycemic control, early drainage of liver abscess and appropriate antibiotic application are recommended for treating this condition, further progress on the pathogenesis and treatment of K. pneumoniae meningitis may help patients gain a better prognosis.
Background
Over a century ago, bacterial meningitis was virtually 100% fatal [1]. Despite current antibiotics being able to clear bacteria from the cerebrospinal fluid (CSF), mortality remains approximately 25%, and, even among survivors, 21–28% of patients have chronic neurologic complications [2, 3]. Streptococcus pneumoniae is the most common bacterial cause of community-acquired meningitis in adults. The distribution of other pathogens, such as Neisseria meningitidis, group B Streptococcus, Haemophilus influenzae and Listeria monocytogenes, depends upon the age of the patient, their vaccination status and the regional epidemiological trends where the patient lives [4, 5]. Besides the more common organisms listed above, Klebsiella pneumoniae (K. pneumoniae) has been reported as a cause of community-acquired meningitis in Taiwan with a mortality rate of 30–40% in patients with liver abscesses [6, 7]. Diabetes and age > 65 years old were independent predictors of septic ocular or CNS complications in patients with liver abscesses [8]. Besides Taiwan, in South Korea, K. pneumoniae was the third most common cause of community-acquired bacterial meningitis [9]. However, K. pneumoniae meningitis is rarely identified in other regions, including mainland China. In 2018, our emergency department received three cases of K. pneumoniae meningitis. These three initially presented with fever and altered mental status, and all three died within two days after admission. We report these cases in order to illustrate the early signs of K. pneumoniae meningitis and discuss potentially effective strategies to improve the prognosis of these patients.
Case presentations
Case 1
At 07:23 on June 3, 2018, we received a 39-year-old male patient in our emergency room. He came from Zhangjiakou in Hebei province, China and presented with five days of fever and three hours of altered mental status. He had a history of poorly controlled diabetes mellitus. At the time of admission, his vital signs included a body temperature of 39 °C, a heart rate of 146 beats/min, blood pressure of 125/84 mmHg, respiratory rate of 42 breaths/min, and an oxygen saturation of 99% on room air. He had a Glasgow coma scale (GCS) of E1 + V1 + M3 with nuchal rigidity on an otherwise unremarkable physical examination.
White blood cell count was 25.73 × 109/L with an elevated neutrophil percentage of 84.9%. The concentration of C-reactive protein (CRP) was > 240 mg/L, glucose was 30 mmol/L, arterial blood gas (ABG) results were as follows (on 3 L/min of oxygen via nasal cannula): pH: 7.09, arterial pressure of CO2 (PaCO2): 9.7 mmHg, arterial pressure of oxygen (PaO2): 141 mmHg, HCO3: 2.8 mmol/L, lactic acid: 3.9 mmol/L, liver and renal function tests were within normal limits. Alb:39 g/L, PCT:2-10 ng/ml. Two sets of peripheral blood cultures were obtained (and were negative). Head and abdominal computed tomography (CT) scans demonstrated diffuse cerebral edema and possible brain and liver abscesses (see Fig. 1).
Fig. 1 a: Head CT scan showed diffuse cerebral edema; b: Abdominal CT scan demonstrating an area of abnormal attenuation measuring 24 mm × 19 mm in the right lobe of the liver, suggestive of a single abscess
The patient next underwent a lumbar puncture examination. The opening pressure was 150 mm H2O. CSF appeared yellow and purulent, revealing a 178,640 × 106/μL white blood cell count with a multinucleated cells percentage of 86.2%, protein 32.41 g/L and glucose 10.2 mmol/L. CSF was submitted for Gram staining and bacterial culture. The above findings led to the diagnoses of purulent meningitis, sepsis, diabetic ketoacidosis (DKA), as well as (possible) brain and liver abscesses. Meropenem 2 g every 8 h combined with vancomycin 1 g every 12 h were given intravenously. Due to the loss of spontaneous breathing, mechanical ventilation was started. Intensive care was begun and his DKA was treated. However, further invasive examinations (e.g. brain or liver abscess aspirations) were deemed too dangerous for him. At 11:41, the patient was transferred to the Emergency Department’s Intensive Care Unit (EICU).
By June 4, the patient’s condition had not improved. His body temperature fluctuated between 35.3 °C and 39.5 °C. His blood pressure dropped to 91/64 mmHg while the pulse rate rose to 142 beats/min. Norepinephrine was pumped venously to maintain a mean arterial pressure (MAP) > 65 mmHg. Pupils were bilaterally dilated at 3 mm’s with a slow light reflex, a GCS score of E1 + (Ventilated) + M1. Based on his worsening situation, emergency bedside lateral ventricular drainage was performed. During the operation, his cerebrospinal fluid was examined again, demonstrating a white blood cell count of 19,054 cells/μL with a multinucleated cells ratio of 78.9%, protein of 1.06 g/L and a glucose level of 0.1 mmol/L. After the operation, his intracranial pressure was consistently over 330mmH2O while undergoing continuous renal replacement therapy along with a maximal dose of mannitol.
K. pneumoniae was isolated from the patient’s cerebrospinal fluid and was found to be sensitive to all tested antibiotics including meropenem. However, the patient’s vital signs deteriorated, and he eventually died of cardiac arrest later on June 4.
Case 2
A 49-year-old woman was admitted to the emergency department of our hospital at 14:00 on July 3, 2018 because of fever and “twitching” for the past three days. She was born and currently lived in Zhangjiakou city of Hebei Province, she had a history of untreated diabetes mellitus and hypertension. At the time of admission, the patient was found to have intermittent convulsions and was unable to cooperate for a physical examination. Her temperature was 38 °C, pulse rate was 152 beats/min, respiratory rate 39 breaths/min, blood pressure was 158/88 mmHg, and her oxygen saturation was 92% on 3 L/min of oxygen via nasal cannula.
The patient’s white blood count was 24.87 × 109/L with an elevated neutrophil percentage of 91.4%, a hemoglobin of 148 g/L and a platelet count of 108 × 109/L. The CRP was 242 mg/L, glucose was 42.4 mmol/L. Arterial blood gas results were as follows (on 3 L/min oxygen via nasal cannula): pH of 7.09, PaCO2: 9.7 mmHg, PaO2: 141 mmHg, HCO3: 2.8 mmol/L, lactic acid: 3.9 mmol/L, creatinine 125 μmol/l, Urea 13.9 mmol/l, other liver and kidney function testing was normal. The patient’s procalcitonin level was > 10 ng/ml. Head CT scans revealed bilateral basal ganglia hemorrhages and a subarachnoid hemorrhage. Abdominal CT scan demonstrated a possible liver abscess (Fig. 2). Puncture examination showed the intracranial pressure was > 330 mm H2O. CSF was pale red and purulent, and revealed 4263 × 106/L white blood cells/μL with multinucleated cells ratio of 43.1%, protein 8.82 g/L and glucose 0.6 mmol/L.
Fig. 2 a and b: head CT scan showed bilateral basal ganglia hemorrhages and a subarachnoid hemorrhage; c: Abdominal CT scan demonstrating an area of abnormal attenuation measuring 18 mm × 14 mm in the right lobe of the liver
The patient was diagnosed with purulent meningitis, septic shock, cerebral hemorrhage, subarachnoid hemorrhage, DKA and a probable liver abscess. The patient was intubated for airway protection and mechanical ventilation was begun. Meropenem 2 g every 8 h was given intravenously, and lateral ventricular drainage was performed at 12:00. After the operation, the patient’s condition did not improve, and she died that afternoon due to cerebral herniation.
Two days later, blood, sputum and cerebrospinal fluid cultures all grew K. pneumoniae (sensitive to all the tested antibiotics including Meropenem).
Case 3
A 62-year-old male also from Zhangjiakou city of Hebei Province with a history of uncontrolled diabetes mellitus was admitted to the emergency department after he developed confusion for the past 11 h. Two days ago, the patient complained of a fever and vomiting. The patient was seen at a different local hospital, but his condition worsened. On arrival to our hospital, his initial vital signs were: body temperature, 37 °C, heart rate 119 beats/min, blood pressure, 159/126 mmHg, respiratory rate, 32 breaths/min, and oxygen saturation 92% on air. His physical examination was significant for a GCS of 5 (E1 + V1 + M3).
His white blood count was 12.39 × 109/L with an elevated neutrophil percentage of 92.8%, hemoglobin 165 g/L and a platelet count 25 × 109/L. ABG results were: pH 7.28, PaCO2: 24.1 mmHg, PaO2: 89.3 mmHg, HCO3: 10.9 mmol/L, lactic acid: 3.4 mmol/L, CRP was > 160 mg/L, procalcitonin > 100 ng/ml, blood glucose was 24.1 mmol/L, alanine transaminase was 139 U/L, total bilirubin/direct bilirubin were 62.0/31.4umol/L, creatinine was 274umol, and urea was 22.79 mmol/L. An abdominal CT scan demonstrated a single liver abscess (Fig. 3). A lumbar puncture was performed after the patient received a platelet transfusion. The opening pressure was too low to measure, and the CSF was a murky yellow and revealed 17,148 × 106/L white blood cells/μL with a multinucleated cells percentage of 84.3%, protein of 12.82 g/L and a glucose of < 0.1 mmol/L. The patient was diagnosed with purulent meningitis, septic shock and DKA. Meropenem 2 g every 8 h combined with vancomycin 1 g every 12 h were given intravenously and blood glucose (BG) was well controlled by insulin. However, the patient got worse and his relatives decided to withdraw care. A telephone follow-up revealed that the patient died on his way back home. Two days later, K. pneumoniae was isolated from his CSF and was sensitive to all available antibiotics.
Fig. 3 Abdominal CT scan demonstrating an area of abnormal attenuation measuring 25 mm × 19 mm in the right lobe of the liver
Discussion and conclusions
Cases of spontaneous K. pneumoniae meningitis are rare and commonly observed in hospitalized postoperative patients. Community-acquired K. pneumoniae meningitis could be associated with an invasive liver abscess syndrome (ILAS). In a study, two cases (2/15, 13.3%) were associated with K. pneumoniae liver abscess. In another study from South Korea, 4 (14.8%) of 27 patients with K. pneumoniae meningitis had a concomitant liver abscess [10]. But this situation is still rare, in a study, only 1 (0.9%) of 112 patients with K. pneumoniae liver abscess had CNS involvement [11]. We reviewed the case reports and related original articles about adult community-acquired K. pneumoniae meningitis and found that only two cases have been recorded in the mainland of China [12, 13]. As all three patients we received died relatively quickly, we summarized above the key points of their diagnosis and treatment and will now shift to analyzing the reasons for our patients’ unfortunate outcomes.
The three patients with community-acquired K. pneumoniae meningitis in this article had poorly controlled T2DM. Meningitis was preceded by an ILAS. Accordingly, when patients with T2DM present with fever, headache, coma and confusion, a high degree of suspicion should be held for ILAS besides meningitis, including possible K. pneumoniae infection [14]. However, sometimes community-acquired K. pneumoniae meningitis appears independently without a liver abscess [13, 15–17]. Besides T2DM, other risk factors may include alcohol-related chronic diseases, especially alcoholic cirrhosis, which is also related to ILAS [15, 16, 18]. The clinical manifestation and high leukocyte, high protein, and low glucose in each patients’ CSF are often found in cases of gram-negative bacilli meningitis [19]. So, the key points for diagnosing community-acquired K. pneumoniae meningitis are risk factors and pathogen culture.
Currently, there are no clear guidelines for the management of K. pneumoniae meningitis as a manifestation of ILAS. Besides strict glycemic control, a combination of early drainage of the abscess and appropriate antibiotic application is the standard treatment for this condition [20]. The selection of antibiotics should be based on in-vitro susceptibilities and clinical response. In view of the better penetration into the CSF, large doses of third-generation cephalosporins including cefotaxime (up to 2 g every four hours) and ceftriaxone (2 g twice a day) are the drugs of choice for K. pneumoniae meningitis. Imipenem and meropenem can be given to patients when strains containing extended-spectrum beta-lactamases are suspected [19]. As reported in the literature, surviving patients with K. pneumoniae meningitis were treated with ceftazidime, ceftriaxone, cefmetazole, cefotaxime, cefepime or meropenem [13, 16, 17, 21–27]. In our cases, K. pneumoniae cultured from the CSF were susceptible to all the remaining antibiotics tested, but meropenem was the antibiotic chosen for all three patients, and vancomycin was also used in two of them.
Unfortunately, each patient’s ending was still tragic. We noticed that the CSF protein levels in our patients (32.41 g/L, 8.82 g/L and 12.82 g/L, respectively) were extremely high. Previous studies of neonatal bacterial meningitis showed that high CSF protein levels, which with an optimal cutoff value of 1.88 g/L [28], were associated with poor prognosis [29–31]. The only reported case of K. pneumoniae meningitis who died mentioned a CSF protein of 2.34 g/L [12]. Another study into the clinical features of patients with adult bacterial meningitis showed the CSF protein levels in such patients with good or poor outcomes were 2.18 ± 1.47 g/L and 4.03 ± 4.19 g/L, respectively [32]. Additionally, white blood cells, immunoglobulins, and complements are normally absent in CSF, but the inflammatory response triggered by bacteria during meningitis results in increasing protein levels in the CSF which coincides with the intensity of the inflammatory response. Cytokines produced in inflammation may cause impairment of cell structure and organ function, thus increasing the risk of morbidity [28]. Overall then, the sky-high level of CSF protein in our patients may have foreshadowed their outcomes.
It is also noteworthy that all three patients came from Zhangjiakou city in Hebei Province. We suspect that the virulence of the K. pneumoniae species in this area may be particularly high. Five major virulence factors of K. pneumoniae are known to contribute to the pathogenesis of infection. These are the capsular serotype, hypermucoviscosity phenotype, lipopolysaccharide, siderophores, and pili. K [10, 33]. Based on previous study, we also know that severe manifestations such as comatose mental status, septic shock, and concomitant extra meningeal infections were more common in community- acquired K. pneumoniae meningitis patients compared with community-acquired Streptococcus pneumoniae meningitis, and the 28-day mortality (44.4% versus 10.7%; P = 0.001) and inhospitable mortality (51.9% versus 14.3%; P = 0.001) were much higher [9]. Besides the 100% mortality, all of the three patients had comatose mental status, septic shock, and live abscesses, the characters tallied with the reported study and may due to the high virulence of K. pneumoniae. What’s worse, multidrug-resistant and hypervirulent (MDR-HV) K. pneumoniae strains had spread in the community, 13 MDR-HV strains were identified from a total of 218 K. pneumoniae liver abscess episodes in a Taiwan Hospital [34]. Given the three cases in our study all occurred in one city in Hebei province, a future study might examine the particular virulence factors of this strain of K. pneumoniae.
Although liver abscess drainage has been recommended for a better clinical response [19] and hepatic resection is preferred for patients with Acute Physiology and Chronic Health Evaluation II (APACHE II) scores of ≥15 [28]. In our cases, liver abscesses were less than 5 cm, Percutaneous drainage for small liver abscess adjacent to the liver capsule can cause complications such as bleeding or peritonitis. The poor outcomes might have no business with the lack of liver abscess drainage.
In conclusion, K. pneumoniae meningitis is a rare cause of meningitis around the world. When patients with risk factors such as T2DM and alcoholic cirrhosis present to the emergency department with clinical features of meningitis, providers should maintain a high degree of suspicion for potential K. pneumoniae-related ILAS complicated by meningitis. Strict glycemic control, early drainage of liver abscesses and appropriate antibiotic application are all recommended for treating this condition. All three patients we received unfortunately died in short order, and it’s uncertain whether emergent liver abscess drainage would have helped at that point given the patients’ already high levels of CSF protein indicating severe inflammation. Potentially unknown virulence factors of K. pneumoniae in Zhangjiakou may also play a role in these patients’ poor outcomes. These cases were shared with the international medical community with the hope for timely diagnoses of K. pneumoniae meningitis in the future and to promote progress on learning more about this bacteria’s pathogenesis and treatment.
Abbreviations
APACHE IIAcute Physiology and Chronic Health Evaluation II
BGBlood glucose
CSFCerebrospinal fluid
CRPC-reactive protein
CTComputed tomography
DKADiabetic ketoacidosis
EDEmergency Department
EICUEmergency Department Intensive Care Unit
GCSGlasgow coma scale
ILASInvasive liver abscess syndrome
K. pneumoniaeKlebsiella pneumoniae bacteria
magAMucoid-associated gene A
rmpARegulator of mucoid phenotype gene A
T2DMType 2 diabetes mellitus
Publisher’s Note
Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
Acknowledgements
Not applicable.
Authors’ contributions
YC X and XZ Y contributed to the study conception and design. Case collection and description were performed by RX S, HZ1 and JX. The first draft of the manuscript was written by RX S and JX, HZ2 revised the study design and initial manuscript, and all authors commented on previous versions of the manuscript. All authors read and approved the final manuscript.
Funding
No funding.
Availability of data and materials
The datasets used and analyzed during the current study are available from the corresponding author on reasonable request.
Ethics approval and consent to participate
The Institutional Review Board (IRB) of Peking Union Medical College Hospital has reviewed the study and has determined that this is a retrospective study and the design is scientifically and is up to the ethics standards. The IRB thus approve the study.
Consent for publication
Consent for publication has been obtained from the patients reported in this article. And each patients next-of-kin have given written consent for their relative’s personal or clinical details along with any identifying images to be published in this study.
Competing interests
The authors declare that they have no conflicts of interests. | Intravenous (not otherwise specified) | DrugAdministrationRoute | CC BY | 33407192 | 19,395,094 | 2021-01-06 |
What was the dosage of drug 'MANNITOL'? | Klebsiella pneumoniae-related invasive liver abscess syndrome complicated by purulent meningitis: a review of the literature and description of three cases.
BACKGROUND
Klebsiella pneumoniae (K. pneumoniae) invasive liver abscess syndrome (ILAS) with purulent meningitis was rarely identified the mainland of China. Last winter, we received 3 cases of K. pneumoniae meningitis and all of them died in a short time. We report these cases in order to find the reason of high mortality and discuss effective effort to improve these patients' prognosis.
METHODS
Three patients with uncontrolled diabetes developed live abscess and purulent meningitis. Upon admission, the clinical manifestations, laboratory result of blood and cerebrospinal fluid (CSF) and imaging examinations were compatible with K. pneumoniae ILAS which had metastasis infection of meningitis. Even with timely adequate antibiotic therapy and strict glycemic control, all of the patients' condition deteriorated rapidly and died in a short time.
CONCLUSIONS
The reason of patients' poor prognosis might be the absence of liver abscess drainage, high level of CSF protein which indicates severe inflammation and unknown special but stronger virulence factors of K. pneumoniae the patients' living place Zhangjiakou. Strict glycemic control, early drainage of liver abscess and appropriate antibiotic application are recommended for treating this condition, further progress on the pathogenesis and treatment of K. pneumoniae meningitis may help patients gain a better prognosis.
Background
Over a century ago, bacterial meningitis was virtually 100% fatal [1]. Despite current antibiotics being able to clear bacteria from the cerebrospinal fluid (CSF), mortality remains approximately 25%, and, even among survivors, 21–28% of patients have chronic neurologic complications [2, 3]. Streptococcus pneumoniae is the most common bacterial cause of community-acquired meningitis in adults. The distribution of other pathogens, such as Neisseria meningitidis, group B Streptococcus, Haemophilus influenzae and Listeria monocytogenes, depends upon the age of the patient, their vaccination status and the regional epidemiological trends where the patient lives [4, 5]. Besides the more common organisms listed above, Klebsiella pneumoniae (K. pneumoniae) has been reported as a cause of community-acquired meningitis in Taiwan with a mortality rate of 30–40% in patients with liver abscesses [6, 7]. Diabetes and age > 65 years old were independent predictors of septic ocular or CNS complications in patients with liver abscesses [8]. Besides Taiwan, in South Korea, K. pneumoniae was the third most common cause of community-acquired bacterial meningitis [9]. However, K. pneumoniae meningitis is rarely identified in other regions, including mainland China. In 2018, our emergency department received three cases of K. pneumoniae meningitis. These three initially presented with fever and altered mental status, and all three died within two days after admission. We report these cases in order to illustrate the early signs of K. pneumoniae meningitis and discuss potentially effective strategies to improve the prognosis of these patients.
Case presentations
Case 1
At 07:23 on June 3, 2018, we received a 39-year-old male patient in our emergency room. He came from Zhangjiakou in Hebei province, China and presented with five days of fever and three hours of altered mental status. He had a history of poorly controlled diabetes mellitus. At the time of admission, his vital signs included a body temperature of 39 °C, a heart rate of 146 beats/min, blood pressure of 125/84 mmHg, respiratory rate of 42 breaths/min, and an oxygen saturation of 99% on room air. He had a Glasgow coma scale (GCS) of E1 + V1 + M3 with nuchal rigidity on an otherwise unremarkable physical examination.
White blood cell count was 25.73 × 109/L with an elevated neutrophil percentage of 84.9%. The concentration of C-reactive protein (CRP) was > 240 mg/L, glucose was 30 mmol/L, arterial blood gas (ABG) results were as follows (on 3 L/min of oxygen via nasal cannula): pH: 7.09, arterial pressure of CO2 (PaCO2): 9.7 mmHg, arterial pressure of oxygen (PaO2): 141 mmHg, HCO3: 2.8 mmol/L, lactic acid: 3.9 mmol/L, liver and renal function tests were within normal limits. Alb:39 g/L, PCT:2-10 ng/ml. Two sets of peripheral blood cultures were obtained (and were negative). Head and abdominal computed tomography (CT) scans demonstrated diffuse cerebral edema and possible brain and liver abscesses (see Fig. 1).
Fig. 1 a: Head CT scan showed diffuse cerebral edema; b: Abdominal CT scan demonstrating an area of abnormal attenuation measuring 24 mm × 19 mm in the right lobe of the liver, suggestive of a single abscess
The patient next underwent a lumbar puncture examination. The opening pressure was 150 mm H2O. CSF appeared yellow and purulent, revealing a 178,640 × 106/μL white blood cell count with a multinucleated cells percentage of 86.2%, protein 32.41 g/L and glucose 10.2 mmol/L. CSF was submitted for Gram staining and bacterial culture. The above findings led to the diagnoses of purulent meningitis, sepsis, diabetic ketoacidosis (DKA), as well as (possible) brain and liver abscesses. Meropenem 2 g every 8 h combined with vancomycin 1 g every 12 h were given intravenously. Due to the loss of spontaneous breathing, mechanical ventilation was started. Intensive care was begun and his DKA was treated. However, further invasive examinations (e.g. brain or liver abscess aspirations) were deemed too dangerous for him. At 11:41, the patient was transferred to the Emergency Department’s Intensive Care Unit (EICU).
By June 4, the patient’s condition had not improved. His body temperature fluctuated between 35.3 °C and 39.5 °C. His blood pressure dropped to 91/64 mmHg while the pulse rate rose to 142 beats/min. Norepinephrine was pumped venously to maintain a mean arterial pressure (MAP) > 65 mmHg. Pupils were bilaterally dilated at 3 mm’s with a slow light reflex, a GCS score of E1 + (Ventilated) + M1. Based on his worsening situation, emergency bedside lateral ventricular drainage was performed. During the operation, his cerebrospinal fluid was examined again, demonstrating a white blood cell count of 19,054 cells/μL with a multinucleated cells ratio of 78.9%, protein of 1.06 g/L and a glucose level of 0.1 mmol/L. After the operation, his intracranial pressure was consistently over 330mmH2O while undergoing continuous renal replacement therapy along with a maximal dose of mannitol.
K. pneumoniae was isolated from the patient’s cerebrospinal fluid and was found to be sensitive to all tested antibiotics including meropenem. However, the patient’s vital signs deteriorated, and he eventually died of cardiac arrest later on June 4.
Case 2
A 49-year-old woman was admitted to the emergency department of our hospital at 14:00 on July 3, 2018 because of fever and “twitching” for the past three days. She was born and currently lived in Zhangjiakou city of Hebei Province, she had a history of untreated diabetes mellitus and hypertension. At the time of admission, the patient was found to have intermittent convulsions and was unable to cooperate for a physical examination. Her temperature was 38 °C, pulse rate was 152 beats/min, respiratory rate 39 breaths/min, blood pressure was 158/88 mmHg, and her oxygen saturation was 92% on 3 L/min of oxygen via nasal cannula.
The patient’s white blood count was 24.87 × 109/L with an elevated neutrophil percentage of 91.4%, a hemoglobin of 148 g/L and a platelet count of 108 × 109/L. The CRP was 242 mg/L, glucose was 42.4 mmol/L. Arterial blood gas results were as follows (on 3 L/min oxygen via nasal cannula): pH of 7.09, PaCO2: 9.7 mmHg, PaO2: 141 mmHg, HCO3: 2.8 mmol/L, lactic acid: 3.9 mmol/L, creatinine 125 μmol/l, Urea 13.9 mmol/l, other liver and kidney function testing was normal. The patient’s procalcitonin level was > 10 ng/ml. Head CT scans revealed bilateral basal ganglia hemorrhages and a subarachnoid hemorrhage. Abdominal CT scan demonstrated a possible liver abscess (Fig. 2). Puncture examination showed the intracranial pressure was > 330 mm H2O. CSF was pale red and purulent, and revealed 4263 × 106/L white blood cells/μL with multinucleated cells ratio of 43.1%, protein 8.82 g/L and glucose 0.6 mmol/L.
Fig. 2 a and b: head CT scan showed bilateral basal ganglia hemorrhages and a subarachnoid hemorrhage; c: Abdominal CT scan demonstrating an area of abnormal attenuation measuring 18 mm × 14 mm in the right lobe of the liver
The patient was diagnosed with purulent meningitis, septic shock, cerebral hemorrhage, subarachnoid hemorrhage, DKA and a probable liver abscess. The patient was intubated for airway protection and mechanical ventilation was begun. Meropenem 2 g every 8 h was given intravenously, and lateral ventricular drainage was performed at 12:00. After the operation, the patient’s condition did not improve, and she died that afternoon due to cerebral herniation.
Two days later, blood, sputum and cerebrospinal fluid cultures all grew K. pneumoniae (sensitive to all the tested antibiotics including Meropenem).
Case 3
A 62-year-old male also from Zhangjiakou city of Hebei Province with a history of uncontrolled diabetes mellitus was admitted to the emergency department after he developed confusion for the past 11 h. Two days ago, the patient complained of a fever and vomiting. The patient was seen at a different local hospital, but his condition worsened. On arrival to our hospital, his initial vital signs were: body temperature, 37 °C, heart rate 119 beats/min, blood pressure, 159/126 mmHg, respiratory rate, 32 breaths/min, and oxygen saturation 92% on air. His physical examination was significant for a GCS of 5 (E1 + V1 + M3).
His white blood count was 12.39 × 109/L with an elevated neutrophil percentage of 92.8%, hemoglobin 165 g/L and a platelet count 25 × 109/L. ABG results were: pH 7.28, PaCO2: 24.1 mmHg, PaO2: 89.3 mmHg, HCO3: 10.9 mmol/L, lactic acid: 3.4 mmol/L, CRP was > 160 mg/L, procalcitonin > 100 ng/ml, blood glucose was 24.1 mmol/L, alanine transaminase was 139 U/L, total bilirubin/direct bilirubin were 62.0/31.4umol/L, creatinine was 274umol, and urea was 22.79 mmol/L. An abdominal CT scan demonstrated a single liver abscess (Fig. 3). A lumbar puncture was performed after the patient received a platelet transfusion. The opening pressure was too low to measure, and the CSF was a murky yellow and revealed 17,148 × 106/L white blood cells/μL with a multinucleated cells percentage of 84.3%, protein of 12.82 g/L and a glucose of < 0.1 mmol/L. The patient was diagnosed with purulent meningitis, septic shock and DKA. Meropenem 2 g every 8 h combined with vancomycin 1 g every 12 h were given intravenously and blood glucose (BG) was well controlled by insulin. However, the patient got worse and his relatives decided to withdraw care. A telephone follow-up revealed that the patient died on his way back home. Two days later, K. pneumoniae was isolated from his CSF and was sensitive to all available antibiotics.
Fig. 3 Abdominal CT scan demonstrating an area of abnormal attenuation measuring 25 mm × 19 mm in the right lobe of the liver
Discussion and conclusions
Cases of spontaneous K. pneumoniae meningitis are rare and commonly observed in hospitalized postoperative patients. Community-acquired K. pneumoniae meningitis could be associated with an invasive liver abscess syndrome (ILAS). In a study, two cases (2/15, 13.3%) were associated with K. pneumoniae liver abscess. In another study from South Korea, 4 (14.8%) of 27 patients with K. pneumoniae meningitis had a concomitant liver abscess [10]. But this situation is still rare, in a study, only 1 (0.9%) of 112 patients with K. pneumoniae liver abscess had CNS involvement [11]. We reviewed the case reports and related original articles about adult community-acquired K. pneumoniae meningitis and found that only two cases have been recorded in the mainland of China [12, 13]. As all three patients we received died relatively quickly, we summarized above the key points of their diagnosis and treatment and will now shift to analyzing the reasons for our patients’ unfortunate outcomes.
The three patients with community-acquired K. pneumoniae meningitis in this article had poorly controlled T2DM. Meningitis was preceded by an ILAS. Accordingly, when patients with T2DM present with fever, headache, coma and confusion, a high degree of suspicion should be held for ILAS besides meningitis, including possible K. pneumoniae infection [14]. However, sometimes community-acquired K. pneumoniae meningitis appears independently without a liver abscess [13, 15–17]. Besides T2DM, other risk factors may include alcohol-related chronic diseases, especially alcoholic cirrhosis, which is also related to ILAS [15, 16, 18]. The clinical manifestation and high leukocyte, high protein, and low glucose in each patients’ CSF are often found in cases of gram-negative bacilli meningitis [19]. So, the key points for diagnosing community-acquired K. pneumoniae meningitis are risk factors and pathogen culture.
Currently, there are no clear guidelines for the management of K. pneumoniae meningitis as a manifestation of ILAS. Besides strict glycemic control, a combination of early drainage of the abscess and appropriate antibiotic application is the standard treatment for this condition [20]. The selection of antibiotics should be based on in-vitro susceptibilities and clinical response. In view of the better penetration into the CSF, large doses of third-generation cephalosporins including cefotaxime (up to 2 g every four hours) and ceftriaxone (2 g twice a day) are the drugs of choice for K. pneumoniae meningitis. Imipenem and meropenem can be given to patients when strains containing extended-spectrum beta-lactamases are suspected [19]. As reported in the literature, surviving patients with K. pneumoniae meningitis were treated with ceftazidime, ceftriaxone, cefmetazole, cefotaxime, cefepime or meropenem [13, 16, 17, 21–27]. In our cases, K. pneumoniae cultured from the CSF were susceptible to all the remaining antibiotics tested, but meropenem was the antibiotic chosen for all three patients, and vancomycin was also used in two of them.
Unfortunately, each patient’s ending was still tragic. We noticed that the CSF protein levels in our patients (32.41 g/L, 8.82 g/L and 12.82 g/L, respectively) were extremely high. Previous studies of neonatal bacterial meningitis showed that high CSF protein levels, which with an optimal cutoff value of 1.88 g/L [28], were associated with poor prognosis [29–31]. The only reported case of K. pneumoniae meningitis who died mentioned a CSF protein of 2.34 g/L [12]. Another study into the clinical features of patients with adult bacterial meningitis showed the CSF protein levels in such patients with good or poor outcomes were 2.18 ± 1.47 g/L and 4.03 ± 4.19 g/L, respectively [32]. Additionally, white blood cells, immunoglobulins, and complements are normally absent in CSF, but the inflammatory response triggered by bacteria during meningitis results in increasing protein levels in the CSF which coincides with the intensity of the inflammatory response. Cytokines produced in inflammation may cause impairment of cell structure and organ function, thus increasing the risk of morbidity [28]. Overall then, the sky-high level of CSF protein in our patients may have foreshadowed their outcomes.
It is also noteworthy that all three patients came from Zhangjiakou city in Hebei Province. We suspect that the virulence of the K. pneumoniae species in this area may be particularly high. Five major virulence factors of K. pneumoniae are known to contribute to the pathogenesis of infection. These are the capsular serotype, hypermucoviscosity phenotype, lipopolysaccharide, siderophores, and pili. K [10, 33]. Based on previous study, we also know that severe manifestations such as comatose mental status, septic shock, and concomitant extra meningeal infections were more common in community- acquired K. pneumoniae meningitis patients compared with community-acquired Streptococcus pneumoniae meningitis, and the 28-day mortality (44.4% versus 10.7%; P = 0.001) and inhospitable mortality (51.9% versus 14.3%; P = 0.001) were much higher [9]. Besides the 100% mortality, all of the three patients had comatose mental status, septic shock, and live abscesses, the characters tallied with the reported study and may due to the high virulence of K. pneumoniae. What’s worse, multidrug-resistant and hypervirulent (MDR-HV) K. pneumoniae strains had spread in the community, 13 MDR-HV strains were identified from a total of 218 K. pneumoniae liver abscess episodes in a Taiwan Hospital [34]. Given the three cases in our study all occurred in one city in Hebei province, a future study might examine the particular virulence factors of this strain of K. pneumoniae.
Although liver abscess drainage has been recommended for a better clinical response [19] and hepatic resection is preferred for patients with Acute Physiology and Chronic Health Evaluation II (APACHE II) scores of ≥15 [28]. In our cases, liver abscesses were less than 5 cm, Percutaneous drainage for small liver abscess adjacent to the liver capsule can cause complications such as bleeding or peritonitis. The poor outcomes might have no business with the lack of liver abscess drainage.
In conclusion, K. pneumoniae meningitis is a rare cause of meningitis around the world. When patients with risk factors such as T2DM and alcoholic cirrhosis present to the emergency department with clinical features of meningitis, providers should maintain a high degree of suspicion for potential K. pneumoniae-related ILAS complicated by meningitis. Strict glycemic control, early drainage of liver abscesses and appropriate antibiotic application are all recommended for treating this condition. All three patients we received unfortunately died in short order, and it’s uncertain whether emergent liver abscess drainage would have helped at that point given the patients’ already high levels of CSF protein indicating severe inflammation. Potentially unknown virulence factors of K. pneumoniae in Zhangjiakou may also play a role in these patients’ poor outcomes. These cases were shared with the international medical community with the hope for timely diagnoses of K. pneumoniae meningitis in the future and to promote progress on learning more about this bacteria’s pathogenesis and treatment.
Abbreviations
APACHE IIAcute Physiology and Chronic Health Evaluation II
BGBlood glucose
CSFCerebrospinal fluid
CRPC-reactive protein
CTComputed tomography
DKADiabetic ketoacidosis
EDEmergency Department
EICUEmergency Department Intensive Care Unit
GCSGlasgow coma scale
ILASInvasive liver abscess syndrome
K. pneumoniaeKlebsiella pneumoniae bacteria
magAMucoid-associated gene A
rmpARegulator of mucoid phenotype gene A
T2DMType 2 diabetes mellitus
Publisher’s Note
Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
Acknowledgements
Not applicable.
Authors’ contributions
YC X and XZ Y contributed to the study conception and design. Case collection and description were performed by RX S, HZ1 and JX. The first draft of the manuscript was written by RX S and JX, HZ2 revised the study design and initial manuscript, and all authors commented on previous versions of the manuscript. All authors read and approved the final manuscript.
Funding
No funding.
Availability of data and materials
The datasets used and analyzed during the current study are available from the corresponding author on reasonable request.
Ethics approval and consent to participate
The Institutional Review Board (IRB) of Peking Union Medical College Hospital has reviewed the study and has determined that this is a retrospective study and the design is scientifically and is up to the ethics standards. The IRB thus approve the study.
Consent for publication
Consent for publication has been obtained from the patients reported in this article. And each patients next-of-kin have given written consent for their relative’s personal or clinical details along with any identifying images to be published in this study.
Competing interests
The authors declare that they have no conflicts of interests. | UNK, (MAXIMAL DOSE) | DrugDosageText | CC BY | 33407192 | 19,512,215 | 2021-01-06 |
What was the outcome of reaction 'Cardiac arrest'? | Klebsiella pneumoniae-related invasive liver abscess syndrome complicated by purulent meningitis: a review of the literature and description of three cases.
BACKGROUND
Klebsiella pneumoniae (K. pneumoniae) invasive liver abscess syndrome (ILAS) with purulent meningitis was rarely identified the mainland of China. Last winter, we received 3 cases of K. pneumoniae meningitis and all of them died in a short time. We report these cases in order to find the reason of high mortality and discuss effective effort to improve these patients' prognosis.
METHODS
Three patients with uncontrolled diabetes developed live abscess and purulent meningitis. Upon admission, the clinical manifestations, laboratory result of blood and cerebrospinal fluid (CSF) and imaging examinations were compatible with K. pneumoniae ILAS which had metastasis infection of meningitis. Even with timely adequate antibiotic therapy and strict glycemic control, all of the patients' condition deteriorated rapidly and died in a short time.
CONCLUSIONS
The reason of patients' poor prognosis might be the absence of liver abscess drainage, high level of CSF protein which indicates severe inflammation and unknown special but stronger virulence factors of K. pneumoniae the patients' living place Zhangjiakou. Strict glycemic control, early drainage of liver abscess and appropriate antibiotic application are recommended for treating this condition, further progress on the pathogenesis and treatment of K. pneumoniae meningitis may help patients gain a better prognosis.
Background
Over a century ago, bacterial meningitis was virtually 100% fatal [1]. Despite current antibiotics being able to clear bacteria from the cerebrospinal fluid (CSF), mortality remains approximately 25%, and, even among survivors, 21–28% of patients have chronic neurologic complications [2, 3]. Streptococcus pneumoniae is the most common bacterial cause of community-acquired meningitis in adults. The distribution of other pathogens, such as Neisseria meningitidis, group B Streptococcus, Haemophilus influenzae and Listeria monocytogenes, depends upon the age of the patient, their vaccination status and the regional epidemiological trends where the patient lives [4, 5]. Besides the more common organisms listed above, Klebsiella pneumoniae (K. pneumoniae) has been reported as a cause of community-acquired meningitis in Taiwan with a mortality rate of 30–40% in patients with liver abscesses [6, 7]. Diabetes and age > 65 years old were independent predictors of septic ocular or CNS complications in patients with liver abscesses [8]. Besides Taiwan, in South Korea, K. pneumoniae was the third most common cause of community-acquired bacterial meningitis [9]. However, K. pneumoniae meningitis is rarely identified in other regions, including mainland China. In 2018, our emergency department received three cases of K. pneumoniae meningitis. These three initially presented with fever and altered mental status, and all three died within two days after admission. We report these cases in order to illustrate the early signs of K. pneumoniae meningitis and discuss potentially effective strategies to improve the prognosis of these patients.
Case presentations
Case 1
At 07:23 on June 3, 2018, we received a 39-year-old male patient in our emergency room. He came from Zhangjiakou in Hebei province, China and presented with five days of fever and three hours of altered mental status. He had a history of poorly controlled diabetes mellitus. At the time of admission, his vital signs included a body temperature of 39 °C, a heart rate of 146 beats/min, blood pressure of 125/84 mmHg, respiratory rate of 42 breaths/min, and an oxygen saturation of 99% on room air. He had a Glasgow coma scale (GCS) of E1 + V1 + M3 with nuchal rigidity on an otherwise unremarkable physical examination.
White blood cell count was 25.73 × 109/L with an elevated neutrophil percentage of 84.9%. The concentration of C-reactive protein (CRP) was > 240 mg/L, glucose was 30 mmol/L, arterial blood gas (ABG) results were as follows (on 3 L/min of oxygen via nasal cannula): pH: 7.09, arterial pressure of CO2 (PaCO2): 9.7 mmHg, arterial pressure of oxygen (PaO2): 141 mmHg, HCO3: 2.8 mmol/L, lactic acid: 3.9 mmol/L, liver and renal function tests were within normal limits. Alb:39 g/L, PCT:2-10 ng/ml. Two sets of peripheral blood cultures were obtained (and were negative). Head and abdominal computed tomography (CT) scans demonstrated diffuse cerebral edema and possible brain and liver abscesses (see Fig. 1).
Fig. 1 a: Head CT scan showed diffuse cerebral edema; b: Abdominal CT scan demonstrating an area of abnormal attenuation measuring 24 mm × 19 mm in the right lobe of the liver, suggestive of a single abscess
The patient next underwent a lumbar puncture examination. The opening pressure was 150 mm H2O. CSF appeared yellow and purulent, revealing a 178,640 × 106/μL white blood cell count with a multinucleated cells percentage of 86.2%, protein 32.41 g/L and glucose 10.2 mmol/L. CSF was submitted for Gram staining and bacterial culture. The above findings led to the diagnoses of purulent meningitis, sepsis, diabetic ketoacidosis (DKA), as well as (possible) brain and liver abscesses. Meropenem 2 g every 8 h combined with vancomycin 1 g every 12 h were given intravenously. Due to the loss of spontaneous breathing, mechanical ventilation was started. Intensive care was begun and his DKA was treated. However, further invasive examinations (e.g. brain or liver abscess aspirations) were deemed too dangerous for him. At 11:41, the patient was transferred to the Emergency Department’s Intensive Care Unit (EICU).
By June 4, the patient’s condition had not improved. His body temperature fluctuated between 35.3 °C and 39.5 °C. His blood pressure dropped to 91/64 mmHg while the pulse rate rose to 142 beats/min. Norepinephrine was pumped venously to maintain a mean arterial pressure (MAP) > 65 mmHg. Pupils were bilaterally dilated at 3 mm’s with a slow light reflex, a GCS score of E1 + (Ventilated) + M1. Based on his worsening situation, emergency bedside lateral ventricular drainage was performed. During the operation, his cerebrospinal fluid was examined again, demonstrating a white blood cell count of 19,054 cells/μL with a multinucleated cells ratio of 78.9%, protein of 1.06 g/L and a glucose level of 0.1 mmol/L. After the operation, his intracranial pressure was consistently over 330mmH2O while undergoing continuous renal replacement therapy along with a maximal dose of mannitol.
K. pneumoniae was isolated from the patient’s cerebrospinal fluid and was found to be sensitive to all tested antibiotics including meropenem. However, the patient’s vital signs deteriorated, and he eventually died of cardiac arrest later on June 4.
Case 2
A 49-year-old woman was admitted to the emergency department of our hospital at 14:00 on July 3, 2018 because of fever and “twitching” for the past three days. She was born and currently lived in Zhangjiakou city of Hebei Province, she had a history of untreated diabetes mellitus and hypertension. At the time of admission, the patient was found to have intermittent convulsions and was unable to cooperate for a physical examination. Her temperature was 38 °C, pulse rate was 152 beats/min, respiratory rate 39 breaths/min, blood pressure was 158/88 mmHg, and her oxygen saturation was 92% on 3 L/min of oxygen via nasal cannula.
The patient’s white blood count was 24.87 × 109/L with an elevated neutrophil percentage of 91.4%, a hemoglobin of 148 g/L and a platelet count of 108 × 109/L. The CRP was 242 mg/L, glucose was 42.4 mmol/L. Arterial blood gas results were as follows (on 3 L/min oxygen via nasal cannula): pH of 7.09, PaCO2: 9.7 mmHg, PaO2: 141 mmHg, HCO3: 2.8 mmol/L, lactic acid: 3.9 mmol/L, creatinine 125 μmol/l, Urea 13.9 mmol/l, other liver and kidney function testing was normal. The patient’s procalcitonin level was > 10 ng/ml. Head CT scans revealed bilateral basal ganglia hemorrhages and a subarachnoid hemorrhage. Abdominal CT scan demonstrated a possible liver abscess (Fig. 2). Puncture examination showed the intracranial pressure was > 330 mm H2O. CSF was pale red and purulent, and revealed 4263 × 106/L white blood cells/μL with multinucleated cells ratio of 43.1%, protein 8.82 g/L and glucose 0.6 mmol/L.
Fig. 2 a and b: head CT scan showed bilateral basal ganglia hemorrhages and a subarachnoid hemorrhage; c: Abdominal CT scan demonstrating an area of abnormal attenuation measuring 18 mm × 14 mm in the right lobe of the liver
The patient was diagnosed with purulent meningitis, septic shock, cerebral hemorrhage, subarachnoid hemorrhage, DKA and a probable liver abscess. The patient was intubated for airway protection and mechanical ventilation was begun. Meropenem 2 g every 8 h was given intravenously, and lateral ventricular drainage was performed at 12:00. After the operation, the patient’s condition did not improve, and she died that afternoon due to cerebral herniation.
Two days later, blood, sputum and cerebrospinal fluid cultures all grew K. pneumoniae (sensitive to all the tested antibiotics including Meropenem).
Case 3
A 62-year-old male also from Zhangjiakou city of Hebei Province with a history of uncontrolled diabetes mellitus was admitted to the emergency department after he developed confusion for the past 11 h. Two days ago, the patient complained of a fever and vomiting. The patient was seen at a different local hospital, but his condition worsened. On arrival to our hospital, his initial vital signs were: body temperature, 37 °C, heart rate 119 beats/min, blood pressure, 159/126 mmHg, respiratory rate, 32 breaths/min, and oxygen saturation 92% on air. His physical examination was significant for a GCS of 5 (E1 + V1 + M3).
His white blood count was 12.39 × 109/L with an elevated neutrophil percentage of 92.8%, hemoglobin 165 g/L and a platelet count 25 × 109/L. ABG results were: pH 7.28, PaCO2: 24.1 mmHg, PaO2: 89.3 mmHg, HCO3: 10.9 mmol/L, lactic acid: 3.4 mmol/L, CRP was > 160 mg/L, procalcitonin > 100 ng/ml, blood glucose was 24.1 mmol/L, alanine transaminase was 139 U/L, total bilirubin/direct bilirubin were 62.0/31.4umol/L, creatinine was 274umol, and urea was 22.79 mmol/L. An abdominal CT scan demonstrated a single liver abscess (Fig. 3). A lumbar puncture was performed after the patient received a platelet transfusion. The opening pressure was too low to measure, and the CSF was a murky yellow and revealed 17,148 × 106/L white blood cells/μL with a multinucleated cells percentage of 84.3%, protein of 12.82 g/L and a glucose of < 0.1 mmol/L. The patient was diagnosed with purulent meningitis, septic shock and DKA. Meropenem 2 g every 8 h combined with vancomycin 1 g every 12 h were given intravenously and blood glucose (BG) was well controlled by insulin. However, the patient got worse and his relatives decided to withdraw care. A telephone follow-up revealed that the patient died on his way back home. Two days later, K. pneumoniae was isolated from his CSF and was sensitive to all available antibiotics.
Fig. 3 Abdominal CT scan demonstrating an area of abnormal attenuation measuring 25 mm × 19 mm in the right lobe of the liver
Discussion and conclusions
Cases of spontaneous K. pneumoniae meningitis are rare and commonly observed in hospitalized postoperative patients. Community-acquired K. pneumoniae meningitis could be associated with an invasive liver abscess syndrome (ILAS). In a study, two cases (2/15, 13.3%) were associated with K. pneumoniae liver abscess. In another study from South Korea, 4 (14.8%) of 27 patients with K. pneumoniae meningitis had a concomitant liver abscess [10]. But this situation is still rare, in a study, only 1 (0.9%) of 112 patients with K. pneumoniae liver abscess had CNS involvement [11]. We reviewed the case reports and related original articles about adult community-acquired K. pneumoniae meningitis and found that only two cases have been recorded in the mainland of China [12, 13]. As all three patients we received died relatively quickly, we summarized above the key points of their diagnosis and treatment and will now shift to analyzing the reasons for our patients’ unfortunate outcomes.
The three patients with community-acquired K. pneumoniae meningitis in this article had poorly controlled T2DM. Meningitis was preceded by an ILAS. Accordingly, when patients with T2DM present with fever, headache, coma and confusion, a high degree of suspicion should be held for ILAS besides meningitis, including possible K. pneumoniae infection [14]. However, sometimes community-acquired K. pneumoniae meningitis appears independently without a liver abscess [13, 15–17]. Besides T2DM, other risk factors may include alcohol-related chronic diseases, especially alcoholic cirrhosis, which is also related to ILAS [15, 16, 18]. The clinical manifestation and high leukocyte, high protein, and low glucose in each patients’ CSF are often found in cases of gram-negative bacilli meningitis [19]. So, the key points for diagnosing community-acquired K. pneumoniae meningitis are risk factors and pathogen culture.
Currently, there are no clear guidelines for the management of K. pneumoniae meningitis as a manifestation of ILAS. Besides strict glycemic control, a combination of early drainage of the abscess and appropriate antibiotic application is the standard treatment for this condition [20]. The selection of antibiotics should be based on in-vitro susceptibilities and clinical response. In view of the better penetration into the CSF, large doses of third-generation cephalosporins including cefotaxime (up to 2 g every four hours) and ceftriaxone (2 g twice a day) are the drugs of choice for K. pneumoniae meningitis. Imipenem and meropenem can be given to patients when strains containing extended-spectrum beta-lactamases are suspected [19]. As reported in the literature, surviving patients with K. pneumoniae meningitis were treated with ceftazidime, ceftriaxone, cefmetazole, cefotaxime, cefepime or meropenem [13, 16, 17, 21–27]. In our cases, K. pneumoniae cultured from the CSF were susceptible to all the remaining antibiotics tested, but meropenem was the antibiotic chosen for all three patients, and vancomycin was also used in two of them.
Unfortunately, each patient’s ending was still tragic. We noticed that the CSF protein levels in our patients (32.41 g/L, 8.82 g/L and 12.82 g/L, respectively) were extremely high. Previous studies of neonatal bacterial meningitis showed that high CSF protein levels, which with an optimal cutoff value of 1.88 g/L [28], were associated with poor prognosis [29–31]. The only reported case of K. pneumoniae meningitis who died mentioned a CSF protein of 2.34 g/L [12]. Another study into the clinical features of patients with adult bacterial meningitis showed the CSF protein levels in such patients with good or poor outcomes were 2.18 ± 1.47 g/L and 4.03 ± 4.19 g/L, respectively [32]. Additionally, white blood cells, immunoglobulins, and complements are normally absent in CSF, but the inflammatory response triggered by bacteria during meningitis results in increasing protein levels in the CSF which coincides with the intensity of the inflammatory response. Cytokines produced in inflammation may cause impairment of cell structure and organ function, thus increasing the risk of morbidity [28]. Overall then, the sky-high level of CSF protein in our patients may have foreshadowed their outcomes.
It is also noteworthy that all three patients came from Zhangjiakou city in Hebei Province. We suspect that the virulence of the K. pneumoniae species in this area may be particularly high. Five major virulence factors of K. pneumoniae are known to contribute to the pathogenesis of infection. These are the capsular serotype, hypermucoviscosity phenotype, lipopolysaccharide, siderophores, and pili. K [10, 33]. Based on previous study, we also know that severe manifestations such as comatose mental status, septic shock, and concomitant extra meningeal infections were more common in community- acquired K. pneumoniae meningitis patients compared with community-acquired Streptococcus pneumoniae meningitis, and the 28-day mortality (44.4% versus 10.7%; P = 0.001) and inhospitable mortality (51.9% versus 14.3%; P = 0.001) were much higher [9]. Besides the 100% mortality, all of the three patients had comatose mental status, septic shock, and live abscesses, the characters tallied with the reported study and may due to the high virulence of K. pneumoniae. What’s worse, multidrug-resistant and hypervirulent (MDR-HV) K. pneumoniae strains had spread in the community, 13 MDR-HV strains were identified from a total of 218 K. pneumoniae liver abscess episodes in a Taiwan Hospital [34]. Given the three cases in our study all occurred in one city in Hebei province, a future study might examine the particular virulence factors of this strain of K. pneumoniae.
Although liver abscess drainage has been recommended for a better clinical response [19] and hepatic resection is preferred for patients with Acute Physiology and Chronic Health Evaluation II (APACHE II) scores of ≥15 [28]. In our cases, liver abscesses were less than 5 cm, Percutaneous drainage for small liver abscess adjacent to the liver capsule can cause complications such as bleeding or peritonitis. The poor outcomes might have no business with the lack of liver abscess drainage.
In conclusion, K. pneumoniae meningitis is a rare cause of meningitis around the world. When patients with risk factors such as T2DM and alcoholic cirrhosis present to the emergency department with clinical features of meningitis, providers should maintain a high degree of suspicion for potential K. pneumoniae-related ILAS complicated by meningitis. Strict glycemic control, early drainage of liver abscesses and appropriate antibiotic application are all recommended for treating this condition. All three patients we received unfortunately died in short order, and it’s uncertain whether emergent liver abscess drainage would have helped at that point given the patients’ already high levels of CSF protein indicating severe inflammation. Potentially unknown virulence factors of K. pneumoniae in Zhangjiakou may also play a role in these patients’ poor outcomes. These cases were shared with the international medical community with the hope for timely diagnoses of K. pneumoniae meningitis in the future and to promote progress on learning more about this bacteria’s pathogenesis and treatment.
Abbreviations
APACHE IIAcute Physiology and Chronic Health Evaluation II
BGBlood glucose
CSFCerebrospinal fluid
CRPC-reactive protein
CTComputed tomography
DKADiabetic ketoacidosis
EDEmergency Department
EICUEmergency Department Intensive Care Unit
GCSGlasgow coma scale
ILASInvasive liver abscess syndrome
K. pneumoniaeKlebsiella pneumoniae bacteria
magAMucoid-associated gene A
rmpARegulator of mucoid phenotype gene A
T2DMType 2 diabetes mellitus
Publisher’s Note
Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
Acknowledgements
Not applicable.
Authors’ contributions
YC X and XZ Y contributed to the study conception and design. Case collection and description were performed by RX S, HZ1 and JX. The first draft of the manuscript was written by RX S and JX, HZ2 revised the study design and initial manuscript, and all authors commented on previous versions of the manuscript. All authors read and approved the final manuscript.
Funding
No funding.
Availability of data and materials
The datasets used and analyzed during the current study are available from the corresponding author on reasonable request.
Ethics approval and consent to participate
The Institutional Review Board (IRB) of Peking Union Medical College Hospital has reviewed the study and has determined that this is a retrospective study and the design is scientifically and is up to the ethics standards. The IRB thus approve the study.
Consent for publication
Consent for publication has been obtained from the patients reported in this article. And each patients next-of-kin have given written consent for their relative’s personal or clinical details along with any identifying images to be published in this study.
Competing interests
The authors declare that they have no conflicts of interests. | Fatal | ReactionOutcome | CC BY | 33407192 | 19,395,094 | 2021-01-06 |
What was the outcome of reaction 'Drug ineffective'? | Klebsiella pneumoniae-related invasive liver abscess syndrome complicated by purulent meningitis: a review of the literature and description of three cases.
BACKGROUND
Klebsiella pneumoniae (K. pneumoniae) invasive liver abscess syndrome (ILAS) with purulent meningitis was rarely identified the mainland of China. Last winter, we received 3 cases of K. pneumoniae meningitis and all of them died in a short time. We report these cases in order to find the reason of high mortality and discuss effective effort to improve these patients' prognosis.
METHODS
Three patients with uncontrolled diabetes developed live abscess and purulent meningitis. Upon admission, the clinical manifestations, laboratory result of blood and cerebrospinal fluid (CSF) and imaging examinations were compatible with K. pneumoniae ILAS which had metastasis infection of meningitis. Even with timely adequate antibiotic therapy and strict glycemic control, all of the patients' condition deteriorated rapidly and died in a short time.
CONCLUSIONS
The reason of patients' poor prognosis might be the absence of liver abscess drainage, high level of CSF protein which indicates severe inflammation and unknown special but stronger virulence factors of K. pneumoniae the patients' living place Zhangjiakou. Strict glycemic control, early drainage of liver abscess and appropriate antibiotic application are recommended for treating this condition, further progress on the pathogenesis and treatment of K. pneumoniae meningitis may help patients gain a better prognosis.
Background
Over a century ago, bacterial meningitis was virtually 100% fatal [1]. Despite current antibiotics being able to clear bacteria from the cerebrospinal fluid (CSF), mortality remains approximately 25%, and, even among survivors, 21–28% of patients have chronic neurologic complications [2, 3]. Streptococcus pneumoniae is the most common bacterial cause of community-acquired meningitis in adults. The distribution of other pathogens, such as Neisseria meningitidis, group B Streptococcus, Haemophilus influenzae and Listeria monocytogenes, depends upon the age of the patient, their vaccination status and the regional epidemiological trends where the patient lives [4, 5]. Besides the more common organisms listed above, Klebsiella pneumoniae (K. pneumoniae) has been reported as a cause of community-acquired meningitis in Taiwan with a mortality rate of 30–40% in patients with liver abscesses [6, 7]. Diabetes and age > 65 years old were independent predictors of septic ocular or CNS complications in patients with liver abscesses [8]. Besides Taiwan, in South Korea, K. pneumoniae was the third most common cause of community-acquired bacterial meningitis [9]. However, K. pneumoniae meningitis is rarely identified in other regions, including mainland China. In 2018, our emergency department received three cases of K. pneumoniae meningitis. These three initially presented with fever and altered mental status, and all three died within two days after admission. We report these cases in order to illustrate the early signs of K. pneumoniae meningitis and discuss potentially effective strategies to improve the prognosis of these patients.
Case presentations
Case 1
At 07:23 on June 3, 2018, we received a 39-year-old male patient in our emergency room. He came from Zhangjiakou in Hebei province, China and presented with five days of fever and three hours of altered mental status. He had a history of poorly controlled diabetes mellitus. At the time of admission, his vital signs included a body temperature of 39 °C, a heart rate of 146 beats/min, blood pressure of 125/84 mmHg, respiratory rate of 42 breaths/min, and an oxygen saturation of 99% on room air. He had a Glasgow coma scale (GCS) of E1 + V1 + M3 with nuchal rigidity on an otherwise unremarkable physical examination.
White blood cell count was 25.73 × 109/L with an elevated neutrophil percentage of 84.9%. The concentration of C-reactive protein (CRP) was > 240 mg/L, glucose was 30 mmol/L, arterial blood gas (ABG) results were as follows (on 3 L/min of oxygen via nasal cannula): pH: 7.09, arterial pressure of CO2 (PaCO2): 9.7 mmHg, arterial pressure of oxygen (PaO2): 141 mmHg, HCO3: 2.8 mmol/L, lactic acid: 3.9 mmol/L, liver and renal function tests were within normal limits. Alb:39 g/L, PCT:2-10 ng/ml. Two sets of peripheral blood cultures were obtained (and were negative). Head and abdominal computed tomography (CT) scans demonstrated diffuse cerebral edema and possible brain and liver abscesses (see Fig. 1).
Fig. 1 a: Head CT scan showed diffuse cerebral edema; b: Abdominal CT scan demonstrating an area of abnormal attenuation measuring 24 mm × 19 mm in the right lobe of the liver, suggestive of a single abscess
The patient next underwent a lumbar puncture examination. The opening pressure was 150 mm H2O. CSF appeared yellow and purulent, revealing a 178,640 × 106/μL white blood cell count with a multinucleated cells percentage of 86.2%, protein 32.41 g/L and glucose 10.2 mmol/L. CSF was submitted for Gram staining and bacterial culture. The above findings led to the diagnoses of purulent meningitis, sepsis, diabetic ketoacidosis (DKA), as well as (possible) brain and liver abscesses. Meropenem 2 g every 8 h combined with vancomycin 1 g every 12 h were given intravenously. Due to the loss of spontaneous breathing, mechanical ventilation was started. Intensive care was begun and his DKA was treated. However, further invasive examinations (e.g. brain or liver abscess aspirations) were deemed too dangerous for him. At 11:41, the patient was transferred to the Emergency Department’s Intensive Care Unit (EICU).
By June 4, the patient’s condition had not improved. His body temperature fluctuated between 35.3 °C and 39.5 °C. His blood pressure dropped to 91/64 mmHg while the pulse rate rose to 142 beats/min. Norepinephrine was pumped venously to maintain a mean arterial pressure (MAP) > 65 mmHg. Pupils were bilaterally dilated at 3 mm’s with a slow light reflex, a GCS score of E1 + (Ventilated) + M1. Based on his worsening situation, emergency bedside lateral ventricular drainage was performed. During the operation, his cerebrospinal fluid was examined again, demonstrating a white blood cell count of 19,054 cells/μL with a multinucleated cells ratio of 78.9%, protein of 1.06 g/L and a glucose level of 0.1 mmol/L. After the operation, his intracranial pressure was consistently over 330mmH2O while undergoing continuous renal replacement therapy along with a maximal dose of mannitol.
K. pneumoniae was isolated from the patient’s cerebrospinal fluid and was found to be sensitive to all tested antibiotics including meropenem. However, the patient’s vital signs deteriorated, and he eventually died of cardiac arrest later on June 4.
Case 2
A 49-year-old woman was admitted to the emergency department of our hospital at 14:00 on July 3, 2018 because of fever and “twitching” for the past three days. She was born and currently lived in Zhangjiakou city of Hebei Province, she had a history of untreated diabetes mellitus and hypertension. At the time of admission, the patient was found to have intermittent convulsions and was unable to cooperate for a physical examination. Her temperature was 38 °C, pulse rate was 152 beats/min, respiratory rate 39 breaths/min, blood pressure was 158/88 mmHg, and her oxygen saturation was 92% on 3 L/min of oxygen via nasal cannula.
The patient’s white blood count was 24.87 × 109/L with an elevated neutrophil percentage of 91.4%, a hemoglobin of 148 g/L and a platelet count of 108 × 109/L. The CRP was 242 mg/L, glucose was 42.4 mmol/L. Arterial blood gas results were as follows (on 3 L/min oxygen via nasal cannula): pH of 7.09, PaCO2: 9.7 mmHg, PaO2: 141 mmHg, HCO3: 2.8 mmol/L, lactic acid: 3.9 mmol/L, creatinine 125 μmol/l, Urea 13.9 mmol/l, other liver and kidney function testing was normal. The patient’s procalcitonin level was > 10 ng/ml. Head CT scans revealed bilateral basal ganglia hemorrhages and a subarachnoid hemorrhage. Abdominal CT scan demonstrated a possible liver abscess (Fig. 2). Puncture examination showed the intracranial pressure was > 330 mm H2O. CSF was pale red and purulent, and revealed 4263 × 106/L white blood cells/μL with multinucleated cells ratio of 43.1%, protein 8.82 g/L and glucose 0.6 mmol/L.
Fig. 2 a and b: head CT scan showed bilateral basal ganglia hemorrhages and a subarachnoid hemorrhage; c: Abdominal CT scan demonstrating an area of abnormal attenuation measuring 18 mm × 14 mm in the right lobe of the liver
The patient was diagnosed with purulent meningitis, septic shock, cerebral hemorrhage, subarachnoid hemorrhage, DKA and a probable liver abscess. The patient was intubated for airway protection and mechanical ventilation was begun. Meropenem 2 g every 8 h was given intravenously, and lateral ventricular drainage was performed at 12:00. After the operation, the patient’s condition did not improve, and she died that afternoon due to cerebral herniation.
Two days later, blood, sputum and cerebrospinal fluid cultures all grew K. pneumoniae (sensitive to all the tested antibiotics including Meropenem).
Case 3
A 62-year-old male also from Zhangjiakou city of Hebei Province with a history of uncontrolled diabetes mellitus was admitted to the emergency department after he developed confusion for the past 11 h. Two days ago, the patient complained of a fever and vomiting. The patient was seen at a different local hospital, but his condition worsened. On arrival to our hospital, his initial vital signs were: body temperature, 37 °C, heart rate 119 beats/min, blood pressure, 159/126 mmHg, respiratory rate, 32 breaths/min, and oxygen saturation 92% on air. His physical examination was significant for a GCS of 5 (E1 + V1 + M3).
His white blood count was 12.39 × 109/L with an elevated neutrophil percentage of 92.8%, hemoglobin 165 g/L and a platelet count 25 × 109/L. ABG results were: pH 7.28, PaCO2: 24.1 mmHg, PaO2: 89.3 mmHg, HCO3: 10.9 mmol/L, lactic acid: 3.4 mmol/L, CRP was > 160 mg/L, procalcitonin > 100 ng/ml, blood glucose was 24.1 mmol/L, alanine transaminase was 139 U/L, total bilirubin/direct bilirubin were 62.0/31.4umol/L, creatinine was 274umol, and urea was 22.79 mmol/L. An abdominal CT scan demonstrated a single liver abscess (Fig. 3). A lumbar puncture was performed after the patient received a platelet transfusion. The opening pressure was too low to measure, and the CSF was a murky yellow and revealed 17,148 × 106/L white blood cells/μL with a multinucleated cells percentage of 84.3%, protein of 12.82 g/L and a glucose of < 0.1 mmol/L. The patient was diagnosed with purulent meningitis, septic shock and DKA. Meropenem 2 g every 8 h combined with vancomycin 1 g every 12 h were given intravenously and blood glucose (BG) was well controlled by insulin. However, the patient got worse and his relatives decided to withdraw care. A telephone follow-up revealed that the patient died on his way back home. Two days later, K. pneumoniae was isolated from his CSF and was sensitive to all available antibiotics.
Fig. 3 Abdominal CT scan demonstrating an area of abnormal attenuation measuring 25 mm × 19 mm in the right lobe of the liver
Discussion and conclusions
Cases of spontaneous K. pneumoniae meningitis are rare and commonly observed in hospitalized postoperative patients. Community-acquired K. pneumoniae meningitis could be associated with an invasive liver abscess syndrome (ILAS). In a study, two cases (2/15, 13.3%) were associated with K. pneumoniae liver abscess. In another study from South Korea, 4 (14.8%) of 27 patients with K. pneumoniae meningitis had a concomitant liver abscess [10]. But this situation is still rare, in a study, only 1 (0.9%) of 112 patients with K. pneumoniae liver abscess had CNS involvement [11]. We reviewed the case reports and related original articles about adult community-acquired K. pneumoniae meningitis and found that only two cases have been recorded in the mainland of China [12, 13]. As all three patients we received died relatively quickly, we summarized above the key points of their diagnosis and treatment and will now shift to analyzing the reasons for our patients’ unfortunate outcomes.
The three patients with community-acquired K. pneumoniae meningitis in this article had poorly controlled T2DM. Meningitis was preceded by an ILAS. Accordingly, when patients with T2DM present with fever, headache, coma and confusion, a high degree of suspicion should be held for ILAS besides meningitis, including possible K. pneumoniae infection [14]. However, sometimes community-acquired K. pneumoniae meningitis appears independently without a liver abscess [13, 15–17]. Besides T2DM, other risk factors may include alcohol-related chronic diseases, especially alcoholic cirrhosis, which is also related to ILAS [15, 16, 18]. The clinical manifestation and high leukocyte, high protein, and low glucose in each patients’ CSF are often found in cases of gram-negative bacilli meningitis [19]. So, the key points for diagnosing community-acquired K. pneumoniae meningitis are risk factors and pathogen culture.
Currently, there are no clear guidelines for the management of K. pneumoniae meningitis as a manifestation of ILAS. Besides strict glycemic control, a combination of early drainage of the abscess and appropriate antibiotic application is the standard treatment for this condition [20]. The selection of antibiotics should be based on in-vitro susceptibilities and clinical response. In view of the better penetration into the CSF, large doses of third-generation cephalosporins including cefotaxime (up to 2 g every four hours) and ceftriaxone (2 g twice a day) are the drugs of choice for K. pneumoniae meningitis. Imipenem and meropenem can be given to patients when strains containing extended-spectrum beta-lactamases are suspected [19]. As reported in the literature, surviving patients with K. pneumoniae meningitis were treated with ceftazidime, ceftriaxone, cefmetazole, cefotaxime, cefepime or meropenem [13, 16, 17, 21–27]. In our cases, K. pneumoniae cultured from the CSF were susceptible to all the remaining antibiotics tested, but meropenem was the antibiotic chosen for all three patients, and vancomycin was also used in two of them.
Unfortunately, each patient’s ending was still tragic. We noticed that the CSF protein levels in our patients (32.41 g/L, 8.82 g/L and 12.82 g/L, respectively) were extremely high. Previous studies of neonatal bacterial meningitis showed that high CSF protein levels, which with an optimal cutoff value of 1.88 g/L [28], were associated with poor prognosis [29–31]. The only reported case of K. pneumoniae meningitis who died mentioned a CSF protein of 2.34 g/L [12]. Another study into the clinical features of patients with adult bacterial meningitis showed the CSF protein levels in such patients with good or poor outcomes were 2.18 ± 1.47 g/L and 4.03 ± 4.19 g/L, respectively [32]. Additionally, white blood cells, immunoglobulins, and complements are normally absent in CSF, but the inflammatory response triggered by bacteria during meningitis results in increasing protein levels in the CSF which coincides with the intensity of the inflammatory response. Cytokines produced in inflammation may cause impairment of cell structure and organ function, thus increasing the risk of morbidity [28]. Overall then, the sky-high level of CSF protein in our patients may have foreshadowed their outcomes.
It is also noteworthy that all three patients came from Zhangjiakou city in Hebei Province. We suspect that the virulence of the K. pneumoniae species in this area may be particularly high. Five major virulence factors of K. pneumoniae are known to contribute to the pathogenesis of infection. These are the capsular serotype, hypermucoviscosity phenotype, lipopolysaccharide, siderophores, and pili. K [10, 33]. Based on previous study, we also know that severe manifestations such as comatose mental status, septic shock, and concomitant extra meningeal infections were more common in community- acquired K. pneumoniae meningitis patients compared with community-acquired Streptococcus pneumoniae meningitis, and the 28-day mortality (44.4% versus 10.7%; P = 0.001) and inhospitable mortality (51.9% versus 14.3%; P = 0.001) were much higher [9]. Besides the 100% mortality, all of the three patients had comatose mental status, septic shock, and live abscesses, the characters tallied with the reported study and may due to the high virulence of K. pneumoniae. What’s worse, multidrug-resistant and hypervirulent (MDR-HV) K. pneumoniae strains had spread in the community, 13 MDR-HV strains were identified from a total of 218 K. pneumoniae liver abscess episodes in a Taiwan Hospital [34]. Given the three cases in our study all occurred in one city in Hebei province, a future study might examine the particular virulence factors of this strain of K. pneumoniae.
Although liver abscess drainage has been recommended for a better clinical response [19] and hepatic resection is preferred for patients with Acute Physiology and Chronic Health Evaluation II (APACHE II) scores of ≥15 [28]. In our cases, liver abscesses were less than 5 cm, Percutaneous drainage for small liver abscess adjacent to the liver capsule can cause complications such as bleeding or peritonitis. The poor outcomes might have no business with the lack of liver abscess drainage.
In conclusion, K. pneumoniae meningitis is a rare cause of meningitis around the world. When patients with risk factors such as T2DM and alcoholic cirrhosis present to the emergency department with clinical features of meningitis, providers should maintain a high degree of suspicion for potential K. pneumoniae-related ILAS complicated by meningitis. Strict glycemic control, early drainage of liver abscesses and appropriate antibiotic application are all recommended for treating this condition. All three patients we received unfortunately died in short order, and it’s uncertain whether emergent liver abscess drainage would have helped at that point given the patients’ already high levels of CSF protein indicating severe inflammation. Potentially unknown virulence factors of K. pneumoniae in Zhangjiakou may also play a role in these patients’ poor outcomes. These cases were shared with the international medical community with the hope for timely diagnoses of K. pneumoniae meningitis in the future and to promote progress on learning more about this bacteria’s pathogenesis and treatment.
Abbreviations
APACHE IIAcute Physiology and Chronic Health Evaluation II
BGBlood glucose
CSFCerebrospinal fluid
CRPC-reactive protein
CTComputed tomography
DKADiabetic ketoacidosis
EDEmergency Department
EICUEmergency Department Intensive Care Unit
GCSGlasgow coma scale
ILASInvasive liver abscess syndrome
K. pneumoniaeKlebsiella pneumoniae bacteria
magAMucoid-associated gene A
rmpARegulator of mucoid phenotype gene A
T2DMType 2 diabetes mellitus
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Acknowledgements
Not applicable.
Authors’ contributions
YC X and XZ Y contributed to the study conception and design. Case collection and description were performed by RX S, HZ1 and JX. The first draft of the manuscript was written by RX S and JX, HZ2 revised the study design and initial manuscript, and all authors commented on previous versions of the manuscript. All authors read and approved the final manuscript.
Funding
No funding.
Availability of data and materials
The datasets used and analyzed during the current study are available from the corresponding author on reasonable request.
Ethics approval and consent to participate
The Institutional Review Board (IRB) of Peking Union Medical College Hospital has reviewed the study and has determined that this is a retrospective study and the design is scientifically and is up to the ethics standards. The IRB thus approve the study.
Consent for publication
Consent for publication has been obtained from the patients reported in this article. And each patients next-of-kin have given written consent for their relative’s personal or clinical details along with any identifying images to be published in this study.
Competing interests
The authors declare that they have no conflicts of interests. | Fatal | ReactionOutcome | CC BY | 33407192 | 19,493,037 | 2021-01-06 |
What was the outcome of reaction 'Treatment failure'? | Klebsiella pneumoniae-related invasive liver abscess syndrome complicated by purulent meningitis: a review of the literature and description of three cases.
BACKGROUND
Klebsiella pneumoniae (K. pneumoniae) invasive liver abscess syndrome (ILAS) with purulent meningitis was rarely identified the mainland of China. Last winter, we received 3 cases of K. pneumoniae meningitis and all of them died in a short time. We report these cases in order to find the reason of high mortality and discuss effective effort to improve these patients' prognosis.
METHODS
Three patients with uncontrolled diabetes developed live abscess and purulent meningitis. Upon admission, the clinical manifestations, laboratory result of blood and cerebrospinal fluid (CSF) and imaging examinations were compatible with K. pneumoniae ILAS which had metastasis infection of meningitis. Even with timely adequate antibiotic therapy and strict glycemic control, all of the patients' condition deteriorated rapidly and died in a short time.
CONCLUSIONS
The reason of patients' poor prognosis might be the absence of liver abscess drainage, high level of CSF protein which indicates severe inflammation and unknown special but stronger virulence factors of K. pneumoniae the patients' living place Zhangjiakou. Strict glycemic control, early drainage of liver abscess and appropriate antibiotic application are recommended for treating this condition, further progress on the pathogenesis and treatment of K. pneumoniae meningitis may help patients gain a better prognosis.
Background
Over a century ago, bacterial meningitis was virtually 100% fatal [1]. Despite current antibiotics being able to clear bacteria from the cerebrospinal fluid (CSF), mortality remains approximately 25%, and, even among survivors, 21–28% of patients have chronic neurologic complications [2, 3]. Streptococcus pneumoniae is the most common bacterial cause of community-acquired meningitis in adults. The distribution of other pathogens, such as Neisseria meningitidis, group B Streptococcus, Haemophilus influenzae and Listeria monocytogenes, depends upon the age of the patient, their vaccination status and the regional epidemiological trends where the patient lives [4, 5]. Besides the more common organisms listed above, Klebsiella pneumoniae (K. pneumoniae) has been reported as a cause of community-acquired meningitis in Taiwan with a mortality rate of 30–40% in patients with liver abscesses [6, 7]. Diabetes and age > 65 years old were independent predictors of septic ocular or CNS complications in patients with liver abscesses [8]. Besides Taiwan, in South Korea, K. pneumoniae was the third most common cause of community-acquired bacterial meningitis [9]. However, K. pneumoniae meningitis is rarely identified in other regions, including mainland China. In 2018, our emergency department received three cases of K. pneumoniae meningitis. These three initially presented with fever and altered mental status, and all three died within two days after admission. We report these cases in order to illustrate the early signs of K. pneumoniae meningitis and discuss potentially effective strategies to improve the prognosis of these patients.
Case presentations
Case 1
At 07:23 on June 3, 2018, we received a 39-year-old male patient in our emergency room. He came from Zhangjiakou in Hebei province, China and presented with five days of fever and three hours of altered mental status. He had a history of poorly controlled diabetes mellitus. At the time of admission, his vital signs included a body temperature of 39 °C, a heart rate of 146 beats/min, blood pressure of 125/84 mmHg, respiratory rate of 42 breaths/min, and an oxygen saturation of 99% on room air. He had a Glasgow coma scale (GCS) of E1 + V1 + M3 with nuchal rigidity on an otherwise unremarkable physical examination.
White blood cell count was 25.73 × 109/L with an elevated neutrophil percentage of 84.9%. The concentration of C-reactive protein (CRP) was > 240 mg/L, glucose was 30 mmol/L, arterial blood gas (ABG) results were as follows (on 3 L/min of oxygen via nasal cannula): pH: 7.09, arterial pressure of CO2 (PaCO2): 9.7 mmHg, arterial pressure of oxygen (PaO2): 141 mmHg, HCO3: 2.8 mmol/L, lactic acid: 3.9 mmol/L, liver and renal function tests were within normal limits. Alb:39 g/L, PCT:2-10 ng/ml. Two sets of peripheral blood cultures were obtained (and were negative). Head and abdominal computed tomography (CT) scans demonstrated diffuse cerebral edema and possible brain and liver abscesses (see Fig. 1).
Fig. 1 a: Head CT scan showed diffuse cerebral edema; b: Abdominal CT scan demonstrating an area of abnormal attenuation measuring 24 mm × 19 mm in the right lobe of the liver, suggestive of a single abscess
The patient next underwent a lumbar puncture examination. The opening pressure was 150 mm H2O. CSF appeared yellow and purulent, revealing a 178,640 × 106/μL white blood cell count with a multinucleated cells percentage of 86.2%, protein 32.41 g/L and glucose 10.2 mmol/L. CSF was submitted for Gram staining and bacterial culture. The above findings led to the diagnoses of purulent meningitis, sepsis, diabetic ketoacidosis (DKA), as well as (possible) brain and liver abscesses. Meropenem 2 g every 8 h combined with vancomycin 1 g every 12 h were given intravenously. Due to the loss of spontaneous breathing, mechanical ventilation was started. Intensive care was begun and his DKA was treated. However, further invasive examinations (e.g. brain or liver abscess aspirations) were deemed too dangerous for him. At 11:41, the patient was transferred to the Emergency Department’s Intensive Care Unit (EICU).
By June 4, the patient’s condition had not improved. His body temperature fluctuated between 35.3 °C and 39.5 °C. His blood pressure dropped to 91/64 mmHg while the pulse rate rose to 142 beats/min. Norepinephrine was pumped venously to maintain a mean arterial pressure (MAP) > 65 mmHg. Pupils were bilaterally dilated at 3 mm’s with a slow light reflex, a GCS score of E1 + (Ventilated) + M1. Based on his worsening situation, emergency bedside lateral ventricular drainage was performed. During the operation, his cerebrospinal fluid was examined again, demonstrating a white blood cell count of 19,054 cells/μL with a multinucleated cells ratio of 78.9%, protein of 1.06 g/L and a glucose level of 0.1 mmol/L. After the operation, his intracranial pressure was consistently over 330mmH2O while undergoing continuous renal replacement therapy along with a maximal dose of mannitol.
K. pneumoniae was isolated from the patient’s cerebrospinal fluid and was found to be sensitive to all tested antibiotics including meropenem. However, the patient’s vital signs deteriorated, and he eventually died of cardiac arrest later on June 4.
Case 2
A 49-year-old woman was admitted to the emergency department of our hospital at 14:00 on July 3, 2018 because of fever and “twitching” for the past three days. She was born and currently lived in Zhangjiakou city of Hebei Province, she had a history of untreated diabetes mellitus and hypertension. At the time of admission, the patient was found to have intermittent convulsions and was unable to cooperate for a physical examination. Her temperature was 38 °C, pulse rate was 152 beats/min, respiratory rate 39 breaths/min, blood pressure was 158/88 mmHg, and her oxygen saturation was 92% on 3 L/min of oxygen via nasal cannula.
The patient’s white blood count was 24.87 × 109/L with an elevated neutrophil percentage of 91.4%, a hemoglobin of 148 g/L and a platelet count of 108 × 109/L. The CRP was 242 mg/L, glucose was 42.4 mmol/L. Arterial blood gas results were as follows (on 3 L/min oxygen via nasal cannula): pH of 7.09, PaCO2: 9.7 mmHg, PaO2: 141 mmHg, HCO3: 2.8 mmol/L, lactic acid: 3.9 mmol/L, creatinine 125 μmol/l, Urea 13.9 mmol/l, other liver and kidney function testing was normal. The patient’s procalcitonin level was > 10 ng/ml. Head CT scans revealed bilateral basal ganglia hemorrhages and a subarachnoid hemorrhage. Abdominal CT scan demonstrated a possible liver abscess (Fig. 2). Puncture examination showed the intracranial pressure was > 330 mm H2O. CSF was pale red and purulent, and revealed 4263 × 106/L white blood cells/μL with multinucleated cells ratio of 43.1%, protein 8.82 g/L and glucose 0.6 mmol/L.
Fig. 2 a and b: head CT scan showed bilateral basal ganglia hemorrhages and a subarachnoid hemorrhage; c: Abdominal CT scan demonstrating an area of abnormal attenuation measuring 18 mm × 14 mm in the right lobe of the liver
The patient was diagnosed with purulent meningitis, septic shock, cerebral hemorrhage, subarachnoid hemorrhage, DKA and a probable liver abscess. The patient was intubated for airway protection and mechanical ventilation was begun. Meropenem 2 g every 8 h was given intravenously, and lateral ventricular drainage was performed at 12:00. After the operation, the patient’s condition did not improve, and she died that afternoon due to cerebral herniation.
Two days later, blood, sputum and cerebrospinal fluid cultures all grew K. pneumoniae (sensitive to all the tested antibiotics including Meropenem).
Case 3
A 62-year-old male also from Zhangjiakou city of Hebei Province with a history of uncontrolled diabetes mellitus was admitted to the emergency department after he developed confusion for the past 11 h. Two days ago, the patient complained of a fever and vomiting. The patient was seen at a different local hospital, but his condition worsened. On arrival to our hospital, his initial vital signs were: body temperature, 37 °C, heart rate 119 beats/min, blood pressure, 159/126 mmHg, respiratory rate, 32 breaths/min, and oxygen saturation 92% on air. His physical examination was significant for a GCS of 5 (E1 + V1 + M3).
His white blood count was 12.39 × 109/L with an elevated neutrophil percentage of 92.8%, hemoglobin 165 g/L and a platelet count 25 × 109/L. ABG results were: pH 7.28, PaCO2: 24.1 mmHg, PaO2: 89.3 mmHg, HCO3: 10.9 mmol/L, lactic acid: 3.4 mmol/L, CRP was > 160 mg/L, procalcitonin > 100 ng/ml, blood glucose was 24.1 mmol/L, alanine transaminase was 139 U/L, total bilirubin/direct bilirubin were 62.0/31.4umol/L, creatinine was 274umol, and urea was 22.79 mmol/L. An abdominal CT scan demonstrated a single liver abscess (Fig. 3). A lumbar puncture was performed after the patient received a platelet transfusion. The opening pressure was too low to measure, and the CSF was a murky yellow and revealed 17,148 × 106/L white blood cells/μL with a multinucleated cells percentage of 84.3%, protein of 12.82 g/L and a glucose of < 0.1 mmol/L. The patient was diagnosed with purulent meningitis, septic shock and DKA. Meropenem 2 g every 8 h combined with vancomycin 1 g every 12 h were given intravenously and blood glucose (BG) was well controlled by insulin. However, the patient got worse and his relatives decided to withdraw care. A telephone follow-up revealed that the patient died on his way back home. Two days later, K. pneumoniae was isolated from his CSF and was sensitive to all available antibiotics.
Fig. 3 Abdominal CT scan demonstrating an area of abnormal attenuation measuring 25 mm × 19 mm in the right lobe of the liver
Discussion and conclusions
Cases of spontaneous K. pneumoniae meningitis are rare and commonly observed in hospitalized postoperative patients. Community-acquired K. pneumoniae meningitis could be associated with an invasive liver abscess syndrome (ILAS). In a study, two cases (2/15, 13.3%) were associated with K. pneumoniae liver abscess. In another study from South Korea, 4 (14.8%) of 27 patients with K. pneumoniae meningitis had a concomitant liver abscess [10]. But this situation is still rare, in a study, only 1 (0.9%) of 112 patients with K. pneumoniae liver abscess had CNS involvement [11]. We reviewed the case reports and related original articles about adult community-acquired K. pneumoniae meningitis and found that only two cases have been recorded in the mainland of China [12, 13]. As all three patients we received died relatively quickly, we summarized above the key points of their diagnosis and treatment and will now shift to analyzing the reasons for our patients’ unfortunate outcomes.
The three patients with community-acquired K. pneumoniae meningitis in this article had poorly controlled T2DM. Meningitis was preceded by an ILAS. Accordingly, when patients with T2DM present with fever, headache, coma and confusion, a high degree of suspicion should be held for ILAS besides meningitis, including possible K. pneumoniae infection [14]. However, sometimes community-acquired K. pneumoniae meningitis appears independently without a liver abscess [13, 15–17]. Besides T2DM, other risk factors may include alcohol-related chronic diseases, especially alcoholic cirrhosis, which is also related to ILAS [15, 16, 18]. The clinical manifestation and high leukocyte, high protein, and low glucose in each patients’ CSF are often found in cases of gram-negative bacilli meningitis [19]. So, the key points for diagnosing community-acquired K. pneumoniae meningitis are risk factors and pathogen culture.
Currently, there are no clear guidelines for the management of K. pneumoniae meningitis as a manifestation of ILAS. Besides strict glycemic control, a combination of early drainage of the abscess and appropriate antibiotic application is the standard treatment for this condition [20]. The selection of antibiotics should be based on in-vitro susceptibilities and clinical response. In view of the better penetration into the CSF, large doses of third-generation cephalosporins including cefotaxime (up to 2 g every four hours) and ceftriaxone (2 g twice a day) are the drugs of choice for K. pneumoniae meningitis. Imipenem and meropenem can be given to patients when strains containing extended-spectrum beta-lactamases are suspected [19]. As reported in the literature, surviving patients with K. pneumoniae meningitis were treated with ceftazidime, ceftriaxone, cefmetazole, cefotaxime, cefepime or meropenem [13, 16, 17, 21–27]. In our cases, K. pneumoniae cultured from the CSF were susceptible to all the remaining antibiotics tested, but meropenem was the antibiotic chosen for all three patients, and vancomycin was also used in two of them.
Unfortunately, each patient’s ending was still tragic. We noticed that the CSF protein levels in our patients (32.41 g/L, 8.82 g/L and 12.82 g/L, respectively) were extremely high. Previous studies of neonatal bacterial meningitis showed that high CSF protein levels, which with an optimal cutoff value of 1.88 g/L [28], were associated with poor prognosis [29–31]. The only reported case of K. pneumoniae meningitis who died mentioned a CSF protein of 2.34 g/L [12]. Another study into the clinical features of patients with adult bacterial meningitis showed the CSF protein levels in such patients with good or poor outcomes were 2.18 ± 1.47 g/L and 4.03 ± 4.19 g/L, respectively [32]. Additionally, white blood cells, immunoglobulins, and complements are normally absent in CSF, but the inflammatory response triggered by bacteria during meningitis results in increasing protein levels in the CSF which coincides with the intensity of the inflammatory response. Cytokines produced in inflammation may cause impairment of cell structure and organ function, thus increasing the risk of morbidity [28]. Overall then, the sky-high level of CSF protein in our patients may have foreshadowed their outcomes.
It is also noteworthy that all three patients came from Zhangjiakou city in Hebei Province. We suspect that the virulence of the K. pneumoniae species in this area may be particularly high. Five major virulence factors of K. pneumoniae are known to contribute to the pathogenesis of infection. These are the capsular serotype, hypermucoviscosity phenotype, lipopolysaccharide, siderophores, and pili. K [10, 33]. Based on previous study, we also know that severe manifestations such as comatose mental status, septic shock, and concomitant extra meningeal infections were more common in community- acquired K. pneumoniae meningitis patients compared with community-acquired Streptococcus pneumoniae meningitis, and the 28-day mortality (44.4% versus 10.7%; P = 0.001) and inhospitable mortality (51.9% versus 14.3%; P = 0.001) were much higher [9]. Besides the 100% mortality, all of the three patients had comatose mental status, septic shock, and live abscesses, the characters tallied with the reported study and may due to the high virulence of K. pneumoniae. What’s worse, multidrug-resistant and hypervirulent (MDR-HV) K. pneumoniae strains had spread in the community, 13 MDR-HV strains were identified from a total of 218 K. pneumoniae liver abscess episodes in a Taiwan Hospital [34]. Given the three cases in our study all occurred in one city in Hebei province, a future study might examine the particular virulence factors of this strain of K. pneumoniae.
Although liver abscess drainage has been recommended for a better clinical response [19] and hepatic resection is preferred for patients with Acute Physiology and Chronic Health Evaluation II (APACHE II) scores of ≥15 [28]. In our cases, liver abscesses were less than 5 cm, Percutaneous drainage for small liver abscess adjacent to the liver capsule can cause complications such as bleeding or peritonitis. The poor outcomes might have no business with the lack of liver abscess drainage.
In conclusion, K. pneumoniae meningitis is a rare cause of meningitis around the world. When patients with risk factors such as T2DM and alcoholic cirrhosis present to the emergency department with clinical features of meningitis, providers should maintain a high degree of suspicion for potential K. pneumoniae-related ILAS complicated by meningitis. Strict glycemic control, early drainage of liver abscesses and appropriate antibiotic application are all recommended for treating this condition. All three patients we received unfortunately died in short order, and it’s uncertain whether emergent liver abscess drainage would have helped at that point given the patients’ already high levels of CSF protein indicating severe inflammation. Potentially unknown virulence factors of K. pneumoniae in Zhangjiakou may also play a role in these patients’ poor outcomes. These cases were shared with the international medical community with the hope for timely diagnoses of K. pneumoniae meningitis in the future and to promote progress on learning more about this bacteria’s pathogenesis and treatment.
Abbreviations
APACHE IIAcute Physiology and Chronic Health Evaluation II
BGBlood glucose
CSFCerebrospinal fluid
CRPC-reactive protein
CTComputed tomography
DKADiabetic ketoacidosis
EDEmergency Department
EICUEmergency Department Intensive Care Unit
GCSGlasgow coma scale
ILASInvasive liver abscess syndrome
K. pneumoniaeKlebsiella pneumoniae bacteria
magAMucoid-associated gene A
rmpARegulator of mucoid phenotype gene A
T2DMType 2 diabetes mellitus
Publisher’s Note
Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
Acknowledgements
Not applicable.
Authors’ contributions
YC X and XZ Y contributed to the study conception and design. Case collection and description were performed by RX S, HZ1 and JX. The first draft of the manuscript was written by RX S and JX, HZ2 revised the study design and initial manuscript, and all authors commented on previous versions of the manuscript. All authors read and approved the final manuscript.
Funding
No funding.
Availability of data and materials
The datasets used and analyzed during the current study are available from the corresponding author on reasonable request.
Ethics approval and consent to participate
The Institutional Review Board (IRB) of Peking Union Medical College Hospital has reviewed the study and has determined that this is a retrospective study and the design is scientifically and is up to the ethics standards. The IRB thus approve the study.
Consent for publication
Consent for publication has been obtained from the patients reported in this article. And each patients next-of-kin have given written consent for their relative’s personal or clinical details along with any identifying images to be published in this study.
Competing interests
The authors declare that they have no conflicts of interests. | Fatal | ReactionOutcome | CC BY | 33407192 | 19,395,094 | 2021-01-06 |
Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Diarrhoea'. | Programmed cell death-1 blockade in kidney carcinoma may induce eosinophilic granulomatosis with polyangiitis: a case report.
BACKGROUND
Immune checkpoint inhibitors have potential applications in treating various cancers but are associated with immune-related adverse events, such as inflammation, in a wide range of organs; however, allergic inflammation caused by these agents has not been extensively studied.
METHODS
A 65-year-old man was diagnosed with a kidney neuroendocrine carcinoma. Three months after kidney resection surgery, the tumor cells had metastasized to his liver and lymph nodes. Subsequently, the patient started chemotherapy; however, regardless of treatment, the tumor grew, and the patient experienced a series of adverse effects, such as taste disorder, anorexia, and general fatigue. Finally, he was administered a programmed cell death (PD)-1 inhibitor, nivolumab (biweekly, toal 200 mg/body), which was effective against kidney carcinoma. However, the patient had a bronchial asthma attack at 22 cycles of nivolumab treatment and chest computed tomography (CT) revealed an abnormal bilateral shadow after 37 cycles of nivolumab treatment. Bronchoscopy findings revealed eosinophil infiltration in the lungs along with severe alveolar hemorrhage. Paranasal sinus CT scanning indicated sinusitis and nerve conduction analysis indicated a decrease in his right ulnar nerve conduction velocity. Based on these findings, the patient was diagnosed with eosinophilic granulomatosis with polyangiitis; he was treated with prednisolone, which alleviated his bronchial asthma. To restart nivolumab treatment, the dose of prednisolone was gradually tapered, and the patient was administered a monthly dose of mepolizumab and biweekly dose of nivolumab. To date, there have been no bronchial attacks or CT scan abnormalities upon follow up.
CONCLUSIONS
We present a rare case in which a patient with cancer was diagnosed with eosinophilic granulomatosis with polyangiitis following treatment with a PD-1 inhibitor. Blockade of PD-1 and the programmed cell death ligand (PD-L) 1/PD-1 and PD-L2/PD-1 signaling cascade may cause allergic inflammation. Further studies are needed to identify the specific mechanisms underlying allergic inflammation after PD-1 blockade.
Background
Immune checkpoint inhibitors (ICIs) have been employed to treat several cancers. The ICI nivolumab shows inhibitory effects by blocking immune system suppressors, such as programmed cell death protein 1 (PD-1), and decreasing T helper cell signaling [1]. However, nivolumab is also associated with several immune-related adverse events (irAEs) [2]. Among them, immune-related eosinophilia cases in patients treated with anti-PD-1 or anti-programmed cell death ligand (PD-L) 1 are rare, with an estimated frequency of only 2.9–3.3% [3, 4]. Eosinophil-induced adverse events (Eo-irAEs) occur in almost half of these cases. The most frequently damaged organ is the skin, followed by the lungs; eosinophilic pneumonia or bronchitis occurs in only 0.3% of cases. These allergic irAEs associated with ICIs have rarely been reported in the literature.
Here, we report a case of a patient with cancer who was treated with nivolumab and subsequently developed eosinophilic granulomatosis with polyangiitis (EGPA).
Case presentation
A 65-year-old Japanese man was diagnosed with kidney large cell neuroendocrine carcinoma (G3 grade, 52.1% Ki67-positive stained cells, PD-L1 TPS 70%), and had undergone total left kidney resection and descending colectomy 3 years prior to visiting our hospital. Three months after surgery, the tumor cells had metastasized to his liver and lymph nodes around the abdominal aorta. At the time, there was no established treatment against neuroendocrine cell carcinoma of the renal cells in Japan. The patient provided written informed consent and started chemotherapy. First, he was administered two courses of carboplatin plus irinotecan; however, the tumor size increased. The patient then started second-line treatment with sunitinib, which was discontinued after 3 months because he developed a taste disorder and watery diarrhea. Next, the patient was administered everolimus as a third-line therapy; however, the patient developed anorexia and general fatigue, and treatment with everolimus was discontinued. Because there were no other standard therapies for treating neuroendocrine kidney carcinoma, bi-weekly nivolumab (200 mg/body) treatment was administered to the patient. After nivolumab treatment, the tumor gradually disappeared, and no adverse events other than a mildly increased peripheral absolute eosinophil count (300–500/μL) were observed after 5 cycles of nivolumab treatment.
The patient experience his first bronchial asthma attack at 22 cycles of nivolumab treatment and was treated with a short course of corticosteroid burst therapy with 20 mg prednisolone along with inhalation therapy with budesonide/formoterol fumarate. This bronchial asthma attack was thought to be an adverse event associated with nivolumab; however, the patient continued the same dose of nivolumab treatment until 37 cycles because a good response against the kidney neuroendocrine carcinoma had been achieved. This clinical course is summarized in the Additional file 1: supplementary figure. Although nivolumab treatment had been discontinued until 37 cycles, the absolute eosinophil count remained high (26.6%, 1782.2 cells/μL) and his serum immunoglobulin E (IgE) levels were increased (924 IU/mL). Titers of anti-nuclear antibodies and anti-neutrophil cytoplasmic antibodies remained in the normal range. An IgE-radioallergosorbent test detected normal IgE levels, except against Japanese cedar and white cedar pollen. His fractional exhaled nitric oxide level was elevated to 107 ppb (normal range: 15–37 ppb). The patient had no history of allergy: however, all of his children had allergic bronchial asthma. He also showed dyspnea on exertion, developed sputum, and exhibited swelling and pain in his bilateral fingers. There were no other physical findings, including wheezing. Chest X-ray and computed tomography (CT) scanning detected a bilateral linear shadow which was not detected at his first visit to our hospital (Fig. 1a–d), and paranasal sinus CT scanning showed inflamed ethmoid, frontal, and maximal sinuses, indicating sinusitis (Fig. 1e–g). Although he had a normal respiratory function before initiating nivolumab treatment (FEV1.0 = 3.08 L, FEV1.0/FVC = 71.0%), his respiratory function test indicated an obstructive ventilation disorder (FEV1.0 = 1.63 L, FEV1.0/FVC = 50.6%). These results suggested that he had either eosinophilic pneumonia or EGPA. To confirm our hypothesis, we performed a bronchoscopy; the bronchoalveolar lavage fluid collected from the right B5 contained 40% lymphocytes and 3% eosinophils. Histopathological examination of a transbronchial lung biopsy sample from the right B8 showed small blood vessel hyperplasia with neutrophil infiltration and thickening of the alveolar septa with prominent eosinophil infiltration. Large numbers of red blood cells were observed on the lung tissue along with intra-alveolar bleeding (Fig. 2a, b), suggesting distinct alveolar hemorrhage with eosinophilic pneumonia. However hemosiderin-laden macrophages were not detected by Berlin blue staining, suggesting that the alveolar hemorrhage was an occasional event. Because he had experienced several bronchial asthma attacks and was already being treated with medication, the representative clinical findings needed for the bronchial asthma diagnosis were likely masked. To confirm the pathological findings of bronchial asthma, transbronchial mucosal biopsy was conducted. A bronchial mucosal lesion of the secondary carina also showed smooth muscle hyperplasia and thickening of the basement membrane with eosinophil infiltration (Fig. 2c). These findings suggested that the patient had bronchial asthma, eosinophilic pneumonia, and small vessel vasculitis. Finally, nerve conduction analysis showed that his right ulnar nerve conduction velocity was slightly decreased. There were no brain metastatic diseases, cervical spondylosis, or abnormalities related to rheumatoid arthritis. Although we could not definitively diagnose his neurological abnormalities, EGPA was thought to be one cause of the neuropathy. According to these findings with small vessel vasculitis, the patient was diagnosed with EGPA as per the American College of Rheumatology criteria for EGPA [5]. Distinct alveolar hemorrhage was not severe in the clinical setting and no heart involvement was detected; thus, treatment with 20 mg/day oral prednisolone was started. After 3 months, his bronchial asthma was improved, and bilateral infiltration had disappeared, as shown in Fig. 3. Steroid therapy was gradually tapered; during its discontinuation to less than 10 mg/day, a biweekly dose of mepolizumab (300 mg/day) was started to treat the EGPA. Currently, the patient is being treated with both nivolumab and mepolizumab, his peripheral eosinophilia has almost disappeared, and his respiratory function has improved (FEV1.0 = 2.94 L, FEV1.0/FVC = 71.2%), with paranasal sinus CT scanning showed normal findings (Fig. 3) after a year of treatment. He appears to be stable except for his neuropathy; to date, there have been no bronchial asthma attacks or CT scan abnormalities (Fig. 3).Fig. 1 Thoracic radiogram and computed tomography (CT) scan at the bronchoscopy exam. Chest radiogram (a) showed bilateral linear shadow. Thoracic CT scan of upper (b, c) and lower lobes (d) showed bilateral ground-glass opacity. e–g Paranasal sinus CT scan; Ethmoid sinus (e), frontal sinus (f) and maxillary sinus (g). Each arrow indicates nasal mucosa thickening and fluid collection in the sinus. These appearances suggest paranasal sinusitis
Fig. 2 a, b Transbronchial lung biopsy sample from right lower lung (right B8); sample stained with hematoxylin and eosin (HE) and viewed at high power. c Airway mucosal biopsy sample from secondary carina; sample stained with HE and viewed at high power. Bar indicates 200 μm. a shows small blood vessel with neutrophil and eosinophil infiltration. Alveolar septa are thickened. b Shows lots of red blood cells on the lung tissue and intra-alveolar bleeding with septal edema. c Shows smooth muscle hyperplasia and thickened basement membrane with eosinophil infiltration
Fig. 3 Thoracic radiogram (a), CT scans of chest (b–d) and ethmoid sinus (e), frontal sinus (f) and maxillary sinus (g) after a year from initiation of treatment for EGPA. Chest radiogram (a) shows no any abnormal shadows. Thoracic CT scan of upper (b, c) and lower lobes (d) also does not show any ground-glass opacity. Each arrow in e–g indicates nasal mucosa thickening and fluid collection that was shown in e–g
Discussion and conclusions
We report a rare case in which a patient with kidney neuroendocrine carcinoma was diagnosed with EGPA after treatment with nivolumab (a PD-1 checkpoint inhibitor). ICIs, such as nivolumab, are used to treat several cancers and have been associated with immune-related eosinophilia. The exact mechanisms mediating Eo-irAEs are not fully understood but a few clinical cases related to Eo-irAEs have been reported [6–8] (Table 1). Eo-irAEs can occur in systemic organs after ICI therapy and damage various organs, including the skin, lung, kidney, heart, and biliary ducts [4]. In the cases shown in Table 1, the Eo-irAEs were limited to the respiratory tract and showed a duration of development of 2–12 months. In the current case, the initial Eo-irAE was bronchial asthma, which occurred 9 months after starting nivolumab treatment; however, eosinophil infiltration was systemic and damaged the lungs, paranasal sinus, and peripheral nervous system. Before treatment with nivolumab, the patient’s absolute eosinophil count was normal; therefore, nivolumab was thought to be the main cause of the Eo-irAE. In a recent case, ipilimumab and nivolumab therapy (which was continued after Eo-ir) led to systemic infiltration of peripheral eosinophils [9]; however, there was a lack of sufficient pathological evidence of lung eosinophil infiltration. In our case, pathological evidence revealed eosinophil infiltration around the small vessels in the lung tissues and severe alveolar hemorrhage. These findings indicated eosinophilic vasculitis and eosinophilic pneumonia and were confirmed by CT scanning, although the damage to the paranasal sinus and peripheral nervous system in the pathological findings may differ from the damage to the lungs.Table 1 Clinical appearances of previous case reports and our case
Case reports Johdai et al. 2018 [4] Maeno et al. 2017 [5] Donato et al. 2019 [3] This case
Age/sex 62/M 50/M 47/M 67/M
Diagnosis AEP BA ABPA EGPA
BA histoly − − + −
Length to AE 2 M 6 M 12 M 9 M
Tumor Lung-sq Lung-adeno Lung-adeno Kidney-NEC
PD-L1 N.F N.F 50% 70%
ICI Nivo Nivo Pembro Nivo
Treatment PSL PSL PSL/VRCZ PSL/mepolizumab
Efficacy imp imp imp imp
AEP: acute eosinophilic pneumonia, BA: bronchial asthma, ABPA: allergic bronchopulmonary aspergillaosis, EGPA: Eosinophlic Granulomatosis with Polyangitis, lung-sq: lung squamous cell carcinoma, lung-adeno: lung adenocarcinoma, kidney-NEC: kidney neuroendocrine carcinoma, N.F: no findings, Nivo: nivolumab, Pembro: pembrolizumab, PSL: prednisolone, VRCZ: voriconazol, imp: improvement
Prolonged nivolumab treatment induced not only bronchial asthma but also systemic eosinophilic infiltration in our patient. The Eo-irAEs were thought to be an allergic reaction due to PD-1 inhibition. The underlying pathological mechanisms remain unclear; however, recent evidence suggests several hypotheses such as PD-L2/PD-1 signaling inhibition or PD-L2 intrinsic dysfunction.
PD-1 is a negative regulator of CD4-positive T-cells. The ligands for PD-1 are PD-L1 (B7-H1) and PD-L2 (B7-DC), both of which belong to the B7-CD28 family [10]. PD-L1 is expressed by different resting cells, such as dendritic cells, macrophages, T-cells, and B-cells, whereas PD-L2 expression appears to be restricted to activated dendritic cells and macrophages [11]. Furthermore, only 40% homology has been reported among the two ligands [12]. Studies of the roles of PD-1 and its ligands PD-L1 and PD-L2 have yielded conflicting results in allergen-induced inflammation and airway hyper-reactivity (AHR). AHR is one of the characteristics of bronchial asthma; PD-L1 and PD-L2 show opposing functions in airway modulation. PD-L1/PD-1 induces AHR, whereas PD-L2/PD-1 blocks the initiation and progression of airway inflammation [13]. In our case, PD-1 blockade induced peripheral eosinophilia and bronchial asthma attacks. Therefore, the interaction of PD-L2 with PD-1 may be stronger than that of PD-L1.
Matsumoto et al. reported that PD-L2 blockade induced not only AHR and eosinophilia, but also increased the production of interleukin (IL)-5 and IL-13 and decreased the production of interferon-γ [14]. Oflazoglu et al. reported that exogenous PD-L2 administration in an in vivo mouse asthma model resulted in elevation of serum IgE levels, eosinophilic and lymphocytic infiltration, and production of IL-5 and IL-13 [15]. In our case, PD-1 blockade by nivolumab induced an increase in the production of both interferon-γ and Th2-type immune cytokines. In addition to PD-L2 intrinsic regulation, allergen-driven enhancement of PD-L2 also limits the secretion of IL-12 and leads to exacerbation of AHR via a PD-1 independent mechanism [16]. These results suggest unknown signaling cascades (other than PD-1 signaling) underlying the AHR mechanisms.
Finally, in our case, mepolizumab (an IL-5 inhibitor) was useful during nivolumab discontinuation. Because the IL-5 signaling cascade is thought to be an important factor related to Eo-irAEs [6], the use of mepolizumab may have prevented nivolumab from inducing Eo-irAEs in the patient. Therefore, it is necessary to investigate the effects of Eo-irAEs on systemic organs.
In summary, we reported a rare case in which nivolumab treatment for kidney neuroendocrine carcinoma induced recurrent bronchial asthma attacks and led to systemic eosinophilic inflammation and EGPA. Although the exact mechanisms underlying allergic inflammation after PD-1 blockade remain unclear, PD-L1/PD-1 and PD-L2/PD-1 signaling may be key in deciphering the mechanisms mediating allergic inflammation.
Supplementary information
Additional file 1. A clinical coarse after initiation of nivolumab treatment. Treatment cycles of nivolumab shows on the upper black bar. Black triangle represents oral 30mg/day prednisolone treatments for bronchial asthma attacks. BA-AE: bronchial asthma attack, BUD/FP: budesonide/formoterol fumarate, Tio: Tiotropium bromide, solid line represents peripheral absolute eosinophil count (EOS). Tumor size of live metastasis was represented as maximum diameter in the bottom rectangle area.
Abbreviations
CTComputed tomography
EGPAEosinophilic granulomatosis with polyangiitis
Eo-irImmune-related eosinophilia
Eo-irAEEosinophil-induced adverse event
ICIImmune checkpoint inhibitor
ILInterleukin
IgEImmunoglobulin E
irAEImmune-related adverse event
PD-1Programmed cell death 1
PD-L1Programmed cell death ligand 1
PD-L2Programmed cell death ligand 2
Publisher's Note
Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
Supplementary information
The online version contains supplementary material available at 10.1186/s12890-020-01375-5.
Acknowledgements
We would like to thank the staff of the Department of Endoscopy and Pathology. We would also like to thank Editage (www.editage.com) for English language editing.
Authors’ contributions
MH managed the patient, created the figures, and collected laboratory data. MH and NK wrote the manuscript. MH, HN, KY, YI, NK, TK, EM, MU, SM, MT, and NK contributed to the discussion of results and reviewed the manuscript. All authors read and approved the final manuscript.
Funding
Not applicable.
Availability of data and materials
Not applicable.
Ethical approval and consent to participate
Not applicable.
Consent for publication
Written informed consent was obtained from the patient for the publication of this case report and of the accompanying images.
Competing interests
The authors declare that they have no competing interests. | CARBOPLATIN, IRINOTECAN, SUNITINIB | DrugsGivenReaction | CC BY | 33407304 | 19,263,369 | 2021-01-06 |
Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Disease progression'. | Programmed cell death-1 blockade in kidney carcinoma may induce eosinophilic granulomatosis with polyangiitis: a case report.
BACKGROUND
Immune checkpoint inhibitors have potential applications in treating various cancers but are associated with immune-related adverse events, such as inflammation, in a wide range of organs; however, allergic inflammation caused by these agents has not been extensively studied.
METHODS
A 65-year-old man was diagnosed with a kidney neuroendocrine carcinoma. Three months after kidney resection surgery, the tumor cells had metastasized to his liver and lymph nodes. Subsequently, the patient started chemotherapy; however, regardless of treatment, the tumor grew, and the patient experienced a series of adverse effects, such as taste disorder, anorexia, and general fatigue. Finally, he was administered a programmed cell death (PD)-1 inhibitor, nivolumab (biweekly, toal 200 mg/body), which was effective against kidney carcinoma. However, the patient had a bronchial asthma attack at 22 cycles of nivolumab treatment and chest computed tomography (CT) revealed an abnormal bilateral shadow after 37 cycles of nivolumab treatment. Bronchoscopy findings revealed eosinophil infiltration in the lungs along with severe alveolar hemorrhage. Paranasal sinus CT scanning indicated sinusitis and nerve conduction analysis indicated a decrease in his right ulnar nerve conduction velocity. Based on these findings, the patient was diagnosed with eosinophilic granulomatosis with polyangiitis; he was treated with prednisolone, which alleviated his bronchial asthma. To restart nivolumab treatment, the dose of prednisolone was gradually tapered, and the patient was administered a monthly dose of mepolizumab and biweekly dose of nivolumab. To date, there have been no bronchial attacks or CT scan abnormalities upon follow up.
CONCLUSIONS
We present a rare case in which a patient with cancer was diagnosed with eosinophilic granulomatosis with polyangiitis following treatment with a PD-1 inhibitor. Blockade of PD-1 and the programmed cell death ligand (PD-L) 1/PD-1 and PD-L2/PD-1 signaling cascade may cause allergic inflammation. Further studies are needed to identify the specific mechanisms underlying allergic inflammation after PD-1 blockade.
Background
Immune checkpoint inhibitors (ICIs) have been employed to treat several cancers. The ICI nivolumab shows inhibitory effects by blocking immune system suppressors, such as programmed cell death protein 1 (PD-1), and decreasing T helper cell signaling [1]. However, nivolumab is also associated with several immune-related adverse events (irAEs) [2]. Among them, immune-related eosinophilia cases in patients treated with anti-PD-1 or anti-programmed cell death ligand (PD-L) 1 are rare, with an estimated frequency of only 2.9–3.3% [3, 4]. Eosinophil-induced adverse events (Eo-irAEs) occur in almost half of these cases. The most frequently damaged organ is the skin, followed by the lungs; eosinophilic pneumonia or bronchitis occurs in only 0.3% of cases. These allergic irAEs associated with ICIs have rarely been reported in the literature.
Here, we report a case of a patient with cancer who was treated with nivolumab and subsequently developed eosinophilic granulomatosis with polyangiitis (EGPA).
Case presentation
A 65-year-old Japanese man was diagnosed with kidney large cell neuroendocrine carcinoma (G3 grade, 52.1% Ki67-positive stained cells, PD-L1 TPS 70%), and had undergone total left kidney resection and descending colectomy 3 years prior to visiting our hospital. Three months after surgery, the tumor cells had metastasized to his liver and lymph nodes around the abdominal aorta. At the time, there was no established treatment against neuroendocrine cell carcinoma of the renal cells in Japan. The patient provided written informed consent and started chemotherapy. First, he was administered two courses of carboplatin plus irinotecan; however, the tumor size increased. The patient then started second-line treatment with sunitinib, which was discontinued after 3 months because he developed a taste disorder and watery diarrhea. Next, the patient was administered everolimus as a third-line therapy; however, the patient developed anorexia and general fatigue, and treatment with everolimus was discontinued. Because there were no other standard therapies for treating neuroendocrine kidney carcinoma, bi-weekly nivolumab (200 mg/body) treatment was administered to the patient. After nivolumab treatment, the tumor gradually disappeared, and no adverse events other than a mildly increased peripheral absolute eosinophil count (300–500/μL) were observed after 5 cycles of nivolumab treatment.
The patient experience his first bronchial asthma attack at 22 cycles of nivolumab treatment and was treated with a short course of corticosteroid burst therapy with 20 mg prednisolone along with inhalation therapy with budesonide/formoterol fumarate. This bronchial asthma attack was thought to be an adverse event associated with nivolumab; however, the patient continued the same dose of nivolumab treatment until 37 cycles because a good response against the kidney neuroendocrine carcinoma had been achieved. This clinical course is summarized in the Additional file 1: supplementary figure. Although nivolumab treatment had been discontinued until 37 cycles, the absolute eosinophil count remained high (26.6%, 1782.2 cells/μL) and his serum immunoglobulin E (IgE) levels were increased (924 IU/mL). Titers of anti-nuclear antibodies and anti-neutrophil cytoplasmic antibodies remained in the normal range. An IgE-radioallergosorbent test detected normal IgE levels, except against Japanese cedar and white cedar pollen. His fractional exhaled nitric oxide level was elevated to 107 ppb (normal range: 15–37 ppb). The patient had no history of allergy: however, all of his children had allergic bronchial asthma. He also showed dyspnea on exertion, developed sputum, and exhibited swelling and pain in his bilateral fingers. There were no other physical findings, including wheezing. Chest X-ray and computed tomography (CT) scanning detected a bilateral linear shadow which was not detected at his first visit to our hospital (Fig. 1a–d), and paranasal sinus CT scanning showed inflamed ethmoid, frontal, and maximal sinuses, indicating sinusitis (Fig. 1e–g). Although he had a normal respiratory function before initiating nivolumab treatment (FEV1.0 = 3.08 L, FEV1.0/FVC = 71.0%), his respiratory function test indicated an obstructive ventilation disorder (FEV1.0 = 1.63 L, FEV1.0/FVC = 50.6%). These results suggested that he had either eosinophilic pneumonia or EGPA. To confirm our hypothesis, we performed a bronchoscopy; the bronchoalveolar lavage fluid collected from the right B5 contained 40% lymphocytes and 3% eosinophils. Histopathological examination of a transbronchial lung biopsy sample from the right B8 showed small blood vessel hyperplasia with neutrophil infiltration and thickening of the alveolar septa with prominent eosinophil infiltration. Large numbers of red blood cells were observed on the lung tissue along with intra-alveolar bleeding (Fig. 2a, b), suggesting distinct alveolar hemorrhage with eosinophilic pneumonia. However hemosiderin-laden macrophages were not detected by Berlin blue staining, suggesting that the alveolar hemorrhage was an occasional event. Because he had experienced several bronchial asthma attacks and was already being treated with medication, the representative clinical findings needed for the bronchial asthma diagnosis were likely masked. To confirm the pathological findings of bronchial asthma, transbronchial mucosal biopsy was conducted. A bronchial mucosal lesion of the secondary carina also showed smooth muscle hyperplasia and thickening of the basement membrane with eosinophil infiltration (Fig. 2c). These findings suggested that the patient had bronchial asthma, eosinophilic pneumonia, and small vessel vasculitis. Finally, nerve conduction analysis showed that his right ulnar nerve conduction velocity was slightly decreased. There were no brain metastatic diseases, cervical spondylosis, or abnormalities related to rheumatoid arthritis. Although we could not definitively diagnose his neurological abnormalities, EGPA was thought to be one cause of the neuropathy. According to these findings with small vessel vasculitis, the patient was diagnosed with EGPA as per the American College of Rheumatology criteria for EGPA [5]. Distinct alveolar hemorrhage was not severe in the clinical setting and no heart involvement was detected; thus, treatment with 20 mg/day oral prednisolone was started. After 3 months, his bronchial asthma was improved, and bilateral infiltration had disappeared, as shown in Fig. 3. Steroid therapy was gradually tapered; during its discontinuation to less than 10 mg/day, a biweekly dose of mepolizumab (300 mg/day) was started to treat the EGPA. Currently, the patient is being treated with both nivolumab and mepolizumab, his peripheral eosinophilia has almost disappeared, and his respiratory function has improved (FEV1.0 = 2.94 L, FEV1.0/FVC = 71.2%), with paranasal sinus CT scanning showed normal findings (Fig. 3) after a year of treatment. He appears to be stable except for his neuropathy; to date, there have been no bronchial asthma attacks or CT scan abnormalities (Fig. 3).Fig. 1 Thoracic radiogram and computed tomography (CT) scan at the bronchoscopy exam. Chest radiogram (a) showed bilateral linear shadow. Thoracic CT scan of upper (b, c) and lower lobes (d) showed bilateral ground-glass opacity. e–g Paranasal sinus CT scan; Ethmoid sinus (e), frontal sinus (f) and maxillary sinus (g). Each arrow indicates nasal mucosa thickening and fluid collection in the sinus. These appearances suggest paranasal sinusitis
Fig. 2 a, b Transbronchial lung biopsy sample from right lower lung (right B8); sample stained with hematoxylin and eosin (HE) and viewed at high power. c Airway mucosal biopsy sample from secondary carina; sample stained with HE and viewed at high power. Bar indicates 200 μm. a shows small blood vessel with neutrophil and eosinophil infiltration. Alveolar septa are thickened. b Shows lots of red blood cells on the lung tissue and intra-alveolar bleeding with septal edema. c Shows smooth muscle hyperplasia and thickened basement membrane with eosinophil infiltration
Fig. 3 Thoracic radiogram (a), CT scans of chest (b–d) and ethmoid sinus (e), frontal sinus (f) and maxillary sinus (g) after a year from initiation of treatment for EGPA. Chest radiogram (a) shows no any abnormal shadows. Thoracic CT scan of upper (b, c) and lower lobes (d) also does not show any ground-glass opacity. Each arrow in e–g indicates nasal mucosa thickening and fluid collection that was shown in e–g
Discussion and conclusions
We report a rare case in which a patient with kidney neuroendocrine carcinoma was diagnosed with EGPA after treatment with nivolumab (a PD-1 checkpoint inhibitor). ICIs, such as nivolumab, are used to treat several cancers and have been associated with immune-related eosinophilia. The exact mechanisms mediating Eo-irAEs are not fully understood but a few clinical cases related to Eo-irAEs have been reported [6–8] (Table 1). Eo-irAEs can occur in systemic organs after ICI therapy and damage various organs, including the skin, lung, kidney, heart, and biliary ducts [4]. In the cases shown in Table 1, the Eo-irAEs were limited to the respiratory tract and showed a duration of development of 2–12 months. In the current case, the initial Eo-irAE was bronchial asthma, which occurred 9 months after starting nivolumab treatment; however, eosinophil infiltration was systemic and damaged the lungs, paranasal sinus, and peripheral nervous system. Before treatment with nivolumab, the patient’s absolute eosinophil count was normal; therefore, nivolumab was thought to be the main cause of the Eo-irAE. In a recent case, ipilimumab and nivolumab therapy (which was continued after Eo-ir) led to systemic infiltration of peripheral eosinophils [9]; however, there was a lack of sufficient pathological evidence of lung eosinophil infiltration. In our case, pathological evidence revealed eosinophil infiltration around the small vessels in the lung tissues and severe alveolar hemorrhage. These findings indicated eosinophilic vasculitis and eosinophilic pneumonia and were confirmed by CT scanning, although the damage to the paranasal sinus and peripheral nervous system in the pathological findings may differ from the damage to the lungs.Table 1 Clinical appearances of previous case reports and our case
Case reports Johdai et al. 2018 [4] Maeno et al. 2017 [5] Donato et al. 2019 [3] This case
Age/sex 62/M 50/M 47/M 67/M
Diagnosis AEP BA ABPA EGPA
BA histoly − − + −
Length to AE 2 M 6 M 12 M 9 M
Tumor Lung-sq Lung-adeno Lung-adeno Kidney-NEC
PD-L1 N.F N.F 50% 70%
ICI Nivo Nivo Pembro Nivo
Treatment PSL PSL PSL/VRCZ PSL/mepolizumab
Efficacy imp imp imp imp
AEP: acute eosinophilic pneumonia, BA: bronchial asthma, ABPA: allergic bronchopulmonary aspergillaosis, EGPA: Eosinophlic Granulomatosis with Polyangitis, lung-sq: lung squamous cell carcinoma, lung-adeno: lung adenocarcinoma, kidney-NEC: kidney neuroendocrine carcinoma, N.F: no findings, Nivo: nivolumab, Pembro: pembrolizumab, PSL: prednisolone, VRCZ: voriconazol, imp: improvement
Prolonged nivolumab treatment induced not only bronchial asthma but also systemic eosinophilic infiltration in our patient. The Eo-irAEs were thought to be an allergic reaction due to PD-1 inhibition. The underlying pathological mechanisms remain unclear; however, recent evidence suggests several hypotheses such as PD-L2/PD-1 signaling inhibition or PD-L2 intrinsic dysfunction.
PD-1 is a negative regulator of CD4-positive T-cells. The ligands for PD-1 are PD-L1 (B7-H1) and PD-L2 (B7-DC), both of which belong to the B7-CD28 family [10]. PD-L1 is expressed by different resting cells, such as dendritic cells, macrophages, T-cells, and B-cells, whereas PD-L2 expression appears to be restricted to activated dendritic cells and macrophages [11]. Furthermore, only 40% homology has been reported among the two ligands [12]. Studies of the roles of PD-1 and its ligands PD-L1 and PD-L2 have yielded conflicting results in allergen-induced inflammation and airway hyper-reactivity (AHR). AHR is one of the characteristics of bronchial asthma; PD-L1 and PD-L2 show opposing functions in airway modulation. PD-L1/PD-1 induces AHR, whereas PD-L2/PD-1 blocks the initiation and progression of airway inflammation [13]. In our case, PD-1 blockade induced peripheral eosinophilia and bronchial asthma attacks. Therefore, the interaction of PD-L2 with PD-1 may be stronger than that of PD-L1.
Matsumoto et al. reported that PD-L2 blockade induced not only AHR and eosinophilia, but also increased the production of interleukin (IL)-5 and IL-13 and decreased the production of interferon-γ [14]. Oflazoglu et al. reported that exogenous PD-L2 administration in an in vivo mouse asthma model resulted in elevation of serum IgE levels, eosinophilic and lymphocytic infiltration, and production of IL-5 and IL-13 [15]. In our case, PD-1 blockade by nivolumab induced an increase in the production of both interferon-γ and Th2-type immune cytokines. In addition to PD-L2 intrinsic regulation, allergen-driven enhancement of PD-L2 also limits the secretion of IL-12 and leads to exacerbation of AHR via a PD-1 independent mechanism [16]. These results suggest unknown signaling cascades (other than PD-1 signaling) underlying the AHR mechanisms.
Finally, in our case, mepolizumab (an IL-5 inhibitor) was useful during nivolumab discontinuation. Because the IL-5 signaling cascade is thought to be an important factor related to Eo-irAEs [6], the use of mepolizumab may have prevented nivolumab from inducing Eo-irAEs in the patient. Therefore, it is necessary to investigate the effects of Eo-irAEs on systemic organs.
In summary, we reported a rare case in which nivolumab treatment for kidney neuroendocrine carcinoma induced recurrent bronchial asthma attacks and led to systemic eosinophilic inflammation and EGPA. Although the exact mechanisms underlying allergic inflammation after PD-1 blockade remain unclear, PD-L1/PD-1 and PD-L2/PD-1 signaling may be key in deciphering the mechanisms mediating allergic inflammation.
Supplementary information
Additional file 1. A clinical coarse after initiation of nivolumab treatment. Treatment cycles of nivolumab shows on the upper black bar. Black triangle represents oral 30mg/day prednisolone treatments for bronchial asthma attacks. BA-AE: bronchial asthma attack, BUD/FP: budesonide/formoterol fumarate, Tio: Tiotropium bromide, solid line represents peripheral absolute eosinophil count (EOS). Tumor size of live metastasis was represented as maximum diameter in the bottom rectangle area.
Abbreviations
CTComputed tomography
EGPAEosinophilic granulomatosis with polyangiitis
Eo-irImmune-related eosinophilia
Eo-irAEEosinophil-induced adverse event
ICIImmune checkpoint inhibitor
ILInterleukin
IgEImmunoglobulin E
irAEImmune-related adverse event
PD-1Programmed cell death 1
PD-L1Programmed cell death ligand 1
PD-L2Programmed cell death ligand 2
Publisher's Note
Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
Supplementary information
The online version contains supplementary material available at 10.1186/s12890-020-01375-5.
Acknowledgements
We would like to thank the staff of the Department of Endoscopy and Pathology. We would also like to thank Editage (www.editage.com) for English language editing.
Authors’ contributions
MH managed the patient, created the figures, and collected laboratory data. MH and NK wrote the manuscript. MH, HN, KY, YI, NK, TK, EM, MU, SM, MT, and NK contributed to the discussion of results and reviewed the manuscript. All authors read and approved the final manuscript.
Funding
Not applicable.
Availability of data and materials
Not applicable.
Ethical approval and consent to participate
Not applicable.
Consent for publication
Written informed consent was obtained from the patient for the publication of this case report and of the accompanying images.
Competing interests
The authors declare that they have no competing interests. | CARBOPLATIN, IRINOTECAN, SUNITINIB | DrugsGivenReaction | CC BY | 33407304 | 19,263,369 | 2021-01-06 |
Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Drug ineffective'. | Programmed cell death-1 blockade in kidney carcinoma may induce eosinophilic granulomatosis with polyangiitis: a case report.
BACKGROUND
Immune checkpoint inhibitors have potential applications in treating various cancers but are associated with immune-related adverse events, such as inflammation, in a wide range of organs; however, allergic inflammation caused by these agents has not been extensively studied.
METHODS
A 65-year-old man was diagnosed with a kidney neuroendocrine carcinoma. Three months after kidney resection surgery, the tumor cells had metastasized to his liver and lymph nodes. Subsequently, the patient started chemotherapy; however, regardless of treatment, the tumor grew, and the patient experienced a series of adverse effects, such as taste disorder, anorexia, and general fatigue. Finally, he was administered a programmed cell death (PD)-1 inhibitor, nivolumab (biweekly, toal 200 mg/body), which was effective against kidney carcinoma. However, the patient had a bronchial asthma attack at 22 cycles of nivolumab treatment and chest computed tomography (CT) revealed an abnormal bilateral shadow after 37 cycles of nivolumab treatment. Bronchoscopy findings revealed eosinophil infiltration in the lungs along with severe alveolar hemorrhage. Paranasal sinus CT scanning indicated sinusitis and nerve conduction analysis indicated a decrease in his right ulnar nerve conduction velocity. Based on these findings, the patient was diagnosed with eosinophilic granulomatosis with polyangiitis; he was treated with prednisolone, which alleviated his bronchial asthma. To restart nivolumab treatment, the dose of prednisolone was gradually tapered, and the patient was administered a monthly dose of mepolizumab and biweekly dose of nivolumab. To date, there have been no bronchial attacks or CT scan abnormalities upon follow up.
CONCLUSIONS
We present a rare case in which a patient with cancer was diagnosed with eosinophilic granulomatosis with polyangiitis following treatment with a PD-1 inhibitor. Blockade of PD-1 and the programmed cell death ligand (PD-L) 1/PD-1 and PD-L2/PD-1 signaling cascade may cause allergic inflammation. Further studies are needed to identify the specific mechanisms underlying allergic inflammation after PD-1 blockade.
Background
Immune checkpoint inhibitors (ICIs) have been employed to treat several cancers. The ICI nivolumab shows inhibitory effects by blocking immune system suppressors, such as programmed cell death protein 1 (PD-1), and decreasing T helper cell signaling [1]. However, nivolumab is also associated with several immune-related adverse events (irAEs) [2]. Among them, immune-related eosinophilia cases in patients treated with anti-PD-1 or anti-programmed cell death ligand (PD-L) 1 are rare, with an estimated frequency of only 2.9–3.3% [3, 4]. Eosinophil-induced adverse events (Eo-irAEs) occur in almost half of these cases. The most frequently damaged organ is the skin, followed by the lungs; eosinophilic pneumonia or bronchitis occurs in only 0.3% of cases. These allergic irAEs associated with ICIs have rarely been reported in the literature.
Here, we report a case of a patient with cancer who was treated with nivolumab and subsequently developed eosinophilic granulomatosis with polyangiitis (EGPA).
Case presentation
A 65-year-old Japanese man was diagnosed with kidney large cell neuroendocrine carcinoma (G3 grade, 52.1% Ki67-positive stained cells, PD-L1 TPS 70%), and had undergone total left kidney resection and descending colectomy 3 years prior to visiting our hospital. Three months after surgery, the tumor cells had metastasized to his liver and lymph nodes around the abdominal aorta. At the time, there was no established treatment against neuroendocrine cell carcinoma of the renal cells in Japan. The patient provided written informed consent and started chemotherapy. First, he was administered two courses of carboplatin plus irinotecan; however, the tumor size increased. The patient then started second-line treatment with sunitinib, which was discontinued after 3 months because he developed a taste disorder and watery diarrhea. Next, the patient was administered everolimus as a third-line therapy; however, the patient developed anorexia and general fatigue, and treatment with everolimus was discontinued. Because there were no other standard therapies for treating neuroendocrine kidney carcinoma, bi-weekly nivolumab (200 mg/body) treatment was administered to the patient. After nivolumab treatment, the tumor gradually disappeared, and no adverse events other than a mildly increased peripheral absolute eosinophil count (300–500/μL) were observed after 5 cycles of nivolumab treatment.
The patient experience his first bronchial asthma attack at 22 cycles of nivolumab treatment and was treated with a short course of corticosteroid burst therapy with 20 mg prednisolone along with inhalation therapy with budesonide/formoterol fumarate. This bronchial asthma attack was thought to be an adverse event associated with nivolumab; however, the patient continued the same dose of nivolumab treatment until 37 cycles because a good response against the kidney neuroendocrine carcinoma had been achieved. This clinical course is summarized in the Additional file 1: supplementary figure. Although nivolumab treatment had been discontinued until 37 cycles, the absolute eosinophil count remained high (26.6%, 1782.2 cells/μL) and his serum immunoglobulin E (IgE) levels were increased (924 IU/mL). Titers of anti-nuclear antibodies and anti-neutrophil cytoplasmic antibodies remained in the normal range. An IgE-radioallergosorbent test detected normal IgE levels, except against Japanese cedar and white cedar pollen. His fractional exhaled nitric oxide level was elevated to 107 ppb (normal range: 15–37 ppb). The patient had no history of allergy: however, all of his children had allergic bronchial asthma. He also showed dyspnea on exertion, developed sputum, and exhibited swelling and pain in his bilateral fingers. There were no other physical findings, including wheezing. Chest X-ray and computed tomography (CT) scanning detected a bilateral linear shadow which was not detected at his first visit to our hospital (Fig. 1a–d), and paranasal sinus CT scanning showed inflamed ethmoid, frontal, and maximal sinuses, indicating sinusitis (Fig. 1e–g). Although he had a normal respiratory function before initiating nivolumab treatment (FEV1.0 = 3.08 L, FEV1.0/FVC = 71.0%), his respiratory function test indicated an obstructive ventilation disorder (FEV1.0 = 1.63 L, FEV1.0/FVC = 50.6%). These results suggested that he had either eosinophilic pneumonia or EGPA. To confirm our hypothesis, we performed a bronchoscopy; the bronchoalveolar lavage fluid collected from the right B5 contained 40% lymphocytes and 3% eosinophils. Histopathological examination of a transbronchial lung biopsy sample from the right B8 showed small blood vessel hyperplasia with neutrophil infiltration and thickening of the alveolar septa with prominent eosinophil infiltration. Large numbers of red blood cells were observed on the lung tissue along with intra-alveolar bleeding (Fig. 2a, b), suggesting distinct alveolar hemorrhage with eosinophilic pneumonia. However hemosiderin-laden macrophages were not detected by Berlin blue staining, suggesting that the alveolar hemorrhage was an occasional event. Because he had experienced several bronchial asthma attacks and was already being treated with medication, the representative clinical findings needed for the bronchial asthma diagnosis were likely masked. To confirm the pathological findings of bronchial asthma, transbronchial mucosal biopsy was conducted. A bronchial mucosal lesion of the secondary carina also showed smooth muscle hyperplasia and thickening of the basement membrane with eosinophil infiltration (Fig. 2c). These findings suggested that the patient had bronchial asthma, eosinophilic pneumonia, and small vessel vasculitis. Finally, nerve conduction analysis showed that his right ulnar nerve conduction velocity was slightly decreased. There were no brain metastatic diseases, cervical spondylosis, or abnormalities related to rheumatoid arthritis. Although we could not definitively diagnose his neurological abnormalities, EGPA was thought to be one cause of the neuropathy. According to these findings with small vessel vasculitis, the patient was diagnosed with EGPA as per the American College of Rheumatology criteria for EGPA [5]. Distinct alveolar hemorrhage was not severe in the clinical setting and no heart involvement was detected; thus, treatment with 20 mg/day oral prednisolone was started. After 3 months, his bronchial asthma was improved, and bilateral infiltration had disappeared, as shown in Fig. 3. Steroid therapy was gradually tapered; during its discontinuation to less than 10 mg/day, a biweekly dose of mepolizumab (300 mg/day) was started to treat the EGPA. Currently, the patient is being treated with both nivolumab and mepolizumab, his peripheral eosinophilia has almost disappeared, and his respiratory function has improved (FEV1.0 = 2.94 L, FEV1.0/FVC = 71.2%), with paranasal sinus CT scanning showed normal findings (Fig. 3) after a year of treatment. He appears to be stable except for his neuropathy; to date, there have been no bronchial asthma attacks or CT scan abnormalities (Fig. 3).Fig. 1 Thoracic radiogram and computed tomography (CT) scan at the bronchoscopy exam. Chest radiogram (a) showed bilateral linear shadow. Thoracic CT scan of upper (b, c) and lower lobes (d) showed bilateral ground-glass opacity. e–g Paranasal sinus CT scan; Ethmoid sinus (e), frontal sinus (f) and maxillary sinus (g). Each arrow indicates nasal mucosa thickening and fluid collection in the sinus. These appearances suggest paranasal sinusitis
Fig. 2 a, b Transbronchial lung biopsy sample from right lower lung (right B8); sample stained with hematoxylin and eosin (HE) and viewed at high power. c Airway mucosal biopsy sample from secondary carina; sample stained with HE and viewed at high power. Bar indicates 200 μm. a shows small blood vessel with neutrophil and eosinophil infiltration. Alveolar septa are thickened. b Shows lots of red blood cells on the lung tissue and intra-alveolar bleeding with septal edema. c Shows smooth muscle hyperplasia and thickened basement membrane with eosinophil infiltration
Fig. 3 Thoracic radiogram (a), CT scans of chest (b–d) and ethmoid sinus (e), frontal sinus (f) and maxillary sinus (g) after a year from initiation of treatment for EGPA. Chest radiogram (a) shows no any abnormal shadows. Thoracic CT scan of upper (b, c) and lower lobes (d) also does not show any ground-glass opacity. Each arrow in e–g indicates nasal mucosa thickening and fluid collection that was shown in e–g
Discussion and conclusions
We report a rare case in which a patient with kidney neuroendocrine carcinoma was diagnosed with EGPA after treatment with nivolumab (a PD-1 checkpoint inhibitor). ICIs, such as nivolumab, are used to treat several cancers and have been associated with immune-related eosinophilia. The exact mechanisms mediating Eo-irAEs are not fully understood but a few clinical cases related to Eo-irAEs have been reported [6–8] (Table 1). Eo-irAEs can occur in systemic organs after ICI therapy and damage various organs, including the skin, lung, kidney, heart, and biliary ducts [4]. In the cases shown in Table 1, the Eo-irAEs were limited to the respiratory tract and showed a duration of development of 2–12 months. In the current case, the initial Eo-irAE was bronchial asthma, which occurred 9 months after starting nivolumab treatment; however, eosinophil infiltration was systemic and damaged the lungs, paranasal sinus, and peripheral nervous system. Before treatment with nivolumab, the patient’s absolute eosinophil count was normal; therefore, nivolumab was thought to be the main cause of the Eo-irAE. In a recent case, ipilimumab and nivolumab therapy (which was continued after Eo-ir) led to systemic infiltration of peripheral eosinophils [9]; however, there was a lack of sufficient pathological evidence of lung eosinophil infiltration. In our case, pathological evidence revealed eosinophil infiltration around the small vessels in the lung tissues and severe alveolar hemorrhage. These findings indicated eosinophilic vasculitis and eosinophilic pneumonia and were confirmed by CT scanning, although the damage to the paranasal sinus and peripheral nervous system in the pathological findings may differ from the damage to the lungs.Table 1 Clinical appearances of previous case reports and our case
Case reports Johdai et al. 2018 [4] Maeno et al. 2017 [5] Donato et al. 2019 [3] This case
Age/sex 62/M 50/M 47/M 67/M
Diagnosis AEP BA ABPA EGPA
BA histoly − − + −
Length to AE 2 M 6 M 12 M 9 M
Tumor Lung-sq Lung-adeno Lung-adeno Kidney-NEC
PD-L1 N.F N.F 50% 70%
ICI Nivo Nivo Pembro Nivo
Treatment PSL PSL PSL/VRCZ PSL/mepolizumab
Efficacy imp imp imp imp
AEP: acute eosinophilic pneumonia, BA: bronchial asthma, ABPA: allergic bronchopulmonary aspergillaosis, EGPA: Eosinophlic Granulomatosis with Polyangitis, lung-sq: lung squamous cell carcinoma, lung-adeno: lung adenocarcinoma, kidney-NEC: kidney neuroendocrine carcinoma, N.F: no findings, Nivo: nivolumab, Pembro: pembrolizumab, PSL: prednisolone, VRCZ: voriconazol, imp: improvement
Prolonged nivolumab treatment induced not only bronchial asthma but also systemic eosinophilic infiltration in our patient. The Eo-irAEs were thought to be an allergic reaction due to PD-1 inhibition. The underlying pathological mechanisms remain unclear; however, recent evidence suggests several hypotheses such as PD-L2/PD-1 signaling inhibition or PD-L2 intrinsic dysfunction.
PD-1 is a negative regulator of CD4-positive T-cells. The ligands for PD-1 are PD-L1 (B7-H1) and PD-L2 (B7-DC), both of which belong to the B7-CD28 family [10]. PD-L1 is expressed by different resting cells, such as dendritic cells, macrophages, T-cells, and B-cells, whereas PD-L2 expression appears to be restricted to activated dendritic cells and macrophages [11]. Furthermore, only 40% homology has been reported among the two ligands [12]. Studies of the roles of PD-1 and its ligands PD-L1 and PD-L2 have yielded conflicting results in allergen-induced inflammation and airway hyper-reactivity (AHR). AHR is one of the characteristics of bronchial asthma; PD-L1 and PD-L2 show opposing functions in airway modulation. PD-L1/PD-1 induces AHR, whereas PD-L2/PD-1 blocks the initiation and progression of airway inflammation [13]. In our case, PD-1 blockade induced peripheral eosinophilia and bronchial asthma attacks. Therefore, the interaction of PD-L2 with PD-1 may be stronger than that of PD-L1.
Matsumoto et al. reported that PD-L2 blockade induced not only AHR and eosinophilia, but also increased the production of interleukin (IL)-5 and IL-13 and decreased the production of interferon-γ [14]. Oflazoglu et al. reported that exogenous PD-L2 administration in an in vivo mouse asthma model resulted in elevation of serum IgE levels, eosinophilic and lymphocytic infiltration, and production of IL-5 and IL-13 [15]. In our case, PD-1 blockade by nivolumab induced an increase in the production of both interferon-γ and Th2-type immune cytokines. In addition to PD-L2 intrinsic regulation, allergen-driven enhancement of PD-L2 also limits the secretion of IL-12 and leads to exacerbation of AHR via a PD-1 independent mechanism [16]. These results suggest unknown signaling cascades (other than PD-1 signaling) underlying the AHR mechanisms.
Finally, in our case, mepolizumab (an IL-5 inhibitor) was useful during nivolumab discontinuation. Because the IL-5 signaling cascade is thought to be an important factor related to Eo-irAEs [6], the use of mepolizumab may have prevented nivolumab from inducing Eo-irAEs in the patient. Therefore, it is necessary to investigate the effects of Eo-irAEs on systemic organs.
In summary, we reported a rare case in which nivolumab treatment for kidney neuroendocrine carcinoma induced recurrent bronchial asthma attacks and led to systemic eosinophilic inflammation and EGPA. Although the exact mechanisms underlying allergic inflammation after PD-1 blockade remain unclear, PD-L1/PD-1 and PD-L2/PD-1 signaling may be key in deciphering the mechanisms mediating allergic inflammation.
Supplementary information
Additional file 1. A clinical coarse after initiation of nivolumab treatment. Treatment cycles of nivolumab shows on the upper black bar. Black triangle represents oral 30mg/day prednisolone treatments for bronchial asthma attacks. BA-AE: bronchial asthma attack, BUD/FP: budesonide/formoterol fumarate, Tio: Tiotropium bromide, solid line represents peripheral absolute eosinophil count (EOS). Tumor size of live metastasis was represented as maximum diameter in the bottom rectangle area.
Abbreviations
CTComputed tomography
EGPAEosinophilic granulomatosis with polyangiitis
Eo-irImmune-related eosinophilia
Eo-irAEEosinophil-induced adverse event
ICIImmune checkpoint inhibitor
ILInterleukin
IgEImmunoglobulin E
irAEImmune-related adverse event
PD-1Programmed cell death 1
PD-L1Programmed cell death ligand 1
PD-L2Programmed cell death ligand 2
Publisher's Note
Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
Supplementary information
The online version contains supplementary material available at 10.1186/s12890-020-01375-5.
Acknowledgements
We would like to thank the staff of the Department of Endoscopy and Pathology. We would also like to thank Editage (www.editage.com) for English language editing.
Authors’ contributions
MH managed the patient, created the figures, and collected laboratory data. MH and NK wrote the manuscript. MH, HN, KY, YI, NK, TK, EM, MU, SM, MT, and NK contributed to the discussion of results and reviewed the manuscript. All authors read and approved the final manuscript.
Funding
Not applicable.
Availability of data and materials
Not applicable.
Ethical approval and consent to participate
Not applicable.
Consent for publication
Written informed consent was obtained from the patient for the publication of this case report and of the accompanying images.
Competing interests
The authors declare that they have no competing interests. | CARBOPLATIN, IRINOTECAN, SUNITINIB | DrugsGivenReaction | CC BY | 33407304 | 19,263,369 | 2021-01-06 |
Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Taste disorder'. | Programmed cell death-1 blockade in kidney carcinoma may induce eosinophilic granulomatosis with polyangiitis: a case report.
BACKGROUND
Immune checkpoint inhibitors have potential applications in treating various cancers but are associated with immune-related adverse events, such as inflammation, in a wide range of organs; however, allergic inflammation caused by these agents has not been extensively studied.
METHODS
A 65-year-old man was diagnosed with a kidney neuroendocrine carcinoma. Three months after kidney resection surgery, the tumor cells had metastasized to his liver and lymph nodes. Subsequently, the patient started chemotherapy; however, regardless of treatment, the tumor grew, and the patient experienced a series of adverse effects, such as taste disorder, anorexia, and general fatigue. Finally, he was administered a programmed cell death (PD)-1 inhibitor, nivolumab (biweekly, toal 200 mg/body), which was effective against kidney carcinoma. However, the patient had a bronchial asthma attack at 22 cycles of nivolumab treatment and chest computed tomography (CT) revealed an abnormal bilateral shadow after 37 cycles of nivolumab treatment. Bronchoscopy findings revealed eosinophil infiltration in the lungs along with severe alveolar hemorrhage. Paranasal sinus CT scanning indicated sinusitis and nerve conduction analysis indicated a decrease in his right ulnar nerve conduction velocity. Based on these findings, the patient was diagnosed with eosinophilic granulomatosis with polyangiitis; he was treated with prednisolone, which alleviated his bronchial asthma. To restart nivolumab treatment, the dose of prednisolone was gradually tapered, and the patient was administered a monthly dose of mepolizumab and biweekly dose of nivolumab. To date, there have been no bronchial attacks or CT scan abnormalities upon follow up.
CONCLUSIONS
We present a rare case in which a patient with cancer was diagnosed with eosinophilic granulomatosis with polyangiitis following treatment with a PD-1 inhibitor. Blockade of PD-1 and the programmed cell death ligand (PD-L) 1/PD-1 and PD-L2/PD-1 signaling cascade may cause allergic inflammation. Further studies are needed to identify the specific mechanisms underlying allergic inflammation after PD-1 blockade.
Background
Immune checkpoint inhibitors (ICIs) have been employed to treat several cancers. The ICI nivolumab shows inhibitory effects by blocking immune system suppressors, such as programmed cell death protein 1 (PD-1), and decreasing T helper cell signaling [1]. However, nivolumab is also associated with several immune-related adverse events (irAEs) [2]. Among them, immune-related eosinophilia cases in patients treated with anti-PD-1 or anti-programmed cell death ligand (PD-L) 1 are rare, with an estimated frequency of only 2.9–3.3% [3, 4]. Eosinophil-induced adverse events (Eo-irAEs) occur in almost half of these cases. The most frequently damaged organ is the skin, followed by the lungs; eosinophilic pneumonia or bronchitis occurs in only 0.3% of cases. These allergic irAEs associated with ICIs have rarely been reported in the literature.
Here, we report a case of a patient with cancer who was treated with nivolumab and subsequently developed eosinophilic granulomatosis with polyangiitis (EGPA).
Case presentation
A 65-year-old Japanese man was diagnosed with kidney large cell neuroendocrine carcinoma (G3 grade, 52.1% Ki67-positive stained cells, PD-L1 TPS 70%), and had undergone total left kidney resection and descending colectomy 3 years prior to visiting our hospital. Three months after surgery, the tumor cells had metastasized to his liver and lymph nodes around the abdominal aorta. At the time, there was no established treatment against neuroendocrine cell carcinoma of the renal cells in Japan. The patient provided written informed consent and started chemotherapy. First, he was administered two courses of carboplatin plus irinotecan; however, the tumor size increased. The patient then started second-line treatment with sunitinib, which was discontinued after 3 months because he developed a taste disorder and watery diarrhea. Next, the patient was administered everolimus as a third-line therapy; however, the patient developed anorexia and general fatigue, and treatment with everolimus was discontinued. Because there were no other standard therapies for treating neuroendocrine kidney carcinoma, bi-weekly nivolumab (200 mg/body) treatment was administered to the patient. After nivolumab treatment, the tumor gradually disappeared, and no adverse events other than a mildly increased peripheral absolute eosinophil count (300–500/μL) were observed after 5 cycles of nivolumab treatment.
The patient experience his first bronchial asthma attack at 22 cycles of nivolumab treatment and was treated with a short course of corticosteroid burst therapy with 20 mg prednisolone along with inhalation therapy with budesonide/formoterol fumarate. This bronchial asthma attack was thought to be an adverse event associated with nivolumab; however, the patient continued the same dose of nivolumab treatment until 37 cycles because a good response against the kidney neuroendocrine carcinoma had been achieved. This clinical course is summarized in the Additional file 1: supplementary figure. Although nivolumab treatment had been discontinued until 37 cycles, the absolute eosinophil count remained high (26.6%, 1782.2 cells/μL) and his serum immunoglobulin E (IgE) levels were increased (924 IU/mL). Titers of anti-nuclear antibodies and anti-neutrophil cytoplasmic antibodies remained in the normal range. An IgE-radioallergosorbent test detected normal IgE levels, except against Japanese cedar and white cedar pollen. His fractional exhaled nitric oxide level was elevated to 107 ppb (normal range: 15–37 ppb). The patient had no history of allergy: however, all of his children had allergic bronchial asthma. He also showed dyspnea on exertion, developed sputum, and exhibited swelling and pain in his bilateral fingers. There were no other physical findings, including wheezing. Chest X-ray and computed tomography (CT) scanning detected a bilateral linear shadow which was not detected at his first visit to our hospital (Fig. 1a–d), and paranasal sinus CT scanning showed inflamed ethmoid, frontal, and maximal sinuses, indicating sinusitis (Fig. 1e–g). Although he had a normal respiratory function before initiating nivolumab treatment (FEV1.0 = 3.08 L, FEV1.0/FVC = 71.0%), his respiratory function test indicated an obstructive ventilation disorder (FEV1.0 = 1.63 L, FEV1.0/FVC = 50.6%). These results suggested that he had either eosinophilic pneumonia or EGPA. To confirm our hypothesis, we performed a bronchoscopy; the bronchoalveolar lavage fluid collected from the right B5 contained 40% lymphocytes and 3% eosinophils. Histopathological examination of a transbronchial lung biopsy sample from the right B8 showed small blood vessel hyperplasia with neutrophil infiltration and thickening of the alveolar septa with prominent eosinophil infiltration. Large numbers of red blood cells were observed on the lung tissue along with intra-alveolar bleeding (Fig. 2a, b), suggesting distinct alveolar hemorrhage with eosinophilic pneumonia. However hemosiderin-laden macrophages were not detected by Berlin blue staining, suggesting that the alveolar hemorrhage was an occasional event. Because he had experienced several bronchial asthma attacks and was already being treated with medication, the representative clinical findings needed for the bronchial asthma diagnosis were likely masked. To confirm the pathological findings of bronchial asthma, transbronchial mucosal biopsy was conducted. A bronchial mucosal lesion of the secondary carina also showed smooth muscle hyperplasia and thickening of the basement membrane with eosinophil infiltration (Fig. 2c). These findings suggested that the patient had bronchial asthma, eosinophilic pneumonia, and small vessel vasculitis. Finally, nerve conduction analysis showed that his right ulnar nerve conduction velocity was slightly decreased. There were no brain metastatic diseases, cervical spondylosis, or abnormalities related to rheumatoid arthritis. Although we could not definitively diagnose his neurological abnormalities, EGPA was thought to be one cause of the neuropathy. According to these findings with small vessel vasculitis, the patient was diagnosed with EGPA as per the American College of Rheumatology criteria for EGPA [5]. Distinct alveolar hemorrhage was not severe in the clinical setting and no heart involvement was detected; thus, treatment with 20 mg/day oral prednisolone was started. After 3 months, his bronchial asthma was improved, and bilateral infiltration had disappeared, as shown in Fig. 3. Steroid therapy was gradually tapered; during its discontinuation to less than 10 mg/day, a biweekly dose of mepolizumab (300 mg/day) was started to treat the EGPA. Currently, the patient is being treated with both nivolumab and mepolizumab, his peripheral eosinophilia has almost disappeared, and his respiratory function has improved (FEV1.0 = 2.94 L, FEV1.0/FVC = 71.2%), with paranasal sinus CT scanning showed normal findings (Fig. 3) after a year of treatment. He appears to be stable except for his neuropathy; to date, there have been no bronchial asthma attacks or CT scan abnormalities (Fig. 3).Fig. 1 Thoracic radiogram and computed tomography (CT) scan at the bronchoscopy exam. Chest radiogram (a) showed bilateral linear shadow. Thoracic CT scan of upper (b, c) and lower lobes (d) showed bilateral ground-glass opacity. e–g Paranasal sinus CT scan; Ethmoid sinus (e), frontal sinus (f) and maxillary sinus (g). Each arrow indicates nasal mucosa thickening and fluid collection in the sinus. These appearances suggest paranasal sinusitis
Fig. 2 a, b Transbronchial lung biopsy sample from right lower lung (right B8); sample stained with hematoxylin and eosin (HE) and viewed at high power. c Airway mucosal biopsy sample from secondary carina; sample stained with HE and viewed at high power. Bar indicates 200 μm. a shows small blood vessel with neutrophil and eosinophil infiltration. Alveolar septa are thickened. b Shows lots of red blood cells on the lung tissue and intra-alveolar bleeding with septal edema. c Shows smooth muscle hyperplasia and thickened basement membrane with eosinophil infiltration
Fig. 3 Thoracic radiogram (a), CT scans of chest (b–d) and ethmoid sinus (e), frontal sinus (f) and maxillary sinus (g) after a year from initiation of treatment for EGPA. Chest radiogram (a) shows no any abnormal shadows. Thoracic CT scan of upper (b, c) and lower lobes (d) also does not show any ground-glass opacity. Each arrow in e–g indicates nasal mucosa thickening and fluid collection that was shown in e–g
Discussion and conclusions
We report a rare case in which a patient with kidney neuroendocrine carcinoma was diagnosed with EGPA after treatment with nivolumab (a PD-1 checkpoint inhibitor). ICIs, such as nivolumab, are used to treat several cancers and have been associated with immune-related eosinophilia. The exact mechanisms mediating Eo-irAEs are not fully understood but a few clinical cases related to Eo-irAEs have been reported [6–8] (Table 1). Eo-irAEs can occur in systemic organs after ICI therapy and damage various organs, including the skin, lung, kidney, heart, and biliary ducts [4]. In the cases shown in Table 1, the Eo-irAEs were limited to the respiratory tract and showed a duration of development of 2–12 months. In the current case, the initial Eo-irAE was bronchial asthma, which occurred 9 months after starting nivolumab treatment; however, eosinophil infiltration was systemic and damaged the lungs, paranasal sinus, and peripheral nervous system. Before treatment with nivolumab, the patient’s absolute eosinophil count was normal; therefore, nivolumab was thought to be the main cause of the Eo-irAE. In a recent case, ipilimumab and nivolumab therapy (which was continued after Eo-ir) led to systemic infiltration of peripheral eosinophils [9]; however, there was a lack of sufficient pathological evidence of lung eosinophil infiltration. In our case, pathological evidence revealed eosinophil infiltration around the small vessels in the lung tissues and severe alveolar hemorrhage. These findings indicated eosinophilic vasculitis and eosinophilic pneumonia and were confirmed by CT scanning, although the damage to the paranasal sinus and peripheral nervous system in the pathological findings may differ from the damage to the lungs.Table 1 Clinical appearances of previous case reports and our case
Case reports Johdai et al. 2018 [4] Maeno et al. 2017 [5] Donato et al. 2019 [3] This case
Age/sex 62/M 50/M 47/M 67/M
Diagnosis AEP BA ABPA EGPA
BA histoly − − + −
Length to AE 2 M 6 M 12 M 9 M
Tumor Lung-sq Lung-adeno Lung-adeno Kidney-NEC
PD-L1 N.F N.F 50% 70%
ICI Nivo Nivo Pembro Nivo
Treatment PSL PSL PSL/VRCZ PSL/mepolizumab
Efficacy imp imp imp imp
AEP: acute eosinophilic pneumonia, BA: bronchial asthma, ABPA: allergic bronchopulmonary aspergillaosis, EGPA: Eosinophlic Granulomatosis with Polyangitis, lung-sq: lung squamous cell carcinoma, lung-adeno: lung adenocarcinoma, kidney-NEC: kidney neuroendocrine carcinoma, N.F: no findings, Nivo: nivolumab, Pembro: pembrolizumab, PSL: prednisolone, VRCZ: voriconazol, imp: improvement
Prolonged nivolumab treatment induced not only bronchial asthma but also systemic eosinophilic infiltration in our patient. The Eo-irAEs were thought to be an allergic reaction due to PD-1 inhibition. The underlying pathological mechanisms remain unclear; however, recent evidence suggests several hypotheses such as PD-L2/PD-1 signaling inhibition or PD-L2 intrinsic dysfunction.
PD-1 is a negative regulator of CD4-positive T-cells. The ligands for PD-1 are PD-L1 (B7-H1) and PD-L2 (B7-DC), both of which belong to the B7-CD28 family [10]. PD-L1 is expressed by different resting cells, such as dendritic cells, macrophages, T-cells, and B-cells, whereas PD-L2 expression appears to be restricted to activated dendritic cells and macrophages [11]. Furthermore, only 40% homology has been reported among the two ligands [12]. Studies of the roles of PD-1 and its ligands PD-L1 and PD-L2 have yielded conflicting results in allergen-induced inflammation and airway hyper-reactivity (AHR). AHR is one of the characteristics of bronchial asthma; PD-L1 and PD-L2 show opposing functions in airway modulation. PD-L1/PD-1 induces AHR, whereas PD-L2/PD-1 blocks the initiation and progression of airway inflammation [13]. In our case, PD-1 blockade induced peripheral eosinophilia and bronchial asthma attacks. Therefore, the interaction of PD-L2 with PD-1 may be stronger than that of PD-L1.
Matsumoto et al. reported that PD-L2 blockade induced not only AHR and eosinophilia, but also increased the production of interleukin (IL)-5 and IL-13 and decreased the production of interferon-γ [14]. Oflazoglu et al. reported that exogenous PD-L2 administration in an in vivo mouse asthma model resulted in elevation of serum IgE levels, eosinophilic and lymphocytic infiltration, and production of IL-5 and IL-13 [15]. In our case, PD-1 blockade by nivolumab induced an increase in the production of both interferon-γ and Th2-type immune cytokines. In addition to PD-L2 intrinsic regulation, allergen-driven enhancement of PD-L2 also limits the secretion of IL-12 and leads to exacerbation of AHR via a PD-1 independent mechanism [16]. These results suggest unknown signaling cascades (other than PD-1 signaling) underlying the AHR mechanisms.
Finally, in our case, mepolizumab (an IL-5 inhibitor) was useful during nivolumab discontinuation. Because the IL-5 signaling cascade is thought to be an important factor related to Eo-irAEs [6], the use of mepolizumab may have prevented nivolumab from inducing Eo-irAEs in the patient. Therefore, it is necessary to investigate the effects of Eo-irAEs on systemic organs.
In summary, we reported a rare case in which nivolumab treatment for kidney neuroendocrine carcinoma induced recurrent bronchial asthma attacks and led to systemic eosinophilic inflammation and EGPA. Although the exact mechanisms underlying allergic inflammation after PD-1 blockade remain unclear, PD-L1/PD-1 and PD-L2/PD-1 signaling may be key in deciphering the mechanisms mediating allergic inflammation.
Supplementary information
Additional file 1. A clinical coarse after initiation of nivolumab treatment. Treatment cycles of nivolumab shows on the upper black bar. Black triangle represents oral 30mg/day prednisolone treatments for bronchial asthma attacks. BA-AE: bronchial asthma attack, BUD/FP: budesonide/formoterol fumarate, Tio: Tiotropium bromide, solid line represents peripheral absolute eosinophil count (EOS). Tumor size of live metastasis was represented as maximum diameter in the bottom rectangle area.
Abbreviations
CTComputed tomography
EGPAEosinophilic granulomatosis with polyangiitis
Eo-irImmune-related eosinophilia
Eo-irAEEosinophil-induced adverse event
ICIImmune checkpoint inhibitor
ILInterleukin
IgEImmunoglobulin E
irAEImmune-related adverse event
PD-1Programmed cell death 1
PD-L1Programmed cell death ligand 1
PD-L2Programmed cell death ligand 2
Publisher's Note
Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
Supplementary information
The online version contains supplementary material available at 10.1186/s12890-020-01375-5.
Acknowledgements
We would like to thank the staff of the Department of Endoscopy and Pathology. We would also like to thank Editage (www.editage.com) for English language editing.
Authors’ contributions
MH managed the patient, created the figures, and collected laboratory data. MH and NK wrote the manuscript. MH, HN, KY, YI, NK, TK, EM, MU, SM, MT, and NK contributed to the discussion of results and reviewed the manuscript. All authors read and approved the final manuscript.
Funding
Not applicable.
Availability of data and materials
Not applicable.
Ethical approval and consent to participate
Not applicable.
Consent for publication
Written informed consent was obtained from the patient for the publication of this case report and of the accompanying images.
Competing interests
The authors declare that they have no competing interests. | CARBOPLATIN, IRINOTECAN, SUNITINIB | DrugsGivenReaction | CC BY | 33407304 | 19,263,369 | 2021-01-06 |
What was the dosage of drug 'CARBOPLATIN'? | Programmed cell death-1 blockade in kidney carcinoma may induce eosinophilic granulomatosis with polyangiitis: a case report.
BACKGROUND
Immune checkpoint inhibitors have potential applications in treating various cancers but are associated with immune-related adverse events, such as inflammation, in a wide range of organs; however, allergic inflammation caused by these agents has not been extensively studied.
METHODS
A 65-year-old man was diagnosed with a kidney neuroendocrine carcinoma. Three months after kidney resection surgery, the tumor cells had metastasized to his liver and lymph nodes. Subsequently, the patient started chemotherapy; however, regardless of treatment, the tumor grew, and the patient experienced a series of adverse effects, such as taste disorder, anorexia, and general fatigue. Finally, he was administered a programmed cell death (PD)-1 inhibitor, nivolumab (biweekly, toal 200 mg/body), which was effective against kidney carcinoma. However, the patient had a bronchial asthma attack at 22 cycles of nivolumab treatment and chest computed tomography (CT) revealed an abnormal bilateral shadow after 37 cycles of nivolumab treatment. Bronchoscopy findings revealed eosinophil infiltration in the lungs along with severe alveolar hemorrhage. Paranasal sinus CT scanning indicated sinusitis and nerve conduction analysis indicated a decrease in his right ulnar nerve conduction velocity. Based on these findings, the patient was diagnosed with eosinophilic granulomatosis with polyangiitis; he was treated with prednisolone, which alleviated his bronchial asthma. To restart nivolumab treatment, the dose of prednisolone was gradually tapered, and the patient was administered a monthly dose of mepolizumab and biweekly dose of nivolumab. To date, there have been no bronchial attacks or CT scan abnormalities upon follow up.
CONCLUSIONS
We present a rare case in which a patient with cancer was diagnosed with eosinophilic granulomatosis with polyangiitis following treatment with a PD-1 inhibitor. Blockade of PD-1 and the programmed cell death ligand (PD-L) 1/PD-1 and PD-L2/PD-1 signaling cascade may cause allergic inflammation. Further studies are needed to identify the specific mechanisms underlying allergic inflammation after PD-1 blockade.
Background
Immune checkpoint inhibitors (ICIs) have been employed to treat several cancers. The ICI nivolumab shows inhibitory effects by blocking immune system suppressors, such as programmed cell death protein 1 (PD-1), and decreasing T helper cell signaling [1]. However, nivolumab is also associated with several immune-related adverse events (irAEs) [2]. Among them, immune-related eosinophilia cases in patients treated with anti-PD-1 or anti-programmed cell death ligand (PD-L) 1 are rare, with an estimated frequency of only 2.9–3.3% [3, 4]. Eosinophil-induced adverse events (Eo-irAEs) occur in almost half of these cases. The most frequently damaged organ is the skin, followed by the lungs; eosinophilic pneumonia or bronchitis occurs in only 0.3% of cases. These allergic irAEs associated with ICIs have rarely been reported in the literature.
Here, we report a case of a patient with cancer who was treated with nivolumab and subsequently developed eosinophilic granulomatosis with polyangiitis (EGPA).
Case presentation
A 65-year-old Japanese man was diagnosed with kidney large cell neuroendocrine carcinoma (G3 grade, 52.1% Ki67-positive stained cells, PD-L1 TPS 70%), and had undergone total left kidney resection and descending colectomy 3 years prior to visiting our hospital. Three months after surgery, the tumor cells had metastasized to his liver and lymph nodes around the abdominal aorta. At the time, there was no established treatment against neuroendocrine cell carcinoma of the renal cells in Japan. The patient provided written informed consent and started chemotherapy. First, he was administered two courses of carboplatin plus irinotecan; however, the tumor size increased. The patient then started second-line treatment with sunitinib, which was discontinued after 3 months because he developed a taste disorder and watery diarrhea. Next, the patient was administered everolimus as a third-line therapy; however, the patient developed anorexia and general fatigue, and treatment with everolimus was discontinued. Because there were no other standard therapies for treating neuroendocrine kidney carcinoma, bi-weekly nivolumab (200 mg/body) treatment was administered to the patient. After nivolumab treatment, the tumor gradually disappeared, and no adverse events other than a mildly increased peripheral absolute eosinophil count (300–500/μL) were observed after 5 cycles of nivolumab treatment.
The patient experience his first bronchial asthma attack at 22 cycles of nivolumab treatment and was treated with a short course of corticosteroid burst therapy with 20 mg prednisolone along with inhalation therapy with budesonide/formoterol fumarate. This bronchial asthma attack was thought to be an adverse event associated with nivolumab; however, the patient continued the same dose of nivolumab treatment until 37 cycles because a good response against the kidney neuroendocrine carcinoma had been achieved. This clinical course is summarized in the Additional file 1: supplementary figure. Although nivolumab treatment had been discontinued until 37 cycles, the absolute eosinophil count remained high (26.6%, 1782.2 cells/μL) and his serum immunoglobulin E (IgE) levels were increased (924 IU/mL). Titers of anti-nuclear antibodies and anti-neutrophil cytoplasmic antibodies remained in the normal range. An IgE-radioallergosorbent test detected normal IgE levels, except against Japanese cedar and white cedar pollen. His fractional exhaled nitric oxide level was elevated to 107 ppb (normal range: 15–37 ppb). The patient had no history of allergy: however, all of his children had allergic bronchial asthma. He also showed dyspnea on exertion, developed sputum, and exhibited swelling and pain in his bilateral fingers. There were no other physical findings, including wheezing. Chest X-ray and computed tomography (CT) scanning detected a bilateral linear shadow which was not detected at his first visit to our hospital (Fig. 1a–d), and paranasal sinus CT scanning showed inflamed ethmoid, frontal, and maximal sinuses, indicating sinusitis (Fig. 1e–g). Although he had a normal respiratory function before initiating nivolumab treatment (FEV1.0 = 3.08 L, FEV1.0/FVC = 71.0%), his respiratory function test indicated an obstructive ventilation disorder (FEV1.0 = 1.63 L, FEV1.0/FVC = 50.6%). These results suggested that he had either eosinophilic pneumonia or EGPA. To confirm our hypothesis, we performed a bronchoscopy; the bronchoalveolar lavage fluid collected from the right B5 contained 40% lymphocytes and 3% eosinophils. Histopathological examination of a transbronchial lung biopsy sample from the right B8 showed small blood vessel hyperplasia with neutrophil infiltration and thickening of the alveolar septa with prominent eosinophil infiltration. Large numbers of red blood cells were observed on the lung tissue along with intra-alveolar bleeding (Fig. 2a, b), suggesting distinct alveolar hemorrhage with eosinophilic pneumonia. However hemosiderin-laden macrophages were not detected by Berlin blue staining, suggesting that the alveolar hemorrhage was an occasional event. Because he had experienced several bronchial asthma attacks and was already being treated with medication, the representative clinical findings needed for the bronchial asthma diagnosis were likely masked. To confirm the pathological findings of bronchial asthma, transbronchial mucosal biopsy was conducted. A bronchial mucosal lesion of the secondary carina also showed smooth muscle hyperplasia and thickening of the basement membrane with eosinophil infiltration (Fig. 2c). These findings suggested that the patient had bronchial asthma, eosinophilic pneumonia, and small vessel vasculitis. Finally, nerve conduction analysis showed that his right ulnar nerve conduction velocity was slightly decreased. There were no brain metastatic diseases, cervical spondylosis, or abnormalities related to rheumatoid arthritis. Although we could not definitively diagnose his neurological abnormalities, EGPA was thought to be one cause of the neuropathy. According to these findings with small vessel vasculitis, the patient was diagnosed with EGPA as per the American College of Rheumatology criteria for EGPA [5]. Distinct alveolar hemorrhage was not severe in the clinical setting and no heart involvement was detected; thus, treatment with 20 mg/day oral prednisolone was started. After 3 months, his bronchial asthma was improved, and bilateral infiltration had disappeared, as shown in Fig. 3. Steroid therapy was gradually tapered; during its discontinuation to less than 10 mg/day, a biweekly dose of mepolizumab (300 mg/day) was started to treat the EGPA. Currently, the patient is being treated with both nivolumab and mepolizumab, his peripheral eosinophilia has almost disappeared, and his respiratory function has improved (FEV1.0 = 2.94 L, FEV1.0/FVC = 71.2%), with paranasal sinus CT scanning showed normal findings (Fig. 3) after a year of treatment. He appears to be stable except for his neuropathy; to date, there have been no bronchial asthma attacks or CT scan abnormalities (Fig. 3).Fig. 1 Thoracic radiogram and computed tomography (CT) scan at the bronchoscopy exam. Chest radiogram (a) showed bilateral linear shadow. Thoracic CT scan of upper (b, c) and lower lobes (d) showed bilateral ground-glass opacity. e–g Paranasal sinus CT scan; Ethmoid sinus (e), frontal sinus (f) and maxillary sinus (g). Each arrow indicates nasal mucosa thickening and fluid collection in the sinus. These appearances suggest paranasal sinusitis
Fig. 2 a, b Transbronchial lung biopsy sample from right lower lung (right B8); sample stained with hematoxylin and eosin (HE) and viewed at high power. c Airway mucosal biopsy sample from secondary carina; sample stained with HE and viewed at high power. Bar indicates 200 μm. a shows small blood vessel with neutrophil and eosinophil infiltration. Alveolar septa are thickened. b Shows lots of red blood cells on the lung tissue and intra-alveolar bleeding with septal edema. c Shows smooth muscle hyperplasia and thickened basement membrane with eosinophil infiltration
Fig. 3 Thoracic radiogram (a), CT scans of chest (b–d) and ethmoid sinus (e), frontal sinus (f) and maxillary sinus (g) after a year from initiation of treatment for EGPA. Chest radiogram (a) shows no any abnormal shadows. Thoracic CT scan of upper (b, c) and lower lobes (d) also does not show any ground-glass opacity. Each arrow in e–g indicates nasal mucosa thickening and fluid collection that was shown in e–g
Discussion and conclusions
We report a rare case in which a patient with kidney neuroendocrine carcinoma was diagnosed with EGPA after treatment with nivolumab (a PD-1 checkpoint inhibitor). ICIs, such as nivolumab, are used to treat several cancers and have been associated with immune-related eosinophilia. The exact mechanisms mediating Eo-irAEs are not fully understood but a few clinical cases related to Eo-irAEs have been reported [6–8] (Table 1). Eo-irAEs can occur in systemic organs after ICI therapy and damage various organs, including the skin, lung, kidney, heart, and biliary ducts [4]. In the cases shown in Table 1, the Eo-irAEs were limited to the respiratory tract and showed a duration of development of 2–12 months. In the current case, the initial Eo-irAE was bronchial asthma, which occurred 9 months after starting nivolumab treatment; however, eosinophil infiltration was systemic and damaged the lungs, paranasal sinus, and peripheral nervous system. Before treatment with nivolumab, the patient’s absolute eosinophil count was normal; therefore, nivolumab was thought to be the main cause of the Eo-irAE. In a recent case, ipilimumab and nivolumab therapy (which was continued after Eo-ir) led to systemic infiltration of peripheral eosinophils [9]; however, there was a lack of sufficient pathological evidence of lung eosinophil infiltration. In our case, pathological evidence revealed eosinophil infiltration around the small vessels in the lung tissues and severe alveolar hemorrhage. These findings indicated eosinophilic vasculitis and eosinophilic pneumonia and were confirmed by CT scanning, although the damage to the paranasal sinus and peripheral nervous system in the pathological findings may differ from the damage to the lungs.Table 1 Clinical appearances of previous case reports and our case
Case reports Johdai et al. 2018 [4] Maeno et al. 2017 [5] Donato et al. 2019 [3] This case
Age/sex 62/M 50/M 47/M 67/M
Diagnosis AEP BA ABPA EGPA
BA histoly − − + −
Length to AE 2 M 6 M 12 M 9 M
Tumor Lung-sq Lung-adeno Lung-adeno Kidney-NEC
PD-L1 N.F N.F 50% 70%
ICI Nivo Nivo Pembro Nivo
Treatment PSL PSL PSL/VRCZ PSL/mepolizumab
Efficacy imp imp imp imp
AEP: acute eosinophilic pneumonia, BA: bronchial asthma, ABPA: allergic bronchopulmonary aspergillaosis, EGPA: Eosinophlic Granulomatosis with Polyangitis, lung-sq: lung squamous cell carcinoma, lung-adeno: lung adenocarcinoma, kidney-NEC: kidney neuroendocrine carcinoma, N.F: no findings, Nivo: nivolumab, Pembro: pembrolizumab, PSL: prednisolone, VRCZ: voriconazol, imp: improvement
Prolonged nivolumab treatment induced not only bronchial asthma but also systemic eosinophilic infiltration in our patient. The Eo-irAEs were thought to be an allergic reaction due to PD-1 inhibition. The underlying pathological mechanisms remain unclear; however, recent evidence suggests several hypotheses such as PD-L2/PD-1 signaling inhibition or PD-L2 intrinsic dysfunction.
PD-1 is a negative regulator of CD4-positive T-cells. The ligands for PD-1 are PD-L1 (B7-H1) and PD-L2 (B7-DC), both of which belong to the B7-CD28 family [10]. PD-L1 is expressed by different resting cells, such as dendritic cells, macrophages, T-cells, and B-cells, whereas PD-L2 expression appears to be restricted to activated dendritic cells and macrophages [11]. Furthermore, only 40% homology has been reported among the two ligands [12]. Studies of the roles of PD-1 and its ligands PD-L1 and PD-L2 have yielded conflicting results in allergen-induced inflammation and airway hyper-reactivity (AHR). AHR is one of the characteristics of bronchial asthma; PD-L1 and PD-L2 show opposing functions in airway modulation. PD-L1/PD-1 induces AHR, whereas PD-L2/PD-1 blocks the initiation and progression of airway inflammation [13]. In our case, PD-1 blockade induced peripheral eosinophilia and bronchial asthma attacks. Therefore, the interaction of PD-L2 with PD-1 may be stronger than that of PD-L1.
Matsumoto et al. reported that PD-L2 blockade induced not only AHR and eosinophilia, but also increased the production of interleukin (IL)-5 and IL-13 and decreased the production of interferon-γ [14]. Oflazoglu et al. reported that exogenous PD-L2 administration in an in vivo mouse asthma model resulted in elevation of serum IgE levels, eosinophilic and lymphocytic infiltration, and production of IL-5 and IL-13 [15]. In our case, PD-1 blockade by nivolumab induced an increase in the production of both interferon-γ and Th2-type immune cytokines. In addition to PD-L2 intrinsic regulation, allergen-driven enhancement of PD-L2 also limits the secretion of IL-12 and leads to exacerbation of AHR via a PD-1 independent mechanism [16]. These results suggest unknown signaling cascades (other than PD-1 signaling) underlying the AHR mechanisms.
Finally, in our case, mepolizumab (an IL-5 inhibitor) was useful during nivolumab discontinuation. Because the IL-5 signaling cascade is thought to be an important factor related to Eo-irAEs [6], the use of mepolizumab may have prevented nivolumab from inducing Eo-irAEs in the patient. Therefore, it is necessary to investigate the effects of Eo-irAEs on systemic organs.
In summary, we reported a rare case in which nivolumab treatment for kidney neuroendocrine carcinoma induced recurrent bronchial asthma attacks and led to systemic eosinophilic inflammation and EGPA. Although the exact mechanisms underlying allergic inflammation after PD-1 blockade remain unclear, PD-L1/PD-1 and PD-L2/PD-1 signaling may be key in deciphering the mechanisms mediating allergic inflammation.
Supplementary information
Additional file 1. A clinical coarse after initiation of nivolumab treatment. Treatment cycles of nivolumab shows on the upper black bar. Black triangle represents oral 30mg/day prednisolone treatments for bronchial asthma attacks. BA-AE: bronchial asthma attack, BUD/FP: budesonide/formoterol fumarate, Tio: Tiotropium bromide, solid line represents peripheral absolute eosinophil count (EOS). Tumor size of live metastasis was represented as maximum diameter in the bottom rectangle area.
Abbreviations
CTComputed tomography
EGPAEosinophilic granulomatosis with polyangiitis
Eo-irImmune-related eosinophilia
Eo-irAEEosinophil-induced adverse event
ICIImmune checkpoint inhibitor
ILInterleukin
IgEImmunoglobulin E
irAEImmune-related adverse event
PD-1Programmed cell death 1
PD-L1Programmed cell death ligand 1
PD-L2Programmed cell death ligand 2
Publisher's Note
Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
Supplementary information
The online version contains supplementary material available at 10.1186/s12890-020-01375-5.
Acknowledgements
We would like to thank the staff of the Department of Endoscopy and Pathology. We would also like to thank Editage (www.editage.com) for English language editing.
Authors’ contributions
MH managed the patient, created the figures, and collected laboratory data. MH and NK wrote the manuscript. MH, HN, KY, YI, NK, TK, EM, MU, SM, MT, and NK contributed to the discussion of results and reviewed the manuscript. All authors read and approved the final manuscript.
Funding
Not applicable.
Availability of data and materials
Not applicable.
Ethical approval and consent to participate
Not applicable.
Consent for publication
Written informed consent was obtained from the patient for the publication of this case report and of the accompanying images.
Competing interests
The authors declare that they have no competing interests. | 2 COURSES | DrugDosageText | CC BY | 33407304 | 19,263,369 | 2021-01-06 |
What was the dosage of drug 'IRINOTECAN'? | Programmed cell death-1 blockade in kidney carcinoma may induce eosinophilic granulomatosis with polyangiitis: a case report.
BACKGROUND
Immune checkpoint inhibitors have potential applications in treating various cancers but are associated with immune-related adverse events, such as inflammation, in a wide range of organs; however, allergic inflammation caused by these agents has not been extensively studied.
METHODS
A 65-year-old man was diagnosed with a kidney neuroendocrine carcinoma. Three months after kidney resection surgery, the tumor cells had metastasized to his liver and lymph nodes. Subsequently, the patient started chemotherapy; however, regardless of treatment, the tumor grew, and the patient experienced a series of adverse effects, such as taste disorder, anorexia, and general fatigue. Finally, he was administered a programmed cell death (PD)-1 inhibitor, nivolumab (biweekly, toal 200 mg/body), which was effective against kidney carcinoma. However, the patient had a bronchial asthma attack at 22 cycles of nivolumab treatment and chest computed tomography (CT) revealed an abnormal bilateral shadow after 37 cycles of nivolumab treatment. Bronchoscopy findings revealed eosinophil infiltration in the lungs along with severe alveolar hemorrhage. Paranasal sinus CT scanning indicated sinusitis and nerve conduction analysis indicated a decrease in his right ulnar nerve conduction velocity. Based on these findings, the patient was diagnosed with eosinophilic granulomatosis with polyangiitis; he was treated with prednisolone, which alleviated his bronchial asthma. To restart nivolumab treatment, the dose of prednisolone was gradually tapered, and the patient was administered a monthly dose of mepolizumab and biweekly dose of nivolumab. To date, there have been no bronchial attacks or CT scan abnormalities upon follow up.
CONCLUSIONS
We present a rare case in which a patient with cancer was diagnosed with eosinophilic granulomatosis with polyangiitis following treatment with a PD-1 inhibitor. Blockade of PD-1 and the programmed cell death ligand (PD-L) 1/PD-1 and PD-L2/PD-1 signaling cascade may cause allergic inflammation. Further studies are needed to identify the specific mechanisms underlying allergic inflammation after PD-1 blockade.
Background
Immune checkpoint inhibitors (ICIs) have been employed to treat several cancers. The ICI nivolumab shows inhibitory effects by blocking immune system suppressors, such as programmed cell death protein 1 (PD-1), and decreasing T helper cell signaling [1]. However, nivolumab is also associated with several immune-related adverse events (irAEs) [2]. Among them, immune-related eosinophilia cases in patients treated with anti-PD-1 or anti-programmed cell death ligand (PD-L) 1 are rare, with an estimated frequency of only 2.9–3.3% [3, 4]. Eosinophil-induced adverse events (Eo-irAEs) occur in almost half of these cases. The most frequently damaged organ is the skin, followed by the lungs; eosinophilic pneumonia or bronchitis occurs in only 0.3% of cases. These allergic irAEs associated with ICIs have rarely been reported in the literature.
Here, we report a case of a patient with cancer who was treated with nivolumab and subsequently developed eosinophilic granulomatosis with polyangiitis (EGPA).
Case presentation
A 65-year-old Japanese man was diagnosed with kidney large cell neuroendocrine carcinoma (G3 grade, 52.1% Ki67-positive stained cells, PD-L1 TPS 70%), and had undergone total left kidney resection and descending colectomy 3 years prior to visiting our hospital. Three months after surgery, the tumor cells had metastasized to his liver and lymph nodes around the abdominal aorta. At the time, there was no established treatment against neuroendocrine cell carcinoma of the renal cells in Japan. The patient provided written informed consent and started chemotherapy. First, he was administered two courses of carboplatin plus irinotecan; however, the tumor size increased. The patient then started second-line treatment with sunitinib, which was discontinued after 3 months because he developed a taste disorder and watery diarrhea. Next, the patient was administered everolimus as a third-line therapy; however, the patient developed anorexia and general fatigue, and treatment with everolimus was discontinued. Because there were no other standard therapies for treating neuroendocrine kidney carcinoma, bi-weekly nivolumab (200 mg/body) treatment was administered to the patient. After nivolumab treatment, the tumor gradually disappeared, and no adverse events other than a mildly increased peripheral absolute eosinophil count (300–500/μL) were observed after 5 cycles of nivolumab treatment.
The patient experience his first bronchial asthma attack at 22 cycles of nivolumab treatment and was treated with a short course of corticosteroid burst therapy with 20 mg prednisolone along with inhalation therapy with budesonide/formoterol fumarate. This bronchial asthma attack was thought to be an adverse event associated with nivolumab; however, the patient continued the same dose of nivolumab treatment until 37 cycles because a good response against the kidney neuroendocrine carcinoma had been achieved. This clinical course is summarized in the Additional file 1: supplementary figure. Although nivolumab treatment had been discontinued until 37 cycles, the absolute eosinophil count remained high (26.6%, 1782.2 cells/μL) and his serum immunoglobulin E (IgE) levels were increased (924 IU/mL). Titers of anti-nuclear antibodies and anti-neutrophil cytoplasmic antibodies remained in the normal range. An IgE-radioallergosorbent test detected normal IgE levels, except against Japanese cedar and white cedar pollen. His fractional exhaled nitric oxide level was elevated to 107 ppb (normal range: 15–37 ppb). The patient had no history of allergy: however, all of his children had allergic bronchial asthma. He also showed dyspnea on exertion, developed sputum, and exhibited swelling and pain in his bilateral fingers. There were no other physical findings, including wheezing. Chest X-ray and computed tomography (CT) scanning detected a bilateral linear shadow which was not detected at his first visit to our hospital (Fig. 1a–d), and paranasal sinus CT scanning showed inflamed ethmoid, frontal, and maximal sinuses, indicating sinusitis (Fig. 1e–g). Although he had a normal respiratory function before initiating nivolumab treatment (FEV1.0 = 3.08 L, FEV1.0/FVC = 71.0%), his respiratory function test indicated an obstructive ventilation disorder (FEV1.0 = 1.63 L, FEV1.0/FVC = 50.6%). These results suggested that he had either eosinophilic pneumonia or EGPA. To confirm our hypothesis, we performed a bronchoscopy; the bronchoalveolar lavage fluid collected from the right B5 contained 40% lymphocytes and 3% eosinophils. Histopathological examination of a transbronchial lung biopsy sample from the right B8 showed small blood vessel hyperplasia with neutrophil infiltration and thickening of the alveolar septa with prominent eosinophil infiltration. Large numbers of red blood cells were observed on the lung tissue along with intra-alveolar bleeding (Fig. 2a, b), suggesting distinct alveolar hemorrhage with eosinophilic pneumonia. However hemosiderin-laden macrophages were not detected by Berlin blue staining, suggesting that the alveolar hemorrhage was an occasional event. Because he had experienced several bronchial asthma attacks and was already being treated with medication, the representative clinical findings needed for the bronchial asthma diagnosis were likely masked. To confirm the pathological findings of bronchial asthma, transbronchial mucosal biopsy was conducted. A bronchial mucosal lesion of the secondary carina also showed smooth muscle hyperplasia and thickening of the basement membrane with eosinophil infiltration (Fig. 2c). These findings suggested that the patient had bronchial asthma, eosinophilic pneumonia, and small vessel vasculitis. Finally, nerve conduction analysis showed that his right ulnar nerve conduction velocity was slightly decreased. There were no brain metastatic diseases, cervical spondylosis, or abnormalities related to rheumatoid arthritis. Although we could not definitively diagnose his neurological abnormalities, EGPA was thought to be one cause of the neuropathy. According to these findings with small vessel vasculitis, the patient was diagnosed with EGPA as per the American College of Rheumatology criteria for EGPA [5]. Distinct alveolar hemorrhage was not severe in the clinical setting and no heart involvement was detected; thus, treatment with 20 mg/day oral prednisolone was started. After 3 months, his bronchial asthma was improved, and bilateral infiltration had disappeared, as shown in Fig. 3. Steroid therapy was gradually tapered; during its discontinuation to less than 10 mg/day, a biweekly dose of mepolizumab (300 mg/day) was started to treat the EGPA. Currently, the patient is being treated with both nivolumab and mepolizumab, his peripheral eosinophilia has almost disappeared, and his respiratory function has improved (FEV1.0 = 2.94 L, FEV1.0/FVC = 71.2%), with paranasal sinus CT scanning showed normal findings (Fig. 3) after a year of treatment. He appears to be stable except for his neuropathy; to date, there have been no bronchial asthma attacks or CT scan abnormalities (Fig. 3).Fig. 1 Thoracic radiogram and computed tomography (CT) scan at the bronchoscopy exam. Chest radiogram (a) showed bilateral linear shadow. Thoracic CT scan of upper (b, c) and lower lobes (d) showed bilateral ground-glass opacity. e–g Paranasal sinus CT scan; Ethmoid sinus (e), frontal sinus (f) and maxillary sinus (g). Each arrow indicates nasal mucosa thickening and fluid collection in the sinus. These appearances suggest paranasal sinusitis
Fig. 2 a, b Transbronchial lung biopsy sample from right lower lung (right B8); sample stained with hematoxylin and eosin (HE) and viewed at high power. c Airway mucosal biopsy sample from secondary carina; sample stained with HE and viewed at high power. Bar indicates 200 μm. a shows small blood vessel with neutrophil and eosinophil infiltration. Alveolar septa are thickened. b Shows lots of red blood cells on the lung tissue and intra-alveolar bleeding with septal edema. c Shows smooth muscle hyperplasia and thickened basement membrane with eosinophil infiltration
Fig. 3 Thoracic radiogram (a), CT scans of chest (b–d) and ethmoid sinus (e), frontal sinus (f) and maxillary sinus (g) after a year from initiation of treatment for EGPA. Chest radiogram (a) shows no any abnormal shadows. Thoracic CT scan of upper (b, c) and lower lobes (d) also does not show any ground-glass opacity. Each arrow in e–g indicates nasal mucosa thickening and fluid collection that was shown in e–g
Discussion and conclusions
We report a rare case in which a patient with kidney neuroendocrine carcinoma was diagnosed with EGPA after treatment with nivolumab (a PD-1 checkpoint inhibitor). ICIs, such as nivolumab, are used to treat several cancers and have been associated with immune-related eosinophilia. The exact mechanisms mediating Eo-irAEs are not fully understood but a few clinical cases related to Eo-irAEs have been reported [6–8] (Table 1). Eo-irAEs can occur in systemic organs after ICI therapy and damage various organs, including the skin, lung, kidney, heart, and biliary ducts [4]. In the cases shown in Table 1, the Eo-irAEs were limited to the respiratory tract and showed a duration of development of 2–12 months. In the current case, the initial Eo-irAE was bronchial asthma, which occurred 9 months after starting nivolumab treatment; however, eosinophil infiltration was systemic and damaged the lungs, paranasal sinus, and peripheral nervous system. Before treatment with nivolumab, the patient’s absolute eosinophil count was normal; therefore, nivolumab was thought to be the main cause of the Eo-irAE. In a recent case, ipilimumab and nivolumab therapy (which was continued after Eo-ir) led to systemic infiltration of peripheral eosinophils [9]; however, there was a lack of sufficient pathological evidence of lung eosinophil infiltration. In our case, pathological evidence revealed eosinophil infiltration around the small vessels in the lung tissues and severe alveolar hemorrhage. These findings indicated eosinophilic vasculitis and eosinophilic pneumonia and were confirmed by CT scanning, although the damage to the paranasal sinus and peripheral nervous system in the pathological findings may differ from the damage to the lungs.Table 1 Clinical appearances of previous case reports and our case
Case reports Johdai et al. 2018 [4] Maeno et al. 2017 [5] Donato et al. 2019 [3] This case
Age/sex 62/M 50/M 47/M 67/M
Diagnosis AEP BA ABPA EGPA
BA histoly − − + −
Length to AE 2 M 6 M 12 M 9 M
Tumor Lung-sq Lung-adeno Lung-adeno Kidney-NEC
PD-L1 N.F N.F 50% 70%
ICI Nivo Nivo Pembro Nivo
Treatment PSL PSL PSL/VRCZ PSL/mepolizumab
Efficacy imp imp imp imp
AEP: acute eosinophilic pneumonia, BA: bronchial asthma, ABPA: allergic bronchopulmonary aspergillaosis, EGPA: Eosinophlic Granulomatosis with Polyangitis, lung-sq: lung squamous cell carcinoma, lung-adeno: lung adenocarcinoma, kidney-NEC: kidney neuroendocrine carcinoma, N.F: no findings, Nivo: nivolumab, Pembro: pembrolizumab, PSL: prednisolone, VRCZ: voriconazol, imp: improvement
Prolonged nivolumab treatment induced not only bronchial asthma but also systemic eosinophilic infiltration in our patient. The Eo-irAEs were thought to be an allergic reaction due to PD-1 inhibition. The underlying pathological mechanisms remain unclear; however, recent evidence suggests several hypotheses such as PD-L2/PD-1 signaling inhibition or PD-L2 intrinsic dysfunction.
PD-1 is a negative regulator of CD4-positive T-cells. The ligands for PD-1 are PD-L1 (B7-H1) and PD-L2 (B7-DC), both of which belong to the B7-CD28 family [10]. PD-L1 is expressed by different resting cells, such as dendritic cells, macrophages, T-cells, and B-cells, whereas PD-L2 expression appears to be restricted to activated dendritic cells and macrophages [11]. Furthermore, only 40% homology has been reported among the two ligands [12]. Studies of the roles of PD-1 and its ligands PD-L1 and PD-L2 have yielded conflicting results in allergen-induced inflammation and airway hyper-reactivity (AHR). AHR is one of the characteristics of bronchial asthma; PD-L1 and PD-L2 show opposing functions in airway modulation. PD-L1/PD-1 induces AHR, whereas PD-L2/PD-1 blocks the initiation and progression of airway inflammation [13]. In our case, PD-1 blockade induced peripheral eosinophilia and bronchial asthma attacks. Therefore, the interaction of PD-L2 with PD-1 may be stronger than that of PD-L1.
Matsumoto et al. reported that PD-L2 blockade induced not only AHR and eosinophilia, but also increased the production of interleukin (IL)-5 and IL-13 and decreased the production of interferon-γ [14]. Oflazoglu et al. reported that exogenous PD-L2 administration in an in vivo mouse asthma model resulted in elevation of serum IgE levels, eosinophilic and lymphocytic infiltration, and production of IL-5 and IL-13 [15]. In our case, PD-1 blockade by nivolumab induced an increase in the production of both interferon-γ and Th2-type immune cytokines. In addition to PD-L2 intrinsic regulation, allergen-driven enhancement of PD-L2 also limits the secretion of IL-12 and leads to exacerbation of AHR via a PD-1 independent mechanism [16]. These results suggest unknown signaling cascades (other than PD-1 signaling) underlying the AHR mechanisms.
Finally, in our case, mepolizumab (an IL-5 inhibitor) was useful during nivolumab discontinuation. Because the IL-5 signaling cascade is thought to be an important factor related to Eo-irAEs [6], the use of mepolizumab may have prevented nivolumab from inducing Eo-irAEs in the patient. Therefore, it is necessary to investigate the effects of Eo-irAEs on systemic organs.
In summary, we reported a rare case in which nivolumab treatment for kidney neuroendocrine carcinoma induced recurrent bronchial asthma attacks and led to systemic eosinophilic inflammation and EGPA. Although the exact mechanisms underlying allergic inflammation after PD-1 blockade remain unclear, PD-L1/PD-1 and PD-L2/PD-1 signaling may be key in deciphering the mechanisms mediating allergic inflammation.
Supplementary information
Additional file 1. A clinical coarse after initiation of nivolumab treatment. Treatment cycles of nivolumab shows on the upper black bar. Black triangle represents oral 30mg/day prednisolone treatments for bronchial asthma attacks. BA-AE: bronchial asthma attack, BUD/FP: budesonide/formoterol fumarate, Tio: Tiotropium bromide, solid line represents peripheral absolute eosinophil count (EOS). Tumor size of live metastasis was represented as maximum diameter in the bottom rectangle area.
Abbreviations
CTComputed tomography
EGPAEosinophilic granulomatosis with polyangiitis
Eo-irImmune-related eosinophilia
Eo-irAEEosinophil-induced adverse event
ICIImmune checkpoint inhibitor
ILInterleukin
IgEImmunoglobulin E
irAEImmune-related adverse event
PD-1Programmed cell death 1
PD-L1Programmed cell death ligand 1
PD-L2Programmed cell death ligand 2
Publisher's Note
Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
Supplementary information
The online version contains supplementary material available at 10.1186/s12890-020-01375-5.
Acknowledgements
We would like to thank the staff of the Department of Endoscopy and Pathology. We would also like to thank Editage (www.editage.com) for English language editing.
Authors’ contributions
MH managed the patient, created the figures, and collected laboratory data. MH and NK wrote the manuscript. MH, HN, KY, YI, NK, TK, EM, MU, SM, MT, and NK contributed to the discussion of results and reviewed the manuscript. All authors read and approved the final manuscript.
Funding
Not applicable.
Availability of data and materials
Not applicable.
Ethical approval and consent to participate
Not applicable.
Consent for publication
Written informed consent was obtained from the patient for the publication of this case report and of the accompanying images.
Competing interests
The authors declare that they have no competing interests. | 2 COURSES | DrugDosageText | CC BY | 33407304 | 19,263,369 | 2021-01-06 |
Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Asthenia'. | A novel somatic BRCA2 point mutation in a metastatic pancreatic cancer patient: a case report.
In addition to ovarian and breast cancers, loss-of-function mutations in BRCA1 and BRCA2 genes are also linked to an increased risk of pancreatic cancer, with ~ 4 to 7% of pancreatic cancer patients harboring germline BRCA mutations. Most BRCA alterations in pancreatic cancer are frame-shifting indels, stop-gain, and splice-site mutations, but single nucleotide substitutions are rare. Recent studies demonstrated a significant progression-free survival (PFS) benefit from maintenance olaparib, a poly (ADP-ribose) polymerase (PARP) inhibitor administered to patients with germline BRCA mutations and metastatic pancreatic cancer.
Here, we report a metastatic pancreatic cancer case who harbored a novel somatic BRCA2 c.6944T > C (p. I2315T) point mutation. After 6 weeks first-line chemotherapy, the patient was refractory to treatment and had a progressive disease. Due to the novel nonsynonymous BRCA2 point mutation, we decided to change the strategy by administering olaparib. The patient benefited from olaparib therapy and achieved a PFS of ~ 6.5 months.
We describe a patient carrying a novel somatic BRCA2 p. I2315T point mutation, which is first reported in metastatic pancreatic cancer. This case report indicates that a gene mutation-based strategy should be considered in the clinic to provide more effective treatment.
Background
Pancreatic cancer is the 7th leading cause of cancer-related deaths worldwide, with a 5-year survival rate of < 5% [1]. This devastating malignancy is generally diagnosed at metastatic stages in the clinic, indicative of its late detection and biological aggressiveness [1]. Tremendous efforts are ongoing with the aims of discovering early diagnostic markers and novel therapeutic avenues for pancreatic cancer; however, progress is remarkably hindered by the complicated heterogeneity within and between patient tumors.
BRCA1 and BRCA2 are essential players involved in homologous recombination repair of double-strand deoxyribonucleic acid (DNA) breaks [2]. BRCA inactivation due to somatic mutations or BRCA1 promoter methylation have been observed in various cancer types, including a small subgroup of metastatic pancreatic cancer [3–5]. Most BRCA alterations in pancreatic cancer are frame-shifting indels, stop-gain, and splice-site mutations, whereas single nucleotide substitutions are rarely identified [2, 4, 5].
A large body of evidence showed that the poly (ADP-ribose) polymerase (PARP) inhibitors are synthetically lethal in BRCA-mutated tumors with DNA repair defects and displayed potent anti-tumor activity when combined with DNA-damaging agents. Thus, patients carrying germline mutations in BRCA or the various patterns of somatic BRCA mutations that could result in the inactivation of BRCA are sensitive to PARP inhibitors [6].
A recent phase 3 POLO (Pancreas Cancer Olaparib Ongoing) trial demonstrated that the administration of a PARP inhibitor, olaparib, as a maintenance therapy significantly prolonged the median progression-free survival (PFS) of patients with germline BRCA mutations and metastatic pancreatic cancer who had not progressed during platinum-based chemotherapy compared to the placebo arm (7.4 months vs. 3.8 months) [7]. More importantly, olaparib treatment did not compromise health-related quality of life in those patients [8]. However, PARP inhibitor resistance is common due to homologous recombination repair restoration (HRR), epigenetic modification, reversion mutations, restoration of ADP-ribosylation (PARylation), and pharmacological alteration [9].
In this report, we present the case of a metastatic pancreatic cancer patient who had progressive disease (PD) following chemotherapy with gemcitabine and nab-paclitaxel. Mutational profiling analysis using targeted next-generation sequencing (NGS) revealed that the patient carried a novel somatic BRCA2 c.6944T > C (p. I2315T) point mutation. Olaparib was thereby administered in combination with a modified FOLFIRINOX regimen or as a monotherapy. The patient showed a significant response to this treatment strategy and exhibited stable disease and a PFS of ~ 6.5 months was observed.
Case presentation
A 57-year-old Chinese male with no obvious symptoms was admitted to the hospital due to the identification of a low-density shadow in the liver during his physical examination. In January 2019, a computed tomography (CT) scan revealed a 5.0 × 3.0 cm tumor in the uncinate process of the pancreas with hepatic metastases (Fig. 1a). The patient had a family history of cancer: his mother was diagnosed with stomach cancer at the age of 65 years and his father had lung cancer. According to the National Comprehensive Cancer Network (NCCN) Guidelines, the patient first received gemcitabine treatment at a dose of 1.4 g once per week, and nab-paclitaxel at a dose of 200 mg every 2 weeks as a first-line chemotherapy in January 2019 (Fig. 1b). Unfortunately, a CT re-evaluation at 6 weeks post-treatment showed progressive enlargement of both pancreatic and hepatic lesions (Fig. 1a), accompanied with a marked elevation of serum carcinoembryonic antigen (CEA, 270.35 ng/mL) and carbohydrate antigen 19-9 (CA19-9, 352.56 U/mL) levels (Fig. 1c); thus, suggesting that the patient was refractory to treatment and had a PD.Fig. 1 CT images and measurements of serum tumor biomarkers during the course of treatment. a Serial CT scans demonstrated a reduction in the size of the pancreatic (red arrows) and metastatic hepatic lesions (green arrows) following olaparib therapy. b A timeline indicating the application of different therapeutic strategies and the patient’s response. c Measurements of serum CEA and CA19-9 levels at different treatment times. Blue line: CEA; green line: CA19-9; orange arrows: time points of the CT scans. PD progressive disease, PR partial response, SD stable disease
To determine a more effective and appropriate targeted therapy, we performed a targeted NGS analysis of 425 cancer-related genes on the patient’s plasma and tumor tissue biopsy samples. The cancer mutation panel test revealed multiple deleterious somatic mutations, such as the driver mutations, KRAS Q61R (c.182A > G), TP53 R110del (c.329_331delGTC), and APC S1465RfsX9 (c.4393_4394dupAG), and copy number gain of several genes (Table 1). Interestingly, we also observed a novel nonsynonymous BRCA2 c.6944T > C (p. I2315T) point mutation with a mutant allele frequency (MAF) of 28.0% in the plasma and 39.5% in the tumor biopsy specimens. The novel BRCA2 point mutation was not detected in white blood cells, and thus, it was confirmed as a somatic mutation.Table 1 Genetic alterations detected in the patient’s plasma and tumor biopsy specimens
Genes Alternations Nucleotide change MAF (plasma) MAF (tumor)
BRCA2 p. I2315T c.6944T > C 28% 39.5%
KRAS p. Q61R c.182A > G 27.4% 43.2%
TP53 p. R110del c.329_331delGTC 37.4% 81.6%
APC p. S1465RfsX9 c.4393_4394dupAG 26.7% 71.7%
CCNE1 Gene amplification NA 16.0-fold 27.4-fold
CCNE1 IGR (downstream UQCRFS1) ~ CCNE1 fusion NA 0.1% –
PIK3CA Gene amplification NA – 1.9-fold
PKHD1 p. R909X truncation c.2725C > T 4.9% 16.9%
SOX2 Gene amplification NA – 2.0-fold
STMN1 Gene amplification NA – 1.8-fold
TERC Gene amplification NA – 1.9-fold
TUBB3 Gene amplification NA – 2.2-fold
–, not detectable; NA, not applicable; MAF, mutant allele frequency. Gene amplification was presented as the relative fold change to normal controls
Given the clinical efficacy of olaparib in treating BRCA-mutated advanced solid tumors, we decided to revise the therapeutic strategy by administering olaparib at a dose of 150 mg twice per day in combination with a modified FOLFIRINOX regimen (irinotecan at a dose of 100 mg on days 1, 8 and 15; oxaliplatin at a dose of 150 mg on days 1 and 15; S-1 at a dose of 40 mg twice per day from day 1 to day 14) for one cycle beginning in March 2019 (Fig. 1b). However, due to the occurrence of adverse events (e.g., diarrhea, general weakness, fatigue, and loss of appetite) and myelosuppression, including grade 2–3 leukopenia and thrombocytopenia, chemotherapy was not given on day 15 and the frequency of irinotecan was reduced to only be administered on days 1 and 15 in the subsequent treatment. Additionally, megestrol acetate and granulocyte-colony stimulating factor (G-CSF) were prescribed to increase appetite and promote the recovery of myelosuppression. In May 2019, a reduction in the size of both pancreatic and hepatic lesions was revealed by the CT scan, while the levels of the serum tumor biomarkers, CEA (63.38 ng/mL) and CA19-9 (40.53 U/mL) were considerably reduced (Fig. 1a, c). Olaparib and modified FOLFIRINOX were thus continued with irinotecan and oxaliplatin being administered only on day 1 (Fig. 1b). After 2 weeks of treatment, CEA and CA19-9 levels decreased to 32.69 ng/mL and 25.57 U/mL, respectively (Fig. 1c). A CT scan performed in June 2019 showed a significant size reduction in the primary and metastatic tumors, which indicated a partial response (PR, Fig. 1a). Since the patient experienced severe marrow suppression during treatment, only olaparib monotherapy was administered since July 2019 to reduce adverse effects (Fig. 1b). Stable disease (SD) was subsequently observed in August 2019 (Fig. 1a). In September 2019, aside from an increase in CEA and CA19-9 levels (Fig. 1c), laboratory blood tests demonstrated that the patient underwent acquired granulocytopenia, anemia, and thrombocytopenia. Consequently, G-CSF, thrombopoietin, and erythropoietin were administered for symptom management. After olaparib treatment for another 1.5 months, PD was indicated by a CT scan (Fig. 1a). The patient achieved a PFS for ~ 6.5 months following olaparib combination and monotherapy.
Discussion and conclusions
Neoplastic cells lacking a functional homologous recombination repair system, such as those carrying BRCA mutations, are sensitive to PARP inhibition through accumulated DNA damage via multiple mechanisms [6]. As a new therapeutic concept, maintenance olaparib has shown promising results in the treatment of germline BRCA-mutated breast, ovarian, and metastatic pancreatic cancer [7, 10, 11]. To date, the majority of BRCA2 mutations identified in pancreatic cancer were frame-shifting indels (e.g., c.6174delT, c.6158insT) and splice-site mutations. In contrast, single point mutations have been rarely reported [4, 5, 12]. Mesman [13] recently assessed the potential pathogenic impact of a large set of BRCA2 missense variants using a mouse embryonic stem cell (mESC)-based functional assay, and found that BRCA2 missense mutations, such as c.93G > T (p. W31C) and c.8351G > A (p. R2784Q), were able to increase susceptibility to PARP inhibitor treatment.
The patient in our report harbored an unreported BRCA2 point mutation [c.6944T > C (p. I2315T)] located in exon 13 of BRCA2 between the G-CSF. Different germline BRCA2 mutations (e.g., p. I2315V, p. I2315L) at the same site have been documented with unknown functional significance [14, 15]. Although the underlying molecular mechanism(s) by which this novel BRCA2 p. I2315T mutation impairs DNA repair and sensitizes tumor cells to PARP inhibition remains to be elucidated. We postulate that it may be related to a change in the polarity of amino acid residues since isoleucine (I), valine (V) and leucine (L) are all non-polar and hydrophobic, while threonine (T) is hydrophilic. Thus, we hypothesize that the p. I2315T mutation is likely to cause a structural abnormality in the BRCA2 protein, which results in defective DNA double strand break (DSB) repair by homologous recombination (HR) and its sensitivity to olaparib. To test this hypothesis, we attempted to generate a three dimensional (3D) structural model of the BRCA2 p. I2315T mutation, but failed due to the absence of an established crystal structure of the full-length human BRCA2 due to its size and segmental nature [16].
In summary, we report a metastatic pancreatic cancer patient carrying a novel somatic BRCA2 p. I2315T point mutation. Furthermore, advances in NGS technology have provided a solid basis for precise detection of well-known driver mutations, and rare or novel mutations. Thus, NGS may provide clinicians with invaluable information (e.g., BRCA1/2 status of tumors) that can be leveraged for therapeutic decision making, and perform better evaluations of patients’ responses during the course of treatment.
Abbreviations
PARPPoly(ADP-ribose) polymerase
PFSProgression-free survival
PDProgressive disease
DNADeoxyribonucleic acid
POLOPancreas cancer olaparib ongoing
CTComputed tomography
NCCNThe National Comprehensive Cancer Network
CEACarcinoembryonic antigen
CA19-9Carbohydrate antigen 19-9
NGSNext-generation sequencing
MAFMutant allele frequency
FOLFIRINOXFOL-folinic acid, F-fluorouracil, IRIN-irinotecan, OX-oxaliplatin
G-CSFGranulocyte-colony stimulating factor
PRPartial response
mESCMouse embryonic stem cell
DSBsDouble strand breaks
HRHomologous recombination
3DThree dimensional
Publisher's Note
Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
Acknowledgements
We would like to thank the patient for providing written informed consent for publication.
Authors' contributions
XL conceptualized and designed the manuscript. QT and DW carried out patient clinical management, sample collection and drafted the manuscript. RG analyzed the data. SL and MY revised the manuscript. All authors read and approved the final manuscript.
Funding
Supported by the Key Project of Zhenjiang City for Health Science and Technology (SH2016038 and SH2019046), and the Project of Young Medical Talents in Jiangsu Province (QNRC2016829), China. The funding body did not have any role in the study design, data collection and analysis, decision to publish, or preparation of the manuscript.
Availability of data and materials
The datasets generated and/or analysed during the current study are not publicly available in order to protect participant confidentiality but are available from the corresponding author on reasonable request.
Ethics approval and consent to participate
The study protocol was approved by the ethical committee of the Affiliated Hospital of Jiangsu University. Written informed consent was provided by the patient.
Consent for publication
Written informed consent was obtained from the patient for publication of the case and all accompanying tables/images. A copy of the written consent is available for review by the Editor of this journal.
Competing interests
Ruting Guan and Sisi Liu are the employees of Nanjing Geneseeq Technology Inc., China; Man Yu is an employee of Geneseeq Technology Inc., Canada. The remaining authors declare no conflicts of interest. | FLUOROURACIL, GIMERACIL\OTERACIL\TEGAFUR, IRINOTECAN, LEUCOVORIN, OLAPARIB, OXALIPLATIN | DrugsGivenReaction | CC BY | 33407459 | 19,274,581 | 2021-01-06 |
Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Decreased appetite'. | A novel somatic BRCA2 point mutation in a metastatic pancreatic cancer patient: a case report.
In addition to ovarian and breast cancers, loss-of-function mutations in BRCA1 and BRCA2 genes are also linked to an increased risk of pancreatic cancer, with ~ 4 to 7% of pancreatic cancer patients harboring germline BRCA mutations. Most BRCA alterations in pancreatic cancer are frame-shifting indels, stop-gain, and splice-site mutations, but single nucleotide substitutions are rare. Recent studies demonstrated a significant progression-free survival (PFS) benefit from maintenance olaparib, a poly (ADP-ribose) polymerase (PARP) inhibitor administered to patients with germline BRCA mutations and metastatic pancreatic cancer.
Here, we report a metastatic pancreatic cancer case who harbored a novel somatic BRCA2 c.6944T > C (p. I2315T) point mutation. After 6 weeks first-line chemotherapy, the patient was refractory to treatment and had a progressive disease. Due to the novel nonsynonymous BRCA2 point mutation, we decided to change the strategy by administering olaparib. The patient benefited from olaparib therapy and achieved a PFS of ~ 6.5 months.
We describe a patient carrying a novel somatic BRCA2 p. I2315T point mutation, which is first reported in metastatic pancreatic cancer. This case report indicates that a gene mutation-based strategy should be considered in the clinic to provide more effective treatment.
Background
Pancreatic cancer is the 7th leading cause of cancer-related deaths worldwide, with a 5-year survival rate of < 5% [1]. This devastating malignancy is generally diagnosed at metastatic stages in the clinic, indicative of its late detection and biological aggressiveness [1]. Tremendous efforts are ongoing with the aims of discovering early diagnostic markers and novel therapeutic avenues for pancreatic cancer; however, progress is remarkably hindered by the complicated heterogeneity within and between patient tumors.
BRCA1 and BRCA2 are essential players involved in homologous recombination repair of double-strand deoxyribonucleic acid (DNA) breaks [2]. BRCA inactivation due to somatic mutations or BRCA1 promoter methylation have been observed in various cancer types, including a small subgroup of metastatic pancreatic cancer [3–5]. Most BRCA alterations in pancreatic cancer are frame-shifting indels, stop-gain, and splice-site mutations, whereas single nucleotide substitutions are rarely identified [2, 4, 5].
A large body of evidence showed that the poly (ADP-ribose) polymerase (PARP) inhibitors are synthetically lethal in BRCA-mutated tumors with DNA repair defects and displayed potent anti-tumor activity when combined with DNA-damaging agents. Thus, patients carrying germline mutations in BRCA or the various patterns of somatic BRCA mutations that could result in the inactivation of BRCA are sensitive to PARP inhibitors [6].
A recent phase 3 POLO (Pancreas Cancer Olaparib Ongoing) trial demonstrated that the administration of a PARP inhibitor, olaparib, as a maintenance therapy significantly prolonged the median progression-free survival (PFS) of patients with germline BRCA mutations and metastatic pancreatic cancer who had not progressed during platinum-based chemotherapy compared to the placebo arm (7.4 months vs. 3.8 months) [7]. More importantly, olaparib treatment did not compromise health-related quality of life in those patients [8]. However, PARP inhibitor resistance is common due to homologous recombination repair restoration (HRR), epigenetic modification, reversion mutations, restoration of ADP-ribosylation (PARylation), and pharmacological alteration [9].
In this report, we present the case of a metastatic pancreatic cancer patient who had progressive disease (PD) following chemotherapy with gemcitabine and nab-paclitaxel. Mutational profiling analysis using targeted next-generation sequencing (NGS) revealed that the patient carried a novel somatic BRCA2 c.6944T > C (p. I2315T) point mutation. Olaparib was thereby administered in combination with a modified FOLFIRINOX regimen or as a monotherapy. The patient showed a significant response to this treatment strategy and exhibited stable disease and a PFS of ~ 6.5 months was observed.
Case presentation
A 57-year-old Chinese male with no obvious symptoms was admitted to the hospital due to the identification of a low-density shadow in the liver during his physical examination. In January 2019, a computed tomography (CT) scan revealed a 5.0 × 3.0 cm tumor in the uncinate process of the pancreas with hepatic metastases (Fig. 1a). The patient had a family history of cancer: his mother was diagnosed with stomach cancer at the age of 65 years and his father had lung cancer. According to the National Comprehensive Cancer Network (NCCN) Guidelines, the patient first received gemcitabine treatment at a dose of 1.4 g once per week, and nab-paclitaxel at a dose of 200 mg every 2 weeks as a first-line chemotherapy in January 2019 (Fig. 1b). Unfortunately, a CT re-evaluation at 6 weeks post-treatment showed progressive enlargement of both pancreatic and hepatic lesions (Fig. 1a), accompanied with a marked elevation of serum carcinoembryonic antigen (CEA, 270.35 ng/mL) and carbohydrate antigen 19-9 (CA19-9, 352.56 U/mL) levels (Fig. 1c); thus, suggesting that the patient was refractory to treatment and had a PD.Fig. 1 CT images and measurements of serum tumor biomarkers during the course of treatment. a Serial CT scans demonstrated a reduction in the size of the pancreatic (red arrows) and metastatic hepatic lesions (green arrows) following olaparib therapy. b A timeline indicating the application of different therapeutic strategies and the patient’s response. c Measurements of serum CEA and CA19-9 levels at different treatment times. Blue line: CEA; green line: CA19-9; orange arrows: time points of the CT scans. PD progressive disease, PR partial response, SD stable disease
To determine a more effective and appropriate targeted therapy, we performed a targeted NGS analysis of 425 cancer-related genes on the patient’s plasma and tumor tissue biopsy samples. The cancer mutation panel test revealed multiple deleterious somatic mutations, such as the driver mutations, KRAS Q61R (c.182A > G), TP53 R110del (c.329_331delGTC), and APC S1465RfsX9 (c.4393_4394dupAG), and copy number gain of several genes (Table 1). Interestingly, we also observed a novel nonsynonymous BRCA2 c.6944T > C (p. I2315T) point mutation with a mutant allele frequency (MAF) of 28.0% in the plasma and 39.5% in the tumor biopsy specimens. The novel BRCA2 point mutation was not detected in white blood cells, and thus, it was confirmed as a somatic mutation.Table 1 Genetic alterations detected in the patient’s plasma and tumor biopsy specimens
Genes Alternations Nucleotide change MAF (plasma) MAF (tumor)
BRCA2 p. I2315T c.6944T > C 28% 39.5%
KRAS p. Q61R c.182A > G 27.4% 43.2%
TP53 p. R110del c.329_331delGTC 37.4% 81.6%
APC p. S1465RfsX9 c.4393_4394dupAG 26.7% 71.7%
CCNE1 Gene amplification NA 16.0-fold 27.4-fold
CCNE1 IGR (downstream UQCRFS1) ~ CCNE1 fusion NA 0.1% –
PIK3CA Gene amplification NA – 1.9-fold
PKHD1 p. R909X truncation c.2725C > T 4.9% 16.9%
SOX2 Gene amplification NA – 2.0-fold
STMN1 Gene amplification NA – 1.8-fold
TERC Gene amplification NA – 1.9-fold
TUBB3 Gene amplification NA – 2.2-fold
–, not detectable; NA, not applicable; MAF, mutant allele frequency. Gene amplification was presented as the relative fold change to normal controls
Given the clinical efficacy of olaparib in treating BRCA-mutated advanced solid tumors, we decided to revise the therapeutic strategy by administering olaparib at a dose of 150 mg twice per day in combination with a modified FOLFIRINOX regimen (irinotecan at a dose of 100 mg on days 1, 8 and 15; oxaliplatin at a dose of 150 mg on days 1 and 15; S-1 at a dose of 40 mg twice per day from day 1 to day 14) for one cycle beginning in March 2019 (Fig. 1b). However, due to the occurrence of adverse events (e.g., diarrhea, general weakness, fatigue, and loss of appetite) and myelosuppression, including grade 2–3 leukopenia and thrombocytopenia, chemotherapy was not given on day 15 and the frequency of irinotecan was reduced to only be administered on days 1 and 15 in the subsequent treatment. Additionally, megestrol acetate and granulocyte-colony stimulating factor (G-CSF) were prescribed to increase appetite and promote the recovery of myelosuppression. In May 2019, a reduction in the size of both pancreatic and hepatic lesions was revealed by the CT scan, while the levels of the serum tumor biomarkers, CEA (63.38 ng/mL) and CA19-9 (40.53 U/mL) were considerably reduced (Fig. 1a, c). Olaparib and modified FOLFIRINOX were thus continued with irinotecan and oxaliplatin being administered only on day 1 (Fig. 1b). After 2 weeks of treatment, CEA and CA19-9 levels decreased to 32.69 ng/mL and 25.57 U/mL, respectively (Fig. 1c). A CT scan performed in June 2019 showed a significant size reduction in the primary and metastatic tumors, which indicated a partial response (PR, Fig. 1a). Since the patient experienced severe marrow suppression during treatment, only olaparib monotherapy was administered since July 2019 to reduce adverse effects (Fig. 1b). Stable disease (SD) was subsequently observed in August 2019 (Fig. 1a). In September 2019, aside from an increase in CEA and CA19-9 levels (Fig. 1c), laboratory blood tests demonstrated that the patient underwent acquired granulocytopenia, anemia, and thrombocytopenia. Consequently, G-CSF, thrombopoietin, and erythropoietin were administered for symptom management. After olaparib treatment for another 1.5 months, PD was indicated by a CT scan (Fig. 1a). The patient achieved a PFS for ~ 6.5 months following olaparib combination and monotherapy.
Discussion and conclusions
Neoplastic cells lacking a functional homologous recombination repair system, such as those carrying BRCA mutations, are sensitive to PARP inhibition through accumulated DNA damage via multiple mechanisms [6]. As a new therapeutic concept, maintenance olaparib has shown promising results in the treatment of germline BRCA-mutated breast, ovarian, and metastatic pancreatic cancer [7, 10, 11]. To date, the majority of BRCA2 mutations identified in pancreatic cancer were frame-shifting indels (e.g., c.6174delT, c.6158insT) and splice-site mutations. In contrast, single point mutations have been rarely reported [4, 5, 12]. Mesman [13] recently assessed the potential pathogenic impact of a large set of BRCA2 missense variants using a mouse embryonic stem cell (mESC)-based functional assay, and found that BRCA2 missense mutations, such as c.93G > T (p. W31C) and c.8351G > A (p. R2784Q), were able to increase susceptibility to PARP inhibitor treatment.
The patient in our report harbored an unreported BRCA2 point mutation [c.6944T > C (p. I2315T)] located in exon 13 of BRCA2 between the G-CSF. Different germline BRCA2 mutations (e.g., p. I2315V, p. I2315L) at the same site have been documented with unknown functional significance [14, 15]. Although the underlying molecular mechanism(s) by which this novel BRCA2 p. I2315T mutation impairs DNA repair and sensitizes tumor cells to PARP inhibition remains to be elucidated. We postulate that it may be related to a change in the polarity of amino acid residues since isoleucine (I), valine (V) and leucine (L) are all non-polar and hydrophobic, while threonine (T) is hydrophilic. Thus, we hypothesize that the p. I2315T mutation is likely to cause a structural abnormality in the BRCA2 protein, which results in defective DNA double strand break (DSB) repair by homologous recombination (HR) and its sensitivity to olaparib. To test this hypothesis, we attempted to generate a three dimensional (3D) structural model of the BRCA2 p. I2315T mutation, but failed due to the absence of an established crystal structure of the full-length human BRCA2 due to its size and segmental nature [16].
In summary, we report a metastatic pancreatic cancer patient carrying a novel somatic BRCA2 p. I2315T point mutation. Furthermore, advances in NGS technology have provided a solid basis for precise detection of well-known driver mutations, and rare or novel mutations. Thus, NGS may provide clinicians with invaluable information (e.g., BRCA1/2 status of tumors) that can be leveraged for therapeutic decision making, and perform better evaluations of patients’ responses during the course of treatment.
Abbreviations
PARPPoly(ADP-ribose) polymerase
PFSProgression-free survival
PDProgressive disease
DNADeoxyribonucleic acid
POLOPancreas cancer olaparib ongoing
CTComputed tomography
NCCNThe National Comprehensive Cancer Network
CEACarcinoembryonic antigen
CA19-9Carbohydrate antigen 19-9
NGSNext-generation sequencing
MAFMutant allele frequency
FOLFIRINOXFOL-folinic acid, F-fluorouracil, IRIN-irinotecan, OX-oxaliplatin
G-CSFGranulocyte-colony stimulating factor
PRPartial response
mESCMouse embryonic stem cell
DSBsDouble strand breaks
HRHomologous recombination
3DThree dimensional
Publisher's Note
Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
Acknowledgements
We would like to thank the patient for providing written informed consent for publication.
Authors' contributions
XL conceptualized and designed the manuscript. QT and DW carried out patient clinical management, sample collection and drafted the manuscript. RG analyzed the data. SL and MY revised the manuscript. All authors read and approved the final manuscript.
Funding
Supported by the Key Project of Zhenjiang City for Health Science and Technology (SH2016038 and SH2019046), and the Project of Young Medical Talents in Jiangsu Province (QNRC2016829), China. The funding body did not have any role in the study design, data collection and analysis, decision to publish, or preparation of the manuscript.
Availability of data and materials
The datasets generated and/or analysed during the current study are not publicly available in order to protect participant confidentiality but are available from the corresponding author on reasonable request.
Ethics approval and consent to participate
The study protocol was approved by the ethical committee of the Affiliated Hospital of Jiangsu University. Written informed consent was provided by the patient.
Consent for publication
Written informed consent was obtained from the patient for publication of the case and all accompanying tables/images. A copy of the written consent is available for review by the Editor of this journal.
Competing interests
Ruting Guan and Sisi Liu are the employees of Nanjing Geneseeq Technology Inc., China; Man Yu is an employee of Geneseeq Technology Inc., Canada. The remaining authors declare no conflicts of interest. | FLUOROURACIL, GIMERACIL\OTERACIL\TEGAFUR, IRINOTECAN, LEUCOVORIN, OLAPARIB, OXALIPLATIN | DrugsGivenReaction | CC BY | 33407459 | 19,274,581 | 2021-01-06 |
Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Diarrhoea'. | A novel somatic BRCA2 point mutation in a metastatic pancreatic cancer patient: a case report.
In addition to ovarian and breast cancers, loss-of-function mutations in BRCA1 and BRCA2 genes are also linked to an increased risk of pancreatic cancer, with ~ 4 to 7% of pancreatic cancer patients harboring germline BRCA mutations. Most BRCA alterations in pancreatic cancer are frame-shifting indels, stop-gain, and splice-site mutations, but single nucleotide substitutions are rare. Recent studies demonstrated a significant progression-free survival (PFS) benefit from maintenance olaparib, a poly (ADP-ribose) polymerase (PARP) inhibitor administered to patients with germline BRCA mutations and metastatic pancreatic cancer.
Here, we report a metastatic pancreatic cancer case who harbored a novel somatic BRCA2 c.6944T > C (p. I2315T) point mutation. After 6 weeks first-line chemotherapy, the patient was refractory to treatment and had a progressive disease. Due to the novel nonsynonymous BRCA2 point mutation, we decided to change the strategy by administering olaparib. The patient benefited from olaparib therapy and achieved a PFS of ~ 6.5 months.
We describe a patient carrying a novel somatic BRCA2 p. I2315T point mutation, which is first reported in metastatic pancreatic cancer. This case report indicates that a gene mutation-based strategy should be considered in the clinic to provide more effective treatment.
Background
Pancreatic cancer is the 7th leading cause of cancer-related deaths worldwide, with a 5-year survival rate of < 5% [1]. This devastating malignancy is generally diagnosed at metastatic stages in the clinic, indicative of its late detection and biological aggressiveness [1]. Tremendous efforts are ongoing with the aims of discovering early diagnostic markers and novel therapeutic avenues for pancreatic cancer; however, progress is remarkably hindered by the complicated heterogeneity within and between patient tumors.
BRCA1 and BRCA2 are essential players involved in homologous recombination repair of double-strand deoxyribonucleic acid (DNA) breaks [2]. BRCA inactivation due to somatic mutations or BRCA1 promoter methylation have been observed in various cancer types, including a small subgroup of metastatic pancreatic cancer [3–5]. Most BRCA alterations in pancreatic cancer are frame-shifting indels, stop-gain, and splice-site mutations, whereas single nucleotide substitutions are rarely identified [2, 4, 5].
A large body of evidence showed that the poly (ADP-ribose) polymerase (PARP) inhibitors are synthetically lethal in BRCA-mutated tumors with DNA repair defects and displayed potent anti-tumor activity when combined with DNA-damaging agents. Thus, patients carrying germline mutations in BRCA or the various patterns of somatic BRCA mutations that could result in the inactivation of BRCA are sensitive to PARP inhibitors [6].
A recent phase 3 POLO (Pancreas Cancer Olaparib Ongoing) trial demonstrated that the administration of a PARP inhibitor, olaparib, as a maintenance therapy significantly prolonged the median progression-free survival (PFS) of patients with germline BRCA mutations and metastatic pancreatic cancer who had not progressed during platinum-based chemotherapy compared to the placebo arm (7.4 months vs. 3.8 months) [7]. More importantly, olaparib treatment did not compromise health-related quality of life in those patients [8]. However, PARP inhibitor resistance is common due to homologous recombination repair restoration (HRR), epigenetic modification, reversion mutations, restoration of ADP-ribosylation (PARylation), and pharmacological alteration [9].
In this report, we present the case of a metastatic pancreatic cancer patient who had progressive disease (PD) following chemotherapy with gemcitabine and nab-paclitaxel. Mutational profiling analysis using targeted next-generation sequencing (NGS) revealed that the patient carried a novel somatic BRCA2 c.6944T > C (p. I2315T) point mutation. Olaparib was thereby administered in combination with a modified FOLFIRINOX regimen or as a monotherapy. The patient showed a significant response to this treatment strategy and exhibited stable disease and a PFS of ~ 6.5 months was observed.
Case presentation
A 57-year-old Chinese male with no obvious symptoms was admitted to the hospital due to the identification of a low-density shadow in the liver during his physical examination. In January 2019, a computed tomography (CT) scan revealed a 5.0 × 3.0 cm tumor in the uncinate process of the pancreas with hepatic metastases (Fig. 1a). The patient had a family history of cancer: his mother was diagnosed with stomach cancer at the age of 65 years and his father had lung cancer. According to the National Comprehensive Cancer Network (NCCN) Guidelines, the patient first received gemcitabine treatment at a dose of 1.4 g once per week, and nab-paclitaxel at a dose of 200 mg every 2 weeks as a first-line chemotherapy in January 2019 (Fig. 1b). Unfortunately, a CT re-evaluation at 6 weeks post-treatment showed progressive enlargement of both pancreatic and hepatic lesions (Fig. 1a), accompanied with a marked elevation of serum carcinoembryonic antigen (CEA, 270.35 ng/mL) and carbohydrate antigen 19-9 (CA19-9, 352.56 U/mL) levels (Fig. 1c); thus, suggesting that the patient was refractory to treatment and had a PD.Fig. 1 CT images and measurements of serum tumor biomarkers during the course of treatment. a Serial CT scans demonstrated a reduction in the size of the pancreatic (red arrows) and metastatic hepatic lesions (green arrows) following olaparib therapy. b A timeline indicating the application of different therapeutic strategies and the patient’s response. c Measurements of serum CEA and CA19-9 levels at different treatment times. Blue line: CEA; green line: CA19-9; orange arrows: time points of the CT scans. PD progressive disease, PR partial response, SD stable disease
To determine a more effective and appropriate targeted therapy, we performed a targeted NGS analysis of 425 cancer-related genes on the patient’s plasma and tumor tissue biopsy samples. The cancer mutation panel test revealed multiple deleterious somatic mutations, such as the driver mutations, KRAS Q61R (c.182A > G), TP53 R110del (c.329_331delGTC), and APC S1465RfsX9 (c.4393_4394dupAG), and copy number gain of several genes (Table 1). Interestingly, we also observed a novel nonsynonymous BRCA2 c.6944T > C (p. I2315T) point mutation with a mutant allele frequency (MAF) of 28.0% in the plasma and 39.5% in the tumor biopsy specimens. The novel BRCA2 point mutation was not detected in white blood cells, and thus, it was confirmed as a somatic mutation.Table 1 Genetic alterations detected in the patient’s plasma and tumor biopsy specimens
Genes Alternations Nucleotide change MAF (plasma) MAF (tumor)
BRCA2 p. I2315T c.6944T > C 28% 39.5%
KRAS p. Q61R c.182A > G 27.4% 43.2%
TP53 p. R110del c.329_331delGTC 37.4% 81.6%
APC p. S1465RfsX9 c.4393_4394dupAG 26.7% 71.7%
CCNE1 Gene amplification NA 16.0-fold 27.4-fold
CCNE1 IGR (downstream UQCRFS1) ~ CCNE1 fusion NA 0.1% –
PIK3CA Gene amplification NA – 1.9-fold
PKHD1 p. R909X truncation c.2725C > T 4.9% 16.9%
SOX2 Gene amplification NA – 2.0-fold
STMN1 Gene amplification NA – 1.8-fold
TERC Gene amplification NA – 1.9-fold
TUBB3 Gene amplification NA – 2.2-fold
–, not detectable; NA, not applicable; MAF, mutant allele frequency. Gene amplification was presented as the relative fold change to normal controls
Given the clinical efficacy of olaparib in treating BRCA-mutated advanced solid tumors, we decided to revise the therapeutic strategy by administering olaparib at a dose of 150 mg twice per day in combination with a modified FOLFIRINOX regimen (irinotecan at a dose of 100 mg on days 1, 8 and 15; oxaliplatin at a dose of 150 mg on days 1 and 15; S-1 at a dose of 40 mg twice per day from day 1 to day 14) for one cycle beginning in March 2019 (Fig. 1b). However, due to the occurrence of adverse events (e.g., diarrhea, general weakness, fatigue, and loss of appetite) and myelosuppression, including grade 2–3 leukopenia and thrombocytopenia, chemotherapy was not given on day 15 and the frequency of irinotecan was reduced to only be administered on days 1 and 15 in the subsequent treatment. Additionally, megestrol acetate and granulocyte-colony stimulating factor (G-CSF) were prescribed to increase appetite and promote the recovery of myelosuppression. In May 2019, a reduction in the size of both pancreatic and hepatic lesions was revealed by the CT scan, while the levels of the serum tumor biomarkers, CEA (63.38 ng/mL) and CA19-9 (40.53 U/mL) were considerably reduced (Fig. 1a, c). Olaparib and modified FOLFIRINOX were thus continued with irinotecan and oxaliplatin being administered only on day 1 (Fig. 1b). After 2 weeks of treatment, CEA and CA19-9 levels decreased to 32.69 ng/mL and 25.57 U/mL, respectively (Fig. 1c). A CT scan performed in June 2019 showed a significant size reduction in the primary and metastatic tumors, which indicated a partial response (PR, Fig. 1a). Since the patient experienced severe marrow suppression during treatment, only olaparib monotherapy was administered since July 2019 to reduce adverse effects (Fig. 1b). Stable disease (SD) was subsequently observed in August 2019 (Fig. 1a). In September 2019, aside from an increase in CEA and CA19-9 levels (Fig. 1c), laboratory blood tests demonstrated that the patient underwent acquired granulocytopenia, anemia, and thrombocytopenia. Consequently, G-CSF, thrombopoietin, and erythropoietin were administered for symptom management. After olaparib treatment for another 1.5 months, PD was indicated by a CT scan (Fig. 1a). The patient achieved a PFS for ~ 6.5 months following olaparib combination and monotherapy.
Discussion and conclusions
Neoplastic cells lacking a functional homologous recombination repair system, such as those carrying BRCA mutations, are sensitive to PARP inhibition through accumulated DNA damage via multiple mechanisms [6]. As a new therapeutic concept, maintenance olaparib has shown promising results in the treatment of germline BRCA-mutated breast, ovarian, and metastatic pancreatic cancer [7, 10, 11]. To date, the majority of BRCA2 mutations identified in pancreatic cancer were frame-shifting indels (e.g., c.6174delT, c.6158insT) and splice-site mutations. In contrast, single point mutations have been rarely reported [4, 5, 12]. Mesman [13] recently assessed the potential pathogenic impact of a large set of BRCA2 missense variants using a mouse embryonic stem cell (mESC)-based functional assay, and found that BRCA2 missense mutations, such as c.93G > T (p. W31C) and c.8351G > A (p. R2784Q), were able to increase susceptibility to PARP inhibitor treatment.
The patient in our report harbored an unreported BRCA2 point mutation [c.6944T > C (p. I2315T)] located in exon 13 of BRCA2 between the G-CSF. Different germline BRCA2 mutations (e.g., p. I2315V, p. I2315L) at the same site have been documented with unknown functional significance [14, 15]. Although the underlying molecular mechanism(s) by which this novel BRCA2 p. I2315T mutation impairs DNA repair and sensitizes tumor cells to PARP inhibition remains to be elucidated. We postulate that it may be related to a change in the polarity of amino acid residues since isoleucine (I), valine (V) and leucine (L) are all non-polar and hydrophobic, while threonine (T) is hydrophilic. Thus, we hypothesize that the p. I2315T mutation is likely to cause a structural abnormality in the BRCA2 protein, which results in defective DNA double strand break (DSB) repair by homologous recombination (HR) and its sensitivity to olaparib. To test this hypothesis, we attempted to generate a three dimensional (3D) structural model of the BRCA2 p. I2315T mutation, but failed due to the absence of an established crystal structure of the full-length human BRCA2 due to its size and segmental nature [16].
In summary, we report a metastatic pancreatic cancer patient carrying a novel somatic BRCA2 p. I2315T point mutation. Furthermore, advances in NGS technology have provided a solid basis for precise detection of well-known driver mutations, and rare or novel mutations. Thus, NGS may provide clinicians with invaluable information (e.g., BRCA1/2 status of tumors) that can be leveraged for therapeutic decision making, and perform better evaluations of patients’ responses during the course of treatment.
Abbreviations
PARPPoly(ADP-ribose) polymerase
PFSProgression-free survival
PDProgressive disease
DNADeoxyribonucleic acid
POLOPancreas cancer olaparib ongoing
CTComputed tomography
NCCNThe National Comprehensive Cancer Network
CEACarcinoembryonic antigen
CA19-9Carbohydrate antigen 19-9
NGSNext-generation sequencing
MAFMutant allele frequency
FOLFIRINOXFOL-folinic acid, F-fluorouracil, IRIN-irinotecan, OX-oxaliplatin
G-CSFGranulocyte-colony stimulating factor
PRPartial response
mESCMouse embryonic stem cell
DSBsDouble strand breaks
HRHomologous recombination
3DThree dimensional
Publisher's Note
Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
Acknowledgements
We would like to thank the patient for providing written informed consent for publication.
Authors' contributions
XL conceptualized and designed the manuscript. QT and DW carried out patient clinical management, sample collection and drafted the manuscript. RG analyzed the data. SL and MY revised the manuscript. All authors read and approved the final manuscript.
Funding
Supported by the Key Project of Zhenjiang City for Health Science and Technology (SH2016038 and SH2019046), and the Project of Young Medical Talents in Jiangsu Province (QNRC2016829), China. The funding body did not have any role in the study design, data collection and analysis, decision to publish, or preparation of the manuscript.
Availability of data and materials
The datasets generated and/or analysed during the current study are not publicly available in order to protect participant confidentiality but are available from the corresponding author on reasonable request.
Ethics approval and consent to participate
The study protocol was approved by the ethical committee of the Affiliated Hospital of Jiangsu University. Written informed consent was provided by the patient.
Consent for publication
Written informed consent was obtained from the patient for publication of the case and all accompanying tables/images. A copy of the written consent is available for review by the Editor of this journal.
Competing interests
Ruting Guan and Sisi Liu are the employees of Nanjing Geneseeq Technology Inc., China; Man Yu is an employee of Geneseeq Technology Inc., Canada. The remaining authors declare no conflicts of interest. | FLUOROURACIL, GIMERACIL\OTERACIL\TEGAFUR, IRINOTECAN, LEUCOVORIN, OLAPARIB, OXALIPLATIN | DrugsGivenReaction | CC BY | 33407459 | 19,274,581 | 2021-01-06 |
Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Fatigue'. | A novel somatic BRCA2 point mutation in a metastatic pancreatic cancer patient: a case report.
In addition to ovarian and breast cancers, loss-of-function mutations in BRCA1 and BRCA2 genes are also linked to an increased risk of pancreatic cancer, with ~ 4 to 7% of pancreatic cancer patients harboring germline BRCA mutations. Most BRCA alterations in pancreatic cancer are frame-shifting indels, stop-gain, and splice-site mutations, but single nucleotide substitutions are rare. Recent studies demonstrated a significant progression-free survival (PFS) benefit from maintenance olaparib, a poly (ADP-ribose) polymerase (PARP) inhibitor administered to patients with germline BRCA mutations and metastatic pancreatic cancer.
Here, we report a metastatic pancreatic cancer case who harbored a novel somatic BRCA2 c.6944T > C (p. I2315T) point mutation. After 6 weeks first-line chemotherapy, the patient was refractory to treatment and had a progressive disease. Due to the novel nonsynonymous BRCA2 point mutation, we decided to change the strategy by administering olaparib. The patient benefited from olaparib therapy and achieved a PFS of ~ 6.5 months.
We describe a patient carrying a novel somatic BRCA2 p. I2315T point mutation, which is first reported in metastatic pancreatic cancer. This case report indicates that a gene mutation-based strategy should be considered in the clinic to provide more effective treatment.
Background
Pancreatic cancer is the 7th leading cause of cancer-related deaths worldwide, with a 5-year survival rate of < 5% [1]. This devastating malignancy is generally diagnosed at metastatic stages in the clinic, indicative of its late detection and biological aggressiveness [1]. Tremendous efforts are ongoing with the aims of discovering early diagnostic markers and novel therapeutic avenues for pancreatic cancer; however, progress is remarkably hindered by the complicated heterogeneity within and between patient tumors.
BRCA1 and BRCA2 are essential players involved in homologous recombination repair of double-strand deoxyribonucleic acid (DNA) breaks [2]. BRCA inactivation due to somatic mutations or BRCA1 promoter methylation have been observed in various cancer types, including a small subgroup of metastatic pancreatic cancer [3–5]. Most BRCA alterations in pancreatic cancer are frame-shifting indels, stop-gain, and splice-site mutations, whereas single nucleotide substitutions are rarely identified [2, 4, 5].
A large body of evidence showed that the poly (ADP-ribose) polymerase (PARP) inhibitors are synthetically lethal in BRCA-mutated tumors with DNA repair defects and displayed potent anti-tumor activity when combined with DNA-damaging agents. Thus, patients carrying germline mutations in BRCA or the various patterns of somatic BRCA mutations that could result in the inactivation of BRCA are sensitive to PARP inhibitors [6].
A recent phase 3 POLO (Pancreas Cancer Olaparib Ongoing) trial demonstrated that the administration of a PARP inhibitor, olaparib, as a maintenance therapy significantly prolonged the median progression-free survival (PFS) of patients with germline BRCA mutations and metastatic pancreatic cancer who had not progressed during platinum-based chemotherapy compared to the placebo arm (7.4 months vs. 3.8 months) [7]. More importantly, olaparib treatment did not compromise health-related quality of life in those patients [8]. However, PARP inhibitor resistance is common due to homologous recombination repair restoration (HRR), epigenetic modification, reversion mutations, restoration of ADP-ribosylation (PARylation), and pharmacological alteration [9].
In this report, we present the case of a metastatic pancreatic cancer patient who had progressive disease (PD) following chemotherapy with gemcitabine and nab-paclitaxel. Mutational profiling analysis using targeted next-generation sequencing (NGS) revealed that the patient carried a novel somatic BRCA2 c.6944T > C (p. I2315T) point mutation. Olaparib was thereby administered in combination with a modified FOLFIRINOX regimen or as a monotherapy. The patient showed a significant response to this treatment strategy and exhibited stable disease and a PFS of ~ 6.5 months was observed.
Case presentation
A 57-year-old Chinese male with no obvious symptoms was admitted to the hospital due to the identification of a low-density shadow in the liver during his physical examination. In January 2019, a computed tomography (CT) scan revealed a 5.0 × 3.0 cm tumor in the uncinate process of the pancreas with hepatic metastases (Fig. 1a). The patient had a family history of cancer: his mother was diagnosed with stomach cancer at the age of 65 years and his father had lung cancer. According to the National Comprehensive Cancer Network (NCCN) Guidelines, the patient first received gemcitabine treatment at a dose of 1.4 g once per week, and nab-paclitaxel at a dose of 200 mg every 2 weeks as a first-line chemotherapy in January 2019 (Fig. 1b). Unfortunately, a CT re-evaluation at 6 weeks post-treatment showed progressive enlargement of both pancreatic and hepatic lesions (Fig. 1a), accompanied with a marked elevation of serum carcinoembryonic antigen (CEA, 270.35 ng/mL) and carbohydrate antigen 19-9 (CA19-9, 352.56 U/mL) levels (Fig. 1c); thus, suggesting that the patient was refractory to treatment and had a PD.Fig. 1 CT images and measurements of serum tumor biomarkers during the course of treatment. a Serial CT scans demonstrated a reduction in the size of the pancreatic (red arrows) and metastatic hepatic lesions (green arrows) following olaparib therapy. b A timeline indicating the application of different therapeutic strategies and the patient’s response. c Measurements of serum CEA and CA19-9 levels at different treatment times. Blue line: CEA; green line: CA19-9; orange arrows: time points of the CT scans. PD progressive disease, PR partial response, SD stable disease
To determine a more effective and appropriate targeted therapy, we performed a targeted NGS analysis of 425 cancer-related genes on the patient’s plasma and tumor tissue biopsy samples. The cancer mutation panel test revealed multiple deleterious somatic mutations, such as the driver mutations, KRAS Q61R (c.182A > G), TP53 R110del (c.329_331delGTC), and APC S1465RfsX9 (c.4393_4394dupAG), and copy number gain of several genes (Table 1). Interestingly, we also observed a novel nonsynonymous BRCA2 c.6944T > C (p. I2315T) point mutation with a mutant allele frequency (MAF) of 28.0% in the plasma and 39.5% in the tumor biopsy specimens. The novel BRCA2 point mutation was not detected in white blood cells, and thus, it was confirmed as a somatic mutation.Table 1 Genetic alterations detected in the patient’s plasma and tumor biopsy specimens
Genes Alternations Nucleotide change MAF (plasma) MAF (tumor)
BRCA2 p. I2315T c.6944T > C 28% 39.5%
KRAS p. Q61R c.182A > G 27.4% 43.2%
TP53 p. R110del c.329_331delGTC 37.4% 81.6%
APC p. S1465RfsX9 c.4393_4394dupAG 26.7% 71.7%
CCNE1 Gene amplification NA 16.0-fold 27.4-fold
CCNE1 IGR (downstream UQCRFS1) ~ CCNE1 fusion NA 0.1% –
PIK3CA Gene amplification NA – 1.9-fold
PKHD1 p. R909X truncation c.2725C > T 4.9% 16.9%
SOX2 Gene amplification NA – 2.0-fold
STMN1 Gene amplification NA – 1.8-fold
TERC Gene amplification NA – 1.9-fold
TUBB3 Gene amplification NA – 2.2-fold
–, not detectable; NA, not applicable; MAF, mutant allele frequency. Gene amplification was presented as the relative fold change to normal controls
Given the clinical efficacy of olaparib in treating BRCA-mutated advanced solid tumors, we decided to revise the therapeutic strategy by administering olaparib at a dose of 150 mg twice per day in combination with a modified FOLFIRINOX regimen (irinotecan at a dose of 100 mg on days 1, 8 and 15; oxaliplatin at a dose of 150 mg on days 1 and 15; S-1 at a dose of 40 mg twice per day from day 1 to day 14) for one cycle beginning in March 2019 (Fig. 1b). However, due to the occurrence of adverse events (e.g., diarrhea, general weakness, fatigue, and loss of appetite) and myelosuppression, including grade 2–3 leukopenia and thrombocytopenia, chemotherapy was not given on day 15 and the frequency of irinotecan was reduced to only be administered on days 1 and 15 in the subsequent treatment. Additionally, megestrol acetate and granulocyte-colony stimulating factor (G-CSF) were prescribed to increase appetite and promote the recovery of myelosuppression. In May 2019, a reduction in the size of both pancreatic and hepatic lesions was revealed by the CT scan, while the levels of the serum tumor biomarkers, CEA (63.38 ng/mL) and CA19-9 (40.53 U/mL) were considerably reduced (Fig. 1a, c). Olaparib and modified FOLFIRINOX were thus continued with irinotecan and oxaliplatin being administered only on day 1 (Fig. 1b). After 2 weeks of treatment, CEA and CA19-9 levels decreased to 32.69 ng/mL and 25.57 U/mL, respectively (Fig. 1c). A CT scan performed in June 2019 showed a significant size reduction in the primary and metastatic tumors, which indicated a partial response (PR, Fig. 1a). Since the patient experienced severe marrow suppression during treatment, only olaparib monotherapy was administered since July 2019 to reduce adverse effects (Fig. 1b). Stable disease (SD) was subsequently observed in August 2019 (Fig. 1a). In September 2019, aside from an increase in CEA and CA19-9 levels (Fig. 1c), laboratory blood tests demonstrated that the patient underwent acquired granulocytopenia, anemia, and thrombocytopenia. Consequently, G-CSF, thrombopoietin, and erythropoietin were administered for symptom management. After olaparib treatment for another 1.5 months, PD was indicated by a CT scan (Fig. 1a). The patient achieved a PFS for ~ 6.5 months following olaparib combination and monotherapy.
Discussion and conclusions
Neoplastic cells lacking a functional homologous recombination repair system, such as those carrying BRCA mutations, are sensitive to PARP inhibition through accumulated DNA damage via multiple mechanisms [6]. As a new therapeutic concept, maintenance olaparib has shown promising results in the treatment of germline BRCA-mutated breast, ovarian, and metastatic pancreatic cancer [7, 10, 11]. To date, the majority of BRCA2 mutations identified in pancreatic cancer were frame-shifting indels (e.g., c.6174delT, c.6158insT) and splice-site mutations. In contrast, single point mutations have been rarely reported [4, 5, 12]. Mesman [13] recently assessed the potential pathogenic impact of a large set of BRCA2 missense variants using a mouse embryonic stem cell (mESC)-based functional assay, and found that BRCA2 missense mutations, such as c.93G > T (p. W31C) and c.8351G > A (p. R2784Q), were able to increase susceptibility to PARP inhibitor treatment.
The patient in our report harbored an unreported BRCA2 point mutation [c.6944T > C (p. I2315T)] located in exon 13 of BRCA2 between the G-CSF. Different germline BRCA2 mutations (e.g., p. I2315V, p. I2315L) at the same site have been documented with unknown functional significance [14, 15]. Although the underlying molecular mechanism(s) by which this novel BRCA2 p. I2315T mutation impairs DNA repair and sensitizes tumor cells to PARP inhibition remains to be elucidated. We postulate that it may be related to a change in the polarity of amino acid residues since isoleucine (I), valine (V) and leucine (L) are all non-polar and hydrophobic, while threonine (T) is hydrophilic. Thus, we hypothesize that the p. I2315T mutation is likely to cause a structural abnormality in the BRCA2 protein, which results in defective DNA double strand break (DSB) repair by homologous recombination (HR) and its sensitivity to olaparib. To test this hypothesis, we attempted to generate a three dimensional (3D) structural model of the BRCA2 p. I2315T mutation, but failed due to the absence of an established crystal structure of the full-length human BRCA2 due to its size and segmental nature [16].
In summary, we report a metastatic pancreatic cancer patient carrying a novel somatic BRCA2 p. I2315T point mutation. Furthermore, advances in NGS technology have provided a solid basis for precise detection of well-known driver mutations, and rare or novel mutations. Thus, NGS may provide clinicians with invaluable information (e.g., BRCA1/2 status of tumors) that can be leveraged for therapeutic decision making, and perform better evaluations of patients’ responses during the course of treatment.
Abbreviations
PARPPoly(ADP-ribose) polymerase
PFSProgression-free survival
PDProgressive disease
DNADeoxyribonucleic acid
POLOPancreas cancer olaparib ongoing
CTComputed tomography
NCCNThe National Comprehensive Cancer Network
CEACarcinoembryonic antigen
CA19-9Carbohydrate antigen 19-9
NGSNext-generation sequencing
MAFMutant allele frequency
FOLFIRINOXFOL-folinic acid, F-fluorouracil, IRIN-irinotecan, OX-oxaliplatin
G-CSFGranulocyte-colony stimulating factor
PRPartial response
mESCMouse embryonic stem cell
DSBsDouble strand breaks
HRHomologous recombination
3DThree dimensional
Publisher's Note
Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
Acknowledgements
We would like to thank the patient for providing written informed consent for publication.
Authors' contributions
XL conceptualized and designed the manuscript. QT and DW carried out patient clinical management, sample collection and drafted the manuscript. RG analyzed the data. SL and MY revised the manuscript. All authors read and approved the final manuscript.
Funding
Supported by the Key Project of Zhenjiang City for Health Science and Technology (SH2016038 and SH2019046), and the Project of Young Medical Talents in Jiangsu Province (QNRC2016829), China. The funding body did not have any role in the study design, data collection and analysis, decision to publish, or preparation of the manuscript.
Availability of data and materials
The datasets generated and/or analysed during the current study are not publicly available in order to protect participant confidentiality but are available from the corresponding author on reasonable request.
Ethics approval and consent to participate
The study protocol was approved by the ethical committee of the Affiliated Hospital of Jiangsu University. Written informed consent was provided by the patient.
Consent for publication
Written informed consent was obtained from the patient for publication of the case and all accompanying tables/images. A copy of the written consent is available for review by the Editor of this journal.
Competing interests
Ruting Guan and Sisi Liu are the employees of Nanjing Geneseeq Technology Inc., China; Man Yu is an employee of Geneseeq Technology Inc., Canada. The remaining authors declare no conflicts of interest. | FLUOROURACIL, GIMERACIL\OTERACIL\TEGAFUR, IRINOTECAN, LEUCOVORIN, OLAPARIB, OXALIPLATIN | DrugsGivenReaction | CC BY | 33407459 | 19,274,581 | 2021-01-06 |
Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Leukopenia'. | A novel somatic BRCA2 point mutation in a metastatic pancreatic cancer patient: a case report.
In addition to ovarian and breast cancers, loss-of-function mutations in BRCA1 and BRCA2 genes are also linked to an increased risk of pancreatic cancer, with ~ 4 to 7% of pancreatic cancer patients harboring germline BRCA mutations. Most BRCA alterations in pancreatic cancer are frame-shifting indels, stop-gain, and splice-site mutations, but single nucleotide substitutions are rare. Recent studies demonstrated a significant progression-free survival (PFS) benefit from maintenance olaparib, a poly (ADP-ribose) polymerase (PARP) inhibitor administered to patients with germline BRCA mutations and metastatic pancreatic cancer.
Here, we report a metastatic pancreatic cancer case who harbored a novel somatic BRCA2 c.6944T > C (p. I2315T) point mutation. After 6 weeks first-line chemotherapy, the patient was refractory to treatment and had a progressive disease. Due to the novel nonsynonymous BRCA2 point mutation, we decided to change the strategy by administering olaparib. The patient benefited from olaparib therapy and achieved a PFS of ~ 6.5 months.
We describe a patient carrying a novel somatic BRCA2 p. I2315T point mutation, which is first reported in metastatic pancreatic cancer. This case report indicates that a gene mutation-based strategy should be considered in the clinic to provide more effective treatment.
Background
Pancreatic cancer is the 7th leading cause of cancer-related deaths worldwide, with a 5-year survival rate of < 5% [1]. This devastating malignancy is generally diagnosed at metastatic stages in the clinic, indicative of its late detection and biological aggressiveness [1]. Tremendous efforts are ongoing with the aims of discovering early diagnostic markers and novel therapeutic avenues for pancreatic cancer; however, progress is remarkably hindered by the complicated heterogeneity within and between patient tumors.
BRCA1 and BRCA2 are essential players involved in homologous recombination repair of double-strand deoxyribonucleic acid (DNA) breaks [2]. BRCA inactivation due to somatic mutations or BRCA1 promoter methylation have been observed in various cancer types, including a small subgroup of metastatic pancreatic cancer [3–5]. Most BRCA alterations in pancreatic cancer are frame-shifting indels, stop-gain, and splice-site mutations, whereas single nucleotide substitutions are rarely identified [2, 4, 5].
A large body of evidence showed that the poly (ADP-ribose) polymerase (PARP) inhibitors are synthetically lethal in BRCA-mutated tumors with DNA repair defects and displayed potent anti-tumor activity when combined with DNA-damaging agents. Thus, patients carrying germline mutations in BRCA or the various patterns of somatic BRCA mutations that could result in the inactivation of BRCA are sensitive to PARP inhibitors [6].
A recent phase 3 POLO (Pancreas Cancer Olaparib Ongoing) trial demonstrated that the administration of a PARP inhibitor, olaparib, as a maintenance therapy significantly prolonged the median progression-free survival (PFS) of patients with germline BRCA mutations and metastatic pancreatic cancer who had not progressed during platinum-based chemotherapy compared to the placebo arm (7.4 months vs. 3.8 months) [7]. More importantly, olaparib treatment did not compromise health-related quality of life in those patients [8]. However, PARP inhibitor resistance is common due to homologous recombination repair restoration (HRR), epigenetic modification, reversion mutations, restoration of ADP-ribosylation (PARylation), and pharmacological alteration [9].
In this report, we present the case of a metastatic pancreatic cancer patient who had progressive disease (PD) following chemotherapy with gemcitabine and nab-paclitaxel. Mutational profiling analysis using targeted next-generation sequencing (NGS) revealed that the patient carried a novel somatic BRCA2 c.6944T > C (p. I2315T) point mutation. Olaparib was thereby administered in combination with a modified FOLFIRINOX regimen or as a monotherapy. The patient showed a significant response to this treatment strategy and exhibited stable disease and a PFS of ~ 6.5 months was observed.
Case presentation
A 57-year-old Chinese male with no obvious symptoms was admitted to the hospital due to the identification of a low-density shadow in the liver during his physical examination. In January 2019, a computed tomography (CT) scan revealed a 5.0 × 3.0 cm tumor in the uncinate process of the pancreas with hepatic metastases (Fig. 1a). The patient had a family history of cancer: his mother was diagnosed with stomach cancer at the age of 65 years and his father had lung cancer. According to the National Comprehensive Cancer Network (NCCN) Guidelines, the patient first received gemcitabine treatment at a dose of 1.4 g once per week, and nab-paclitaxel at a dose of 200 mg every 2 weeks as a first-line chemotherapy in January 2019 (Fig. 1b). Unfortunately, a CT re-evaluation at 6 weeks post-treatment showed progressive enlargement of both pancreatic and hepatic lesions (Fig. 1a), accompanied with a marked elevation of serum carcinoembryonic antigen (CEA, 270.35 ng/mL) and carbohydrate antigen 19-9 (CA19-9, 352.56 U/mL) levels (Fig. 1c); thus, suggesting that the patient was refractory to treatment and had a PD.Fig. 1 CT images and measurements of serum tumor biomarkers during the course of treatment. a Serial CT scans demonstrated a reduction in the size of the pancreatic (red arrows) and metastatic hepatic lesions (green arrows) following olaparib therapy. b A timeline indicating the application of different therapeutic strategies and the patient’s response. c Measurements of serum CEA and CA19-9 levels at different treatment times. Blue line: CEA; green line: CA19-9; orange arrows: time points of the CT scans. PD progressive disease, PR partial response, SD stable disease
To determine a more effective and appropriate targeted therapy, we performed a targeted NGS analysis of 425 cancer-related genes on the patient’s plasma and tumor tissue biopsy samples. The cancer mutation panel test revealed multiple deleterious somatic mutations, such as the driver mutations, KRAS Q61R (c.182A > G), TP53 R110del (c.329_331delGTC), and APC S1465RfsX9 (c.4393_4394dupAG), and copy number gain of several genes (Table 1). Interestingly, we also observed a novel nonsynonymous BRCA2 c.6944T > C (p. I2315T) point mutation with a mutant allele frequency (MAF) of 28.0% in the plasma and 39.5% in the tumor biopsy specimens. The novel BRCA2 point mutation was not detected in white blood cells, and thus, it was confirmed as a somatic mutation.Table 1 Genetic alterations detected in the patient’s plasma and tumor biopsy specimens
Genes Alternations Nucleotide change MAF (plasma) MAF (tumor)
BRCA2 p. I2315T c.6944T > C 28% 39.5%
KRAS p. Q61R c.182A > G 27.4% 43.2%
TP53 p. R110del c.329_331delGTC 37.4% 81.6%
APC p. S1465RfsX9 c.4393_4394dupAG 26.7% 71.7%
CCNE1 Gene amplification NA 16.0-fold 27.4-fold
CCNE1 IGR (downstream UQCRFS1) ~ CCNE1 fusion NA 0.1% –
PIK3CA Gene amplification NA – 1.9-fold
PKHD1 p. R909X truncation c.2725C > T 4.9% 16.9%
SOX2 Gene amplification NA – 2.0-fold
STMN1 Gene amplification NA – 1.8-fold
TERC Gene amplification NA – 1.9-fold
TUBB3 Gene amplification NA – 2.2-fold
–, not detectable; NA, not applicable; MAF, mutant allele frequency. Gene amplification was presented as the relative fold change to normal controls
Given the clinical efficacy of olaparib in treating BRCA-mutated advanced solid tumors, we decided to revise the therapeutic strategy by administering olaparib at a dose of 150 mg twice per day in combination with a modified FOLFIRINOX regimen (irinotecan at a dose of 100 mg on days 1, 8 and 15; oxaliplatin at a dose of 150 mg on days 1 and 15; S-1 at a dose of 40 mg twice per day from day 1 to day 14) for one cycle beginning in March 2019 (Fig. 1b). However, due to the occurrence of adverse events (e.g., diarrhea, general weakness, fatigue, and loss of appetite) and myelosuppression, including grade 2–3 leukopenia and thrombocytopenia, chemotherapy was not given on day 15 and the frequency of irinotecan was reduced to only be administered on days 1 and 15 in the subsequent treatment. Additionally, megestrol acetate and granulocyte-colony stimulating factor (G-CSF) were prescribed to increase appetite and promote the recovery of myelosuppression. In May 2019, a reduction in the size of both pancreatic and hepatic lesions was revealed by the CT scan, while the levels of the serum tumor biomarkers, CEA (63.38 ng/mL) and CA19-9 (40.53 U/mL) were considerably reduced (Fig. 1a, c). Olaparib and modified FOLFIRINOX were thus continued with irinotecan and oxaliplatin being administered only on day 1 (Fig. 1b). After 2 weeks of treatment, CEA and CA19-9 levels decreased to 32.69 ng/mL and 25.57 U/mL, respectively (Fig. 1c). A CT scan performed in June 2019 showed a significant size reduction in the primary and metastatic tumors, which indicated a partial response (PR, Fig. 1a). Since the patient experienced severe marrow suppression during treatment, only olaparib monotherapy was administered since July 2019 to reduce adverse effects (Fig. 1b). Stable disease (SD) was subsequently observed in August 2019 (Fig. 1a). In September 2019, aside from an increase in CEA and CA19-9 levels (Fig. 1c), laboratory blood tests demonstrated that the patient underwent acquired granulocytopenia, anemia, and thrombocytopenia. Consequently, G-CSF, thrombopoietin, and erythropoietin were administered for symptom management. After olaparib treatment for another 1.5 months, PD was indicated by a CT scan (Fig. 1a). The patient achieved a PFS for ~ 6.5 months following olaparib combination and monotherapy.
Discussion and conclusions
Neoplastic cells lacking a functional homologous recombination repair system, such as those carrying BRCA mutations, are sensitive to PARP inhibition through accumulated DNA damage via multiple mechanisms [6]. As a new therapeutic concept, maintenance olaparib has shown promising results in the treatment of germline BRCA-mutated breast, ovarian, and metastatic pancreatic cancer [7, 10, 11]. To date, the majority of BRCA2 mutations identified in pancreatic cancer were frame-shifting indels (e.g., c.6174delT, c.6158insT) and splice-site mutations. In contrast, single point mutations have been rarely reported [4, 5, 12]. Mesman [13] recently assessed the potential pathogenic impact of a large set of BRCA2 missense variants using a mouse embryonic stem cell (mESC)-based functional assay, and found that BRCA2 missense mutations, such as c.93G > T (p. W31C) and c.8351G > A (p. R2784Q), were able to increase susceptibility to PARP inhibitor treatment.
The patient in our report harbored an unreported BRCA2 point mutation [c.6944T > C (p. I2315T)] located in exon 13 of BRCA2 between the G-CSF. Different germline BRCA2 mutations (e.g., p. I2315V, p. I2315L) at the same site have been documented with unknown functional significance [14, 15]. Although the underlying molecular mechanism(s) by which this novel BRCA2 p. I2315T mutation impairs DNA repair and sensitizes tumor cells to PARP inhibition remains to be elucidated. We postulate that it may be related to a change in the polarity of amino acid residues since isoleucine (I), valine (V) and leucine (L) are all non-polar and hydrophobic, while threonine (T) is hydrophilic. Thus, we hypothesize that the p. I2315T mutation is likely to cause a structural abnormality in the BRCA2 protein, which results in defective DNA double strand break (DSB) repair by homologous recombination (HR) and its sensitivity to olaparib. To test this hypothesis, we attempted to generate a three dimensional (3D) structural model of the BRCA2 p. I2315T mutation, but failed due to the absence of an established crystal structure of the full-length human BRCA2 due to its size and segmental nature [16].
In summary, we report a metastatic pancreatic cancer patient carrying a novel somatic BRCA2 p. I2315T point mutation. Furthermore, advances in NGS technology have provided a solid basis for precise detection of well-known driver mutations, and rare or novel mutations. Thus, NGS may provide clinicians with invaluable information (e.g., BRCA1/2 status of tumors) that can be leveraged for therapeutic decision making, and perform better evaluations of patients’ responses during the course of treatment.
Abbreviations
PARPPoly(ADP-ribose) polymerase
PFSProgression-free survival
PDProgressive disease
DNADeoxyribonucleic acid
POLOPancreas cancer olaparib ongoing
CTComputed tomography
NCCNThe National Comprehensive Cancer Network
CEACarcinoembryonic antigen
CA19-9Carbohydrate antigen 19-9
NGSNext-generation sequencing
MAFMutant allele frequency
FOLFIRINOXFOL-folinic acid, F-fluorouracil, IRIN-irinotecan, OX-oxaliplatin
G-CSFGranulocyte-colony stimulating factor
PRPartial response
mESCMouse embryonic stem cell
DSBsDouble strand breaks
HRHomologous recombination
3DThree dimensional
Publisher's Note
Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
Acknowledgements
We would like to thank the patient for providing written informed consent for publication.
Authors' contributions
XL conceptualized and designed the manuscript. QT and DW carried out patient clinical management, sample collection and drafted the manuscript. RG analyzed the data. SL and MY revised the manuscript. All authors read and approved the final manuscript.
Funding
Supported by the Key Project of Zhenjiang City for Health Science and Technology (SH2016038 and SH2019046), and the Project of Young Medical Talents in Jiangsu Province (QNRC2016829), China. The funding body did not have any role in the study design, data collection and analysis, decision to publish, or preparation of the manuscript.
Availability of data and materials
The datasets generated and/or analysed during the current study are not publicly available in order to protect participant confidentiality but are available from the corresponding author on reasonable request.
Ethics approval and consent to participate
The study protocol was approved by the ethical committee of the Affiliated Hospital of Jiangsu University. Written informed consent was provided by the patient.
Consent for publication
Written informed consent was obtained from the patient for publication of the case and all accompanying tables/images. A copy of the written consent is available for review by the Editor of this journal.
Competing interests
Ruting Guan and Sisi Liu are the employees of Nanjing Geneseeq Technology Inc., China; Man Yu is an employee of Geneseeq Technology Inc., Canada. The remaining authors declare no conflicts of interest. | FLUOROURACIL, GIMERACIL\OTERACIL\TEGAFUR, IRINOTECAN, LEUCOVORIN, OLAPARIB, OXALIPLATIN | DrugsGivenReaction | CC BY | 33407459 | 19,274,581 | 2021-01-06 |
Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Myelosuppression'. | A novel somatic BRCA2 point mutation in a metastatic pancreatic cancer patient: a case report.
In addition to ovarian and breast cancers, loss-of-function mutations in BRCA1 and BRCA2 genes are also linked to an increased risk of pancreatic cancer, with ~ 4 to 7% of pancreatic cancer patients harboring germline BRCA mutations. Most BRCA alterations in pancreatic cancer are frame-shifting indels, stop-gain, and splice-site mutations, but single nucleotide substitutions are rare. Recent studies demonstrated a significant progression-free survival (PFS) benefit from maintenance olaparib, a poly (ADP-ribose) polymerase (PARP) inhibitor administered to patients with germline BRCA mutations and metastatic pancreatic cancer.
Here, we report a metastatic pancreatic cancer case who harbored a novel somatic BRCA2 c.6944T > C (p. I2315T) point mutation. After 6 weeks first-line chemotherapy, the patient was refractory to treatment and had a progressive disease. Due to the novel nonsynonymous BRCA2 point mutation, we decided to change the strategy by administering olaparib. The patient benefited from olaparib therapy and achieved a PFS of ~ 6.5 months.
We describe a patient carrying a novel somatic BRCA2 p. I2315T point mutation, which is first reported in metastatic pancreatic cancer. This case report indicates that a gene mutation-based strategy should be considered in the clinic to provide more effective treatment.
Background
Pancreatic cancer is the 7th leading cause of cancer-related deaths worldwide, with a 5-year survival rate of < 5% [1]. This devastating malignancy is generally diagnosed at metastatic stages in the clinic, indicative of its late detection and biological aggressiveness [1]. Tremendous efforts are ongoing with the aims of discovering early diagnostic markers and novel therapeutic avenues for pancreatic cancer; however, progress is remarkably hindered by the complicated heterogeneity within and between patient tumors.
BRCA1 and BRCA2 are essential players involved in homologous recombination repair of double-strand deoxyribonucleic acid (DNA) breaks [2]. BRCA inactivation due to somatic mutations or BRCA1 promoter methylation have been observed in various cancer types, including a small subgroup of metastatic pancreatic cancer [3–5]. Most BRCA alterations in pancreatic cancer are frame-shifting indels, stop-gain, and splice-site mutations, whereas single nucleotide substitutions are rarely identified [2, 4, 5].
A large body of evidence showed that the poly (ADP-ribose) polymerase (PARP) inhibitors are synthetically lethal in BRCA-mutated tumors with DNA repair defects and displayed potent anti-tumor activity when combined with DNA-damaging agents. Thus, patients carrying germline mutations in BRCA or the various patterns of somatic BRCA mutations that could result in the inactivation of BRCA are sensitive to PARP inhibitors [6].
A recent phase 3 POLO (Pancreas Cancer Olaparib Ongoing) trial demonstrated that the administration of a PARP inhibitor, olaparib, as a maintenance therapy significantly prolonged the median progression-free survival (PFS) of patients with germline BRCA mutations and metastatic pancreatic cancer who had not progressed during platinum-based chemotherapy compared to the placebo arm (7.4 months vs. 3.8 months) [7]. More importantly, olaparib treatment did not compromise health-related quality of life in those patients [8]. However, PARP inhibitor resistance is common due to homologous recombination repair restoration (HRR), epigenetic modification, reversion mutations, restoration of ADP-ribosylation (PARylation), and pharmacological alteration [9].
In this report, we present the case of a metastatic pancreatic cancer patient who had progressive disease (PD) following chemotherapy with gemcitabine and nab-paclitaxel. Mutational profiling analysis using targeted next-generation sequencing (NGS) revealed that the patient carried a novel somatic BRCA2 c.6944T > C (p. I2315T) point mutation. Olaparib was thereby administered in combination with a modified FOLFIRINOX regimen or as a monotherapy. The patient showed a significant response to this treatment strategy and exhibited stable disease and a PFS of ~ 6.5 months was observed.
Case presentation
A 57-year-old Chinese male with no obvious symptoms was admitted to the hospital due to the identification of a low-density shadow in the liver during his physical examination. In January 2019, a computed tomography (CT) scan revealed a 5.0 × 3.0 cm tumor in the uncinate process of the pancreas with hepatic metastases (Fig. 1a). The patient had a family history of cancer: his mother was diagnosed with stomach cancer at the age of 65 years and his father had lung cancer. According to the National Comprehensive Cancer Network (NCCN) Guidelines, the patient first received gemcitabine treatment at a dose of 1.4 g once per week, and nab-paclitaxel at a dose of 200 mg every 2 weeks as a first-line chemotherapy in January 2019 (Fig. 1b). Unfortunately, a CT re-evaluation at 6 weeks post-treatment showed progressive enlargement of both pancreatic and hepatic lesions (Fig. 1a), accompanied with a marked elevation of serum carcinoembryonic antigen (CEA, 270.35 ng/mL) and carbohydrate antigen 19-9 (CA19-9, 352.56 U/mL) levels (Fig. 1c); thus, suggesting that the patient was refractory to treatment and had a PD.Fig. 1 CT images and measurements of serum tumor biomarkers during the course of treatment. a Serial CT scans demonstrated a reduction in the size of the pancreatic (red arrows) and metastatic hepatic lesions (green arrows) following olaparib therapy. b A timeline indicating the application of different therapeutic strategies and the patient’s response. c Measurements of serum CEA and CA19-9 levels at different treatment times. Blue line: CEA; green line: CA19-9; orange arrows: time points of the CT scans. PD progressive disease, PR partial response, SD stable disease
To determine a more effective and appropriate targeted therapy, we performed a targeted NGS analysis of 425 cancer-related genes on the patient’s plasma and tumor tissue biopsy samples. The cancer mutation panel test revealed multiple deleterious somatic mutations, such as the driver mutations, KRAS Q61R (c.182A > G), TP53 R110del (c.329_331delGTC), and APC S1465RfsX9 (c.4393_4394dupAG), and copy number gain of several genes (Table 1). Interestingly, we also observed a novel nonsynonymous BRCA2 c.6944T > C (p. I2315T) point mutation with a mutant allele frequency (MAF) of 28.0% in the plasma and 39.5% in the tumor biopsy specimens. The novel BRCA2 point mutation was not detected in white blood cells, and thus, it was confirmed as a somatic mutation.Table 1 Genetic alterations detected in the patient’s plasma and tumor biopsy specimens
Genes Alternations Nucleotide change MAF (plasma) MAF (tumor)
BRCA2 p. I2315T c.6944T > C 28% 39.5%
KRAS p. Q61R c.182A > G 27.4% 43.2%
TP53 p. R110del c.329_331delGTC 37.4% 81.6%
APC p. S1465RfsX9 c.4393_4394dupAG 26.7% 71.7%
CCNE1 Gene amplification NA 16.0-fold 27.4-fold
CCNE1 IGR (downstream UQCRFS1) ~ CCNE1 fusion NA 0.1% –
PIK3CA Gene amplification NA – 1.9-fold
PKHD1 p. R909X truncation c.2725C > T 4.9% 16.9%
SOX2 Gene amplification NA – 2.0-fold
STMN1 Gene amplification NA – 1.8-fold
TERC Gene amplification NA – 1.9-fold
TUBB3 Gene amplification NA – 2.2-fold
–, not detectable; NA, not applicable; MAF, mutant allele frequency. Gene amplification was presented as the relative fold change to normal controls
Given the clinical efficacy of olaparib in treating BRCA-mutated advanced solid tumors, we decided to revise the therapeutic strategy by administering olaparib at a dose of 150 mg twice per day in combination with a modified FOLFIRINOX regimen (irinotecan at a dose of 100 mg on days 1, 8 and 15; oxaliplatin at a dose of 150 mg on days 1 and 15; S-1 at a dose of 40 mg twice per day from day 1 to day 14) for one cycle beginning in March 2019 (Fig. 1b). However, due to the occurrence of adverse events (e.g., diarrhea, general weakness, fatigue, and loss of appetite) and myelosuppression, including grade 2–3 leukopenia and thrombocytopenia, chemotherapy was not given on day 15 and the frequency of irinotecan was reduced to only be administered on days 1 and 15 in the subsequent treatment. Additionally, megestrol acetate and granulocyte-colony stimulating factor (G-CSF) were prescribed to increase appetite and promote the recovery of myelosuppression. In May 2019, a reduction in the size of both pancreatic and hepatic lesions was revealed by the CT scan, while the levels of the serum tumor biomarkers, CEA (63.38 ng/mL) and CA19-9 (40.53 U/mL) were considerably reduced (Fig. 1a, c). Olaparib and modified FOLFIRINOX were thus continued with irinotecan and oxaliplatin being administered only on day 1 (Fig. 1b). After 2 weeks of treatment, CEA and CA19-9 levels decreased to 32.69 ng/mL and 25.57 U/mL, respectively (Fig. 1c). A CT scan performed in June 2019 showed a significant size reduction in the primary and metastatic tumors, which indicated a partial response (PR, Fig. 1a). Since the patient experienced severe marrow suppression during treatment, only olaparib monotherapy was administered since July 2019 to reduce adverse effects (Fig. 1b). Stable disease (SD) was subsequently observed in August 2019 (Fig. 1a). In September 2019, aside from an increase in CEA and CA19-9 levels (Fig. 1c), laboratory blood tests demonstrated that the patient underwent acquired granulocytopenia, anemia, and thrombocytopenia. Consequently, G-CSF, thrombopoietin, and erythropoietin were administered for symptom management. After olaparib treatment for another 1.5 months, PD was indicated by a CT scan (Fig. 1a). The patient achieved a PFS for ~ 6.5 months following olaparib combination and monotherapy.
Discussion and conclusions
Neoplastic cells lacking a functional homologous recombination repair system, such as those carrying BRCA mutations, are sensitive to PARP inhibition through accumulated DNA damage via multiple mechanisms [6]. As a new therapeutic concept, maintenance olaparib has shown promising results in the treatment of germline BRCA-mutated breast, ovarian, and metastatic pancreatic cancer [7, 10, 11]. To date, the majority of BRCA2 mutations identified in pancreatic cancer were frame-shifting indels (e.g., c.6174delT, c.6158insT) and splice-site mutations. In contrast, single point mutations have been rarely reported [4, 5, 12]. Mesman [13] recently assessed the potential pathogenic impact of a large set of BRCA2 missense variants using a mouse embryonic stem cell (mESC)-based functional assay, and found that BRCA2 missense mutations, such as c.93G > T (p. W31C) and c.8351G > A (p. R2784Q), were able to increase susceptibility to PARP inhibitor treatment.
The patient in our report harbored an unreported BRCA2 point mutation [c.6944T > C (p. I2315T)] located in exon 13 of BRCA2 between the G-CSF. Different germline BRCA2 mutations (e.g., p. I2315V, p. I2315L) at the same site have been documented with unknown functional significance [14, 15]. Although the underlying molecular mechanism(s) by which this novel BRCA2 p. I2315T mutation impairs DNA repair and sensitizes tumor cells to PARP inhibition remains to be elucidated. We postulate that it may be related to a change in the polarity of amino acid residues since isoleucine (I), valine (V) and leucine (L) are all non-polar and hydrophobic, while threonine (T) is hydrophilic. Thus, we hypothesize that the p. I2315T mutation is likely to cause a structural abnormality in the BRCA2 protein, which results in defective DNA double strand break (DSB) repair by homologous recombination (HR) and its sensitivity to olaparib. To test this hypothesis, we attempted to generate a three dimensional (3D) structural model of the BRCA2 p. I2315T mutation, but failed due to the absence of an established crystal structure of the full-length human BRCA2 due to its size and segmental nature [16].
In summary, we report a metastatic pancreatic cancer patient carrying a novel somatic BRCA2 p. I2315T point mutation. Furthermore, advances in NGS technology have provided a solid basis for precise detection of well-known driver mutations, and rare or novel mutations. Thus, NGS may provide clinicians with invaluable information (e.g., BRCA1/2 status of tumors) that can be leveraged for therapeutic decision making, and perform better evaluations of patients’ responses during the course of treatment.
Abbreviations
PARPPoly(ADP-ribose) polymerase
PFSProgression-free survival
PDProgressive disease
DNADeoxyribonucleic acid
POLOPancreas cancer olaparib ongoing
CTComputed tomography
NCCNThe National Comprehensive Cancer Network
CEACarcinoembryonic antigen
CA19-9Carbohydrate antigen 19-9
NGSNext-generation sequencing
MAFMutant allele frequency
FOLFIRINOXFOL-folinic acid, F-fluorouracil, IRIN-irinotecan, OX-oxaliplatin
G-CSFGranulocyte-colony stimulating factor
PRPartial response
mESCMouse embryonic stem cell
DSBsDouble strand breaks
HRHomologous recombination
3DThree dimensional
Publisher's Note
Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
Acknowledgements
We would like to thank the patient for providing written informed consent for publication.
Authors' contributions
XL conceptualized and designed the manuscript. QT and DW carried out patient clinical management, sample collection and drafted the manuscript. RG analyzed the data. SL and MY revised the manuscript. All authors read and approved the final manuscript.
Funding
Supported by the Key Project of Zhenjiang City for Health Science and Technology (SH2016038 and SH2019046), and the Project of Young Medical Talents in Jiangsu Province (QNRC2016829), China. The funding body did not have any role in the study design, data collection and analysis, decision to publish, or preparation of the manuscript.
Availability of data and materials
The datasets generated and/or analysed during the current study are not publicly available in order to protect participant confidentiality but are available from the corresponding author on reasonable request.
Ethics approval and consent to participate
The study protocol was approved by the ethical committee of the Affiliated Hospital of Jiangsu University. Written informed consent was provided by the patient.
Consent for publication
Written informed consent was obtained from the patient for publication of the case and all accompanying tables/images. A copy of the written consent is available for review by the Editor of this journal.
Competing interests
Ruting Guan and Sisi Liu are the employees of Nanjing Geneseeq Technology Inc., China; Man Yu is an employee of Geneseeq Technology Inc., Canada. The remaining authors declare no conflicts of interest. | FLUOROURACIL, GIMERACIL\OTERACIL\TEGAFUR, IRINOTECAN, LEUCOVORIN, OLAPARIB, OXALIPLATIN | DrugsGivenReaction | CC BY | 33407459 | 19,274,581 | 2021-01-06 |
Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Thrombocytopenia'. | A novel somatic BRCA2 point mutation in a metastatic pancreatic cancer patient: a case report.
In addition to ovarian and breast cancers, loss-of-function mutations in BRCA1 and BRCA2 genes are also linked to an increased risk of pancreatic cancer, with ~ 4 to 7% of pancreatic cancer patients harboring germline BRCA mutations. Most BRCA alterations in pancreatic cancer are frame-shifting indels, stop-gain, and splice-site mutations, but single nucleotide substitutions are rare. Recent studies demonstrated a significant progression-free survival (PFS) benefit from maintenance olaparib, a poly (ADP-ribose) polymerase (PARP) inhibitor administered to patients with germline BRCA mutations and metastatic pancreatic cancer.
Here, we report a metastatic pancreatic cancer case who harbored a novel somatic BRCA2 c.6944T > C (p. I2315T) point mutation. After 6 weeks first-line chemotherapy, the patient was refractory to treatment and had a progressive disease. Due to the novel nonsynonymous BRCA2 point mutation, we decided to change the strategy by administering olaparib. The patient benefited from olaparib therapy and achieved a PFS of ~ 6.5 months.
We describe a patient carrying a novel somatic BRCA2 p. I2315T point mutation, which is first reported in metastatic pancreatic cancer. This case report indicates that a gene mutation-based strategy should be considered in the clinic to provide more effective treatment.
Background
Pancreatic cancer is the 7th leading cause of cancer-related deaths worldwide, with a 5-year survival rate of < 5% [1]. This devastating malignancy is generally diagnosed at metastatic stages in the clinic, indicative of its late detection and biological aggressiveness [1]. Tremendous efforts are ongoing with the aims of discovering early diagnostic markers and novel therapeutic avenues for pancreatic cancer; however, progress is remarkably hindered by the complicated heterogeneity within and between patient tumors.
BRCA1 and BRCA2 are essential players involved in homologous recombination repair of double-strand deoxyribonucleic acid (DNA) breaks [2]. BRCA inactivation due to somatic mutations or BRCA1 promoter methylation have been observed in various cancer types, including a small subgroup of metastatic pancreatic cancer [3–5]. Most BRCA alterations in pancreatic cancer are frame-shifting indels, stop-gain, and splice-site mutations, whereas single nucleotide substitutions are rarely identified [2, 4, 5].
A large body of evidence showed that the poly (ADP-ribose) polymerase (PARP) inhibitors are synthetically lethal in BRCA-mutated tumors with DNA repair defects and displayed potent anti-tumor activity when combined with DNA-damaging agents. Thus, patients carrying germline mutations in BRCA or the various patterns of somatic BRCA mutations that could result in the inactivation of BRCA are sensitive to PARP inhibitors [6].
A recent phase 3 POLO (Pancreas Cancer Olaparib Ongoing) trial demonstrated that the administration of a PARP inhibitor, olaparib, as a maintenance therapy significantly prolonged the median progression-free survival (PFS) of patients with germline BRCA mutations and metastatic pancreatic cancer who had not progressed during platinum-based chemotherapy compared to the placebo arm (7.4 months vs. 3.8 months) [7]. More importantly, olaparib treatment did not compromise health-related quality of life in those patients [8]. However, PARP inhibitor resistance is common due to homologous recombination repair restoration (HRR), epigenetic modification, reversion mutations, restoration of ADP-ribosylation (PARylation), and pharmacological alteration [9].
In this report, we present the case of a metastatic pancreatic cancer patient who had progressive disease (PD) following chemotherapy with gemcitabine and nab-paclitaxel. Mutational profiling analysis using targeted next-generation sequencing (NGS) revealed that the patient carried a novel somatic BRCA2 c.6944T > C (p. I2315T) point mutation. Olaparib was thereby administered in combination with a modified FOLFIRINOX regimen or as a monotherapy. The patient showed a significant response to this treatment strategy and exhibited stable disease and a PFS of ~ 6.5 months was observed.
Case presentation
A 57-year-old Chinese male with no obvious symptoms was admitted to the hospital due to the identification of a low-density shadow in the liver during his physical examination. In January 2019, a computed tomography (CT) scan revealed a 5.0 × 3.0 cm tumor in the uncinate process of the pancreas with hepatic metastases (Fig. 1a). The patient had a family history of cancer: his mother was diagnosed with stomach cancer at the age of 65 years and his father had lung cancer. According to the National Comprehensive Cancer Network (NCCN) Guidelines, the patient first received gemcitabine treatment at a dose of 1.4 g once per week, and nab-paclitaxel at a dose of 200 mg every 2 weeks as a first-line chemotherapy in January 2019 (Fig. 1b). Unfortunately, a CT re-evaluation at 6 weeks post-treatment showed progressive enlargement of both pancreatic and hepatic lesions (Fig. 1a), accompanied with a marked elevation of serum carcinoembryonic antigen (CEA, 270.35 ng/mL) and carbohydrate antigen 19-9 (CA19-9, 352.56 U/mL) levels (Fig. 1c); thus, suggesting that the patient was refractory to treatment and had a PD.Fig. 1 CT images and measurements of serum tumor biomarkers during the course of treatment. a Serial CT scans demonstrated a reduction in the size of the pancreatic (red arrows) and metastatic hepatic lesions (green arrows) following olaparib therapy. b A timeline indicating the application of different therapeutic strategies and the patient’s response. c Measurements of serum CEA and CA19-9 levels at different treatment times. Blue line: CEA; green line: CA19-9; orange arrows: time points of the CT scans. PD progressive disease, PR partial response, SD stable disease
To determine a more effective and appropriate targeted therapy, we performed a targeted NGS analysis of 425 cancer-related genes on the patient’s plasma and tumor tissue biopsy samples. The cancer mutation panel test revealed multiple deleterious somatic mutations, such as the driver mutations, KRAS Q61R (c.182A > G), TP53 R110del (c.329_331delGTC), and APC S1465RfsX9 (c.4393_4394dupAG), and copy number gain of several genes (Table 1). Interestingly, we also observed a novel nonsynonymous BRCA2 c.6944T > C (p. I2315T) point mutation with a mutant allele frequency (MAF) of 28.0% in the plasma and 39.5% in the tumor biopsy specimens. The novel BRCA2 point mutation was not detected in white blood cells, and thus, it was confirmed as a somatic mutation.Table 1 Genetic alterations detected in the patient’s plasma and tumor biopsy specimens
Genes Alternations Nucleotide change MAF (plasma) MAF (tumor)
BRCA2 p. I2315T c.6944T > C 28% 39.5%
KRAS p. Q61R c.182A > G 27.4% 43.2%
TP53 p. R110del c.329_331delGTC 37.4% 81.6%
APC p. S1465RfsX9 c.4393_4394dupAG 26.7% 71.7%
CCNE1 Gene amplification NA 16.0-fold 27.4-fold
CCNE1 IGR (downstream UQCRFS1) ~ CCNE1 fusion NA 0.1% –
PIK3CA Gene amplification NA – 1.9-fold
PKHD1 p. R909X truncation c.2725C > T 4.9% 16.9%
SOX2 Gene amplification NA – 2.0-fold
STMN1 Gene amplification NA – 1.8-fold
TERC Gene amplification NA – 1.9-fold
TUBB3 Gene amplification NA – 2.2-fold
–, not detectable; NA, not applicable; MAF, mutant allele frequency. Gene amplification was presented as the relative fold change to normal controls
Given the clinical efficacy of olaparib in treating BRCA-mutated advanced solid tumors, we decided to revise the therapeutic strategy by administering olaparib at a dose of 150 mg twice per day in combination with a modified FOLFIRINOX regimen (irinotecan at a dose of 100 mg on days 1, 8 and 15; oxaliplatin at a dose of 150 mg on days 1 and 15; S-1 at a dose of 40 mg twice per day from day 1 to day 14) for one cycle beginning in March 2019 (Fig. 1b). However, due to the occurrence of adverse events (e.g., diarrhea, general weakness, fatigue, and loss of appetite) and myelosuppression, including grade 2–3 leukopenia and thrombocytopenia, chemotherapy was not given on day 15 and the frequency of irinotecan was reduced to only be administered on days 1 and 15 in the subsequent treatment. Additionally, megestrol acetate and granulocyte-colony stimulating factor (G-CSF) were prescribed to increase appetite and promote the recovery of myelosuppression. In May 2019, a reduction in the size of both pancreatic and hepatic lesions was revealed by the CT scan, while the levels of the serum tumor biomarkers, CEA (63.38 ng/mL) and CA19-9 (40.53 U/mL) were considerably reduced (Fig. 1a, c). Olaparib and modified FOLFIRINOX were thus continued with irinotecan and oxaliplatin being administered only on day 1 (Fig. 1b). After 2 weeks of treatment, CEA and CA19-9 levels decreased to 32.69 ng/mL and 25.57 U/mL, respectively (Fig. 1c). A CT scan performed in June 2019 showed a significant size reduction in the primary and metastatic tumors, which indicated a partial response (PR, Fig. 1a). Since the patient experienced severe marrow suppression during treatment, only olaparib monotherapy was administered since July 2019 to reduce adverse effects (Fig. 1b). Stable disease (SD) was subsequently observed in August 2019 (Fig. 1a). In September 2019, aside from an increase in CEA and CA19-9 levels (Fig. 1c), laboratory blood tests demonstrated that the patient underwent acquired granulocytopenia, anemia, and thrombocytopenia. Consequently, G-CSF, thrombopoietin, and erythropoietin were administered for symptom management. After olaparib treatment for another 1.5 months, PD was indicated by a CT scan (Fig. 1a). The patient achieved a PFS for ~ 6.5 months following olaparib combination and monotherapy.
Discussion and conclusions
Neoplastic cells lacking a functional homologous recombination repair system, such as those carrying BRCA mutations, are sensitive to PARP inhibition through accumulated DNA damage via multiple mechanisms [6]. As a new therapeutic concept, maintenance olaparib has shown promising results in the treatment of germline BRCA-mutated breast, ovarian, and metastatic pancreatic cancer [7, 10, 11]. To date, the majority of BRCA2 mutations identified in pancreatic cancer were frame-shifting indels (e.g., c.6174delT, c.6158insT) and splice-site mutations. In contrast, single point mutations have been rarely reported [4, 5, 12]. Mesman [13] recently assessed the potential pathogenic impact of a large set of BRCA2 missense variants using a mouse embryonic stem cell (mESC)-based functional assay, and found that BRCA2 missense mutations, such as c.93G > T (p. W31C) and c.8351G > A (p. R2784Q), were able to increase susceptibility to PARP inhibitor treatment.
The patient in our report harbored an unreported BRCA2 point mutation [c.6944T > C (p. I2315T)] located in exon 13 of BRCA2 between the G-CSF. Different germline BRCA2 mutations (e.g., p. I2315V, p. I2315L) at the same site have been documented with unknown functional significance [14, 15]. Although the underlying molecular mechanism(s) by which this novel BRCA2 p. I2315T mutation impairs DNA repair and sensitizes tumor cells to PARP inhibition remains to be elucidated. We postulate that it may be related to a change in the polarity of amino acid residues since isoleucine (I), valine (V) and leucine (L) are all non-polar and hydrophobic, while threonine (T) is hydrophilic. Thus, we hypothesize that the p. I2315T mutation is likely to cause a structural abnormality in the BRCA2 protein, which results in defective DNA double strand break (DSB) repair by homologous recombination (HR) and its sensitivity to olaparib. To test this hypothesis, we attempted to generate a three dimensional (3D) structural model of the BRCA2 p. I2315T mutation, but failed due to the absence of an established crystal structure of the full-length human BRCA2 due to its size and segmental nature [16].
In summary, we report a metastatic pancreatic cancer patient carrying a novel somatic BRCA2 p. I2315T point mutation. Furthermore, advances in NGS technology have provided a solid basis for precise detection of well-known driver mutations, and rare or novel mutations. Thus, NGS may provide clinicians with invaluable information (e.g., BRCA1/2 status of tumors) that can be leveraged for therapeutic decision making, and perform better evaluations of patients’ responses during the course of treatment.
Abbreviations
PARPPoly(ADP-ribose) polymerase
PFSProgression-free survival
PDProgressive disease
DNADeoxyribonucleic acid
POLOPancreas cancer olaparib ongoing
CTComputed tomography
NCCNThe National Comprehensive Cancer Network
CEACarcinoembryonic antigen
CA19-9Carbohydrate antigen 19-9
NGSNext-generation sequencing
MAFMutant allele frequency
FOLFIRINOXFOL-folinic acid, F-fluorouracil, IRIN-irinotecan, OX-oxaliplatin
G-CSFGranulocyte-colony stimulating factor
PRPartial response
mESCMouse embryonic stem cell
DSBsDouble strand breaks
HRHomologous recombination
3DThree dimensional
Publisher's Note
Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
Acknowledgements
We would like to thank the patient for providing written informed consent for publication.
Authors' contributions
XL conceptualized and designed the manuscript. QT and DW carried out patient clinical management, sample collection and drafted the manuscript. RG analyzed the data. SL and MY revised the manuscript. All authors read and approved the final manuscript.
Funding
Supported by the Key Project of Zhenjiang City for Health Science and Technology (SH2016038 and SH2019046), and the Project of Young Medical Talents in Jiangsu Province (QNRC2016829), China. The funding body did not have any role in the study design, data collection and analysis, decision to publish, or preparation of the manuscript.
Availability of data and materials
The datasets generated and/or analysed during the current study are not publicly available in order to protect participant confidentiality but are available from the corresponding author on reasonable request.
Ethics approval and consent to participate
The study protocol was approved by the ethical committee of the Affiliated Hospital of Jiangsu University. Written informed consent was provided by the patient.
Consent for publication
Written informed consent was obtained from the patient for publication of the case and all accompanying tables/images. A copy of the written consent is available for review by the Editor of this journal.
Competing interests
Ruting Guan and Sisi Liu are the employees of Nanjing Geneseeq Technology Inc., China; Man Yu is an employee of Geneseeq Technology Inc., Canada. The remaining authors declare no conflicts of interest. | FLUOROURACIL, GIMERACIL\OTERACIL\TEGAFUR, IRINOTECAN, LEUCOVORIN, OLAPARIB, OXALIPLATIN | DrugsGivenReaction | CC BY | 33407459 | 19,274,581 | 2021-01-06 |
What was the dosage of drug 'GIMERACIL\OTERACIL\TEGAFUR'? | A novel somatic BRCA2 point mutation in a metastatic pancreatic cancer patient: a case report.
In addition to ovarian and breast cancers, loss-of-function mutations in BRCA1 and BRCA2 genes are also linked to an increased risk of pancreatic cancer, with ~ 4 to 7% of pancreatic cancer patients harboring germline BRCA mutations. Most BRCA alterations in pancreatic cancer are frame-shifting indels, stop-gain, and splice-site mutations, but single nucleotide substitutions are rare. Recent studies demonstrated a significant progression-free survival (PFS) benefit from maintenance olaparib, a poly (ADP-ribose) polymerase (PARP) inhibitor administered to patients with germline BRCA mutations and metastatic pancreatic cancer.
Here, we report a metastatic pancreatic cancer case who harbored a novel somatic BRCA2 c.6944T > C (p. I2315T) point mutation. After 6 weeks first-line chemotherapy, the patient was refractory to treatment and had a progressive disease. Due to the novel nonsynonymous BRCA2 point mutation, we decided to change the strategy by administering olaparib. The patient benefited from olaparib therapy and achieved a PFS of ~ 6.5 months.
We describe a patient carrying a novel somatic BRCA2 p. I2315T point mutation, which is first reported in metastatic pancreatic cancer. This case report indicates that a gene mutation-based strategy should be considered in the clinic to provide more effective treatment.
Background
Pancreatic cancer is the 7th leading cause of cancer-related deaths worldwide, with a 5-year survival rate of < 5% [1]. This devastating malignancy is generally diagnosed at metastatic stages in the clinic, indicative of its late detection and biological aggressiveness [1]. Tremendous efforts are ongoing with the aims of discovering early diagnostic markers and novel therapeutic avenues for pancreatic cancer; however, progress is remarkably hindered by the complicated heterogeneity within and between patient tumors.
BRCA1 and BRCA2 are essential players involved in homologous recombination repair of double-strand deoxyribonucleic acid (DNA) breaks [2]. BRCA inactivation due to somatic mutations or BRCA1 promoter methylation have been observed in various cancer types, including a small subgroup of metastatic pancreatic cancer [3–5]. Most BRCA alterations in pancreatic cancer are frame-shifting indels, stop-gain, and splice-site mutations, whereas single nucleotide substitutions are rarely identified [2, 4, 5].
A large body of evidence showed that the poly (ADP-ribose) polymerase (PARP) inhibitors are synthetically lethal in BRCA-mutated tumors with DNA repair defects and displayed potent anti-tumor activity when combined with DNA-damaging agents. Thus, patients carrying germline mutations in BRCA or the various patterns of somatic BRCA mutations that could result in the inactivation of BRCA are sensitive to PARP inhibitors [6].
A recent phase 3 POLO (Pancreas Cancer Olaparib Ongoing) trial demonstrated that the administration of a PARP inhibitor, olaparib, as a maintenance therapy significantly prolonged the median progression-free survival (PFS) of patients with germline BRCA mutations and metastatic pancreatic cancer who had not progressed during platinum-based chemotherapy compared to the placebo arm (7.4 months vs. 3.8 months) [7]. More importantly, olaparib treatment did not compromise health-related quality of life in those patients [8]. However, PARP inhibitor resistance is common due to homologous recombination repair restoration (HRR), epigenetic modification, reversion mutations, restoration of ADP-ribosylation (PARylation), and pharmacological alteration [9].
In this report, we present the case of a metastatic pancreatic cancer patient who had progressive disease (PD) following chemotherapy with gemcitabine and nab-paclitaxel. Mutational profiling analysis using targeted next-generation sequencing (NGS) revealed that the patient carried a novel somatic BRCA2 c.6944T > C (p. I2315T) point mutation. Olaparib was thereby administered in combination with a modified FOLFIRINOX regimen or as a monotherapy. The patient showed a significant response to this treatment strategy and exhibited stable disease and a PFS of ~ 6.5 months was observed.
Case presentation
A 57-year-old Chinese male with no obvious symptoms was admitted to the hospital due to the identification of a low-density shadow in the liver during his physical examination. In January 2019, a computed tomography (CT) scan revealed a 5.0 × 3.0 cm tumor in the uncinate process of the pancreas with hepatic metastases (Fig. 1a). The patient had a family history of cancer: his mother was diagnosed with stomach cancer at the age of 65 years and his father had lung cancer. According to the National Comprehensive Cancer Network (NCCN) Guidelines, the patient first received gemcitabine treatment at a dose of 1.4 g once per week, and nab-paclitaxel at a dose of 200 mg every 2 weeks as a first-line chemotherapy in January 2019 (Fig. 1b). Unfortunately, a CT re-evaluation at 6 weeks post-treatment showed progressive enlargement of both pancreatic and hepatic lesions (Fig. 1a), accompanied with a marked elevation of serum carcinoembryonic antigen (CEA, 270.35 ng/mL) and carbohydrate antigen 19-9 (CA19-9, 352.56 U/mL) levels (Fig. 1c); thus, suggesting that the patient was refractory to treatment and had a PD.Fig. 1 CT images and measurements of serum tumor biomarkers during the course of treatment. a Serial CT scans demonstrated a reduction in the size of the pancreatic (red arrows) and metastatic hepatic lesions (green arrows) following olaparib therapy. b A timeline indicating the application of different therapeutic strategies and the patient’s response. c Measurements of serum CEA and CA19-9 levels at different treatment times. Blue line: CEA; green line: CA19-9; orange arrows: time points of the CT scans. PD progressive disease, PR partial response, SD stable disease
To determine a more effective and appropriate targeted therapy, we performed a targeted NGS analysis of 425 cancer-related genes on the patient’s plasma and tumor tissue biopsy samples. The cancer mutation panel test revealed multiple deleterious somatic mutations, such as the driver mutations, KRAS Q61R (c.182A > G), TP53 R110del (c.329_331delGTC), and APC S1465RfsX9 (c.4393_4394dupAG), and copy number gain of several genes (Table 1). Interestingly, we also observed a novel nonsynonymous BRCA2 c.6944T > C (p. I2315T) point mutation with a mutant allele frequency (MAF) of 28.0% in the plasma and 39.5% in the tumor biopsy specimens. The novel BRCA2 point mutation was not detected in white blood cells, and thus, it was confirmed as a somatic mutation.Table 1 Genetic alterations detected in the patient’s plasma and tumor biopsy specimens
Genes Alternations Nucleotide change MAF (plasma) MAF (tumor)
BRCA2 p. I2315T c.6944T > C 28% 39.5%
KRAS p. Q61R c.182A > G 27.4% 43.2%
TP53 p. R110del c.329_331delGTC 37.4% 81.6%
APC p. S1465RfsX9 c.4393_4394dupAG 26.7% 71.7%
CCNE1 Gene amplification NA 16.0-fold 27.4-fold
CCNE1 IGR (downstream UQCRFS1) ~ CCNE1 fusion NA 0.1% –
PIK3CA Gene amplification NA – 1.9-fold
PKHD1 p. R909X truncation c.2725C > T 4.9% 16.9%
SOX2 Gene amplification NA – 2.0-fold
STMN1 Gene amplification NA – 1.8-fold
TERC Gene amplification NA – 1.9-fold
TUBB3 Gene amplification NA – 2.2-fold
–, not detectable; NA, not applicable; MAF, mutant allele frequency. Gene amplification was presented as the relative fold change to normal controls
Given the clinical efficacy of olaparib in treating BRCA-mutated advanced solid tumors, we decided to revise the therapeutic strategy by administering olaparib at a dose of 150 mg twice per day in combination with a modified FOLFIRINOX regimen (irinotecan at a dose of 100 mg on days 1, 8 and 15; oxaliplatin at a dose of 150 mg on days 1 and 15; S-1 at a dose of 40 mg twice per day from day 1 to day 14) for one cycle beginning in March 2019 (Fig. 1b). However, due to the occurrence of adverse events (e.g., diarrhea, general weakness, fatigue, and loss of appetite) and myelosuppression, including grade 2–3 leukopenia and thrombocytopenia, chemotherapy was not given on day 15 and the frequency of irinotecan was reduced to only be administered on days 1 and 15 in the subsequent treatment. Additionally, megestrol acetate and granulocyte-colony stimulating factor (G-CSF) were prescribed to increase appetite and promote the recovery of myelosuppression. In May 2019, a reduction in the size of both pancreatic and hepatic lesions was revealed by the CT scan, while the levels of the serum tumor biomarkers, CEA (63.38 ng/mL) and CA19-9 (40.53 U/mL) were considerably reduced (Fig. 1a, c). Olaparib and modified FOLFIRINOX were thus continued with irinotecan and oxaliplatin being administered only on day 1 (Fig. 1b). After 2 weeks of treatment, CEA and CA19-9 levels decreased to 32.69 ng/mL and 25.57 U/mL, respectively (Fig. 1c). A CT scan performed in June 2019 showed a significant size reduction in the primary and metastatic tumors, which indicated a partial response (PR, Fig. 1a). Since the patient experienced severe marrow suppression during treatment, only olaparib monotherapy was administered since July 2019 to reduce adverse effects (Fig. 1b). Stable disease (SD) was subsequently observed in August 2019 (Fig. 1a). In September 2019, aside from an increase in CEA and CA19-9 levels (Fig. 1c), laboratory blood tests demonstrated that the patient underwent acquired granulocytopenia, anemia, and thrombocytopenia. Consequently, G-CSF, thrombopoietin, and erythropoietin were administered for symptom management. After olaparib treatment for another 1.5 months, PD was indicated by a CT scan (Fig. 1a). The patient achieved a PFS for ~ 6.5 months following olaparib combination and monotherapy.
Discussion and conclusions
Neoplastic cells lacking a functional homologous recombination repair system, such as those carrying BRCA mutations, are sensitive to PARP inhibition through accumulated DNA damage via multiple mechanisms [6]. As a new therapeutic concept, maintenance olaparib has shown promising results in the treatment of germline BRCA-mutated breast, ovarian, and metastatic pancreatic cancer [7, 10, 11]. To date, the majority of BRCA2 mutations identified in pancreatic cancer were frame-shifting indels (e.g., c.6174delT, c.6158insT) and splice-site mutations. In contrast, single point mutations have been rarely reported [4, 5, 12]. Mesman [13] recently assessed the potential pathogenic impact of a large set of BRCA2 missense variants using a mouse embryonic stem cell (mESC)-based functional assay, and found that BRCA2 missense mutations, such as c.93G > T (p. W31C) and c.8351G > A (p. R2784Q), were able to increase susceptibility to PARP inhibitor treatment.
The patient in our report harbored an unreported BRCA2 point mutation [c.6944T > C (p. I2315T)] located in exon 13 of BRCA2 between the G-CSF. Different germline BRCA2 mutations (e.g., p. I2315V, p. I2315L) at the same site have been documented with unknown functional significance [14, 15]. Although the underlying molecular mechanism(s) by which this novel BRCA2 p. I2315T mutation impairs DNA repair and sensitizes tumor cells to PARP inhibition remains to be elucidated. We postulate that it may be related to a change in the polarity of amino acid residues since isoleucine (I), valine (V) and leucine (L) are all non-polar and hydrophobic, while threonine (T) is hydrophilic. Thus, we hypothesize that the p. I2315T mutation is likely to cause a structural abnormality in the BRCA2 protein, which results in defective DNA double strand break (DSB) repair by homologous recombination (HR) and its sensitivity to olaparib. To test this hypothesis, we attempted to generate a three dimensional (3D) structural model of the BRCA2 p. I2315T mutation, but failed due to the absence of an established crystal structure of the full-length human BRCA2 due to its size and segmental nature [16].
In summary, we report a metastatic pancreatic cancer patient carrying a novel somatic BRCA2 p. I2315T point mutation. Furthermore, advances in NGS technology have provided a solid basis for precise detection of well-known driver mutations, and rare or novel mutations. Thus, NGS may provide clinicians with invaluable information (e.g., BRCA1/2 status of tumors) that can be leveraged for therapeutic decision making, and perform better evaluations of patients’ responses during the course of treatment.
Abbreviations
PARPPoly(ADP-ribose) polymerase
PFSProgression-free survival
PDProgressive disease
DNADeoxyribonucleic acid
POLOPancreas cancer olaparib ongoing
CTComputed tomography
NCCNThe National Comprehensive Cancer Network
CEACarcinoembryonic antigen
CA19-9Carbohydrate antigen 19-9
NGSNext-generation sequencing
MAFMutant allele frequency
FOLFIRINOXFOL-folinic acid, F-fluorouracil, IRIN-irinotecan, OX-oxaliplatin
G-CSFGranulocyte-colony stimulating factor
PRPartial response
mESCMouse embryonic stem cell
DSBsDouble strand breaks
HRHomologous recombination
3DThree dimensional
Publisher's Note
Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
Acknowledgements
We would like to thank the patient for providing written informed consent for publication.
Authors' contributions
XL conceptualized and designed the manuscript. QT and DW carried out patient clinical management, sample collection and drafted the manuscript. RG analyzed the data. SL and MY revised the manuscript. All authors read and approved the final manuscript.
Funding
Supported by the Key Project of Zhenjiang City for Health Science and Technology (SH2016038 and SH2019046), and the Project of Young Medical Talents in Jiangsu Province (QNRC2016829), China. The funding body did not have any role in the study design, data collection and analysis, decision to publish, or preparation of the manuscript.
Availability of data and materials
The datasets generated and/or analysed during the current study are not publicly available in order to protect participant confidentiality but are available from the corresponding author on reasonable request.
Ethics approval and consent to participate
The study protocol was approved by the ethical committee of the Affiliated Hospital of Jiangsu University. Written informed consent was provided by the patient.
Consent for publication
Written informed consent was obtained from the patient for publication of the case and all accompanying tables/images. A copy of the written consent is available for review by the Editor of this journal.
Competing interests
Ruting Guan and Sisi Liu are the employees of Nanjing Geneseeq Technology Inc., China; Man Yu is an employee of Geneseeq Technology Inc., Canada. The remaining authors declare no conflicts of interest. | 40 MG TWICE PER DAY FROM DAY 1 TODAY 14 | DrugDosageText | CC BY | 33407459 | 19,274,581 | 2021-01-06 |
What was the dosage of drug 'OLAPARIB'? | A novel somatic BRCA2 point mutation in a metastatic pancreatic cancer patient: a case report.
In addition to ovarian and breast cancers, loss-of-function mutations in BRCA1 and BRCA2 genes are also linked to an increased risk of pancreatic cancer, with ~ 4 to 7% of pancreatic cancer patients harboring germline BRCA mutations. Most BRCA alterations in pancreatic cancer are frame-shifting indels, stop-gain, and splice-site mutations, but single nucleotide substitutions are rare. Recent studies demonstrated a significant progression-free survival (PFS) benefit from maintenance olaparib, a poly (ADP-ribose) polymerase (PARP) inhibitor administered to patients with germline BRCA mutations and metastatic pancreatic cancer.
Here, we report a metastatic pancreatic cancer case who harbored a novel somatic BRCA2 c.6944T > C (p. I2315T) point mutation. After 6 weeks first-line chemotherapy, the patient was refractory to treatment and had a progressive disease. Due to the novel nonsynonymous BRCA2 point mutation, we decided to change the strategy by administering olaparib. The patient benefited from olaparib therapy and achieved a PFS of ~ 6.5 months.
We describe a patient carrying a novel somatic BRCA2 p. I2315T point mutation, which is first reported in metastatic pancreatic cancer. This case report indicates that a gene mutation-based strategy should be considered in the clinic to provide more effective treatment.
Background
Pancreatic cancer is the 7th leading cause of cancer-related deaths worldwide, with a 5-year survival rate of < 5% [1]. This devastating malignancy is generally diagnosed at metastatic stages in the clinic, indicative of its late detection and biological aggressiveness [1]. Tremendous efforts are ongoing with the aims of discovering early diagnostic markers and novel therapeutic avenues for pancreatic cancer; however, progress is remarkably hindered by the complicated heterogeneity within and between patient tumors.
BRCA1 and BRCA2 are essential players involved in homologous recombination repair of double-strand deoxyribonucleic acid (DNA) breaks [2]. BRCA inactivation due to somatic mutations or BRCA1 promoter methylation have been observed in various cancer types, including a small subgroup of metastatic pancreatic cancer [3–5]. Most BRCA alterations in pancreatic cancer are frame-shifting indels, stop-gain, and splice-site mutations, whereas single nucleotide substitutions are rarely identified [2, 4, 5].
A large body of evidence showed that the poly (ADP-ribose) polymerase (PARP) inhibitors are synthetically lethal in BRCA-mutated tumors with DNA repair defects and displayed potent anti-tumor activity when combined with DNA-damaging agents. Thus, patients carrying germline mutations in BRCA or the various patterns of somatic BRCA mutations that could result in the inactivation of BRCA are sensitive to PARP inhibitors [6].
A recent phase 3 POLO (Pancreas Cancer Olaparib Ongoing) trial demonstrated that the administration of a PARP inhibitor, olaparib, as a maintenance therapy significantly prolonged the median progression-free survival (PFS) of patients with germline BRCA mutations and metastatic pancreatic cancer who had not progressed during platinum-based chemotherapy compared to the placebo arm (7.4 months vs. 3.8 months) [7]. More importantly, olaparib treatment did not compromise health-related quality of life in those patients [8]. However, PARP inhibitor resistance is common due to homologous recombination repair restoration (HRR), epigenetic modification, reversion mutations, restoration of ADP-ribosylation (PARylation), and pharmacological alteration [9].
In this report, we present the case of a metastatic pancreatic cancer patient who had progressive disease (PD) following chemotherapy with gemcitabine and nab-paclitaxel. Mutational profiling analysis using targeted next-generation sequencing (NGS) revealed that the patient carried a novel somatic BRCA2 c.6944T > C (p. I2315T) point mutation. Olaparib was thereby administered in combination with a modified FOLFIRINOX regimen or as a monotherapy. The patient showed a significant response to this treatment strategy and exhibited stable disease and a PFS of ~ 6.5 months was observed.
Case presentation
A 57-year-old Chinese male with no obvious symptoms was admitted to the hospital due to the identification of a low-density shadow in the liver during his physical examination. In January 2019, a computed tomography (CT) scan revealed a 5.0 × 3.0 cm tumor in the uncinate process of the pancreas with hepatic metastases (Fig. 1a). The patient had a family history of cancer: his mother was diagnosed with stomach cancer at the age of 65 years and his father had lung cancer. According to the National Comprehensive Cancer Network (NCCN) Guidelines, the patient first received gemcitabine treatment at a dose of 1.4 g once per week, and nab-paclitaxel at a dose of 200 mg every 2 weeks as a first-line chemotherapy in January 2019 (Fig. 1b). Unfortunately, a CT re-evaluation at 6 weeks post-treatment showed progressive enlargement of both pancreatic and hepatic lesions (Fig. 1a), accompanied with a marked elevation of serum carcinoembryonic antigen (CEA, 270.35 ng/mL) and carbohydrate antigen 19-9 (CA19-9, 352.56 U/mL) levels (Fig. 1c); thus, suggesting that the patient was refractory to treatment and had a PD.Fig. 1 CT images and measurements of serum tumor biomarkers during the course of treatment. a Serial CT scans demonstrated a reduction in the size of the pancreatic (red arrows) and metastatic hepatic lesions (green arrows) following olaparib therapy. b A timeline indicating the application of different therapeutic strategies and the patient’s response. c Measurements of serum CEA and CA19-9 levels at different treatment times. Blue line: CEA; green line: CA19-9; orange arrows: time points of the CT scans. PD progressive disease, PR partial response, SD stable disease
To determine a more effective and appropriate targeted therapy, we performed a targeted NGS analysis of 425 cancer-related genes on the patient’s plasma and tumor tissue biopsy samples. The cancer mutation panel test revealed multiple deleterious somatic mutations, such as the driver mutations, KRAS Q61R (c.182A > G), TP53 R110del (c.329_331delGTC), and APC S1465RfsX9 (c.4393_4394dupAG), and copy number gain of several genes (Table 1). Interestingly, we also observed a novel nonsynonymous BRCA2 c.6944T > C (p. I2315T) point mutation with a mutant allele frequency (MAF) of 28.0% in the plasma and 39.5% in the tumor biopsy specimens. The novel BRCA2 point mutation was not detected in white blood cells, and thus, it was confirmed as a somatic mutation.Table 1 Genetic alterations detected in the patient’s plasma and tumor biopsy specimens
Genes Alternations Nucleotide change MAF (plasma) MAF (tumor)
BRCA2 p. I2315T c.6944T > C 28% 39.5%
KRAS p. Q61R c.182A > G 27.4% 43.2%
TP53 p. R110del c.329_331delGTC 37.4% 81.6%
APC p. S1465RfsX9 c.4393_4394dupAG 26.7% 71.7%
CCNE1 Gene amplification NA 16.0-fold 27.4-fold
CCNE1 IGR (downstream UQCRFS1) ~ CCNE1 fusion NA 0.1% –
PIK3CA Gene amplification NA – 1.9-fold
PKHD1 p. R909X truncation c.2725C > T 4.9% 16.9%
SOX2 Gene amplification NA – 2.0-fold
STMN1 Gene amplification NA – 1.8-fold
TERC Gene amplification NA – 1.9-fold
TUBB3 Gene amplification NA – 2.2-fold
–, not detectable; NA, not applicable; MAF, mutant allele frequency. Gene amplification was presented as the relative fold change to normal controls
Given the clinical efficacy of olaparib in treating BRCA-mutated advanced solid tumors, we decided to revise the therapeutic strategy by administering olaparib at a dose of 150 mg twice per day in combination with a modified FOLFIRINOX regimen (irinotecan at a dose of 100 mg on days 1, 8 and 15; oxaliplatin at a dose of 150 mg on days 1 and 15; S-1 at a dose of 40 mg twice per day from day 1 to day 14) for one cycle beginning in March 2019 (Fig. 1b). However, due to the occurrence of adverse events (e.g., diarrhea, general weakness, fatigue, and loss of appetite) and myelosuppression, including grade 2–3 leukopenia and thrombocytopenia, chemotherapy was not given on day 15 and the frequency of irinotecan was reduced to only be administered on days 1 and 15 in the subsequent treatment. Additionally, megestrol acetate and granulocyte-colony stimulating factor (G-CSF) were prescribed to increase appetite and promote the recovery of myelosuppression. In May 2019, a reduction in the size of both pancreatic and hepatic lesions was revealed by the CT scan, while the levels of the serum tumor biomarkers, CEA (63.38 ng/mL) and CA19-9 (40.53 U/mL) were considerably reduced (Fig. 1a, c). Olaparib and modified FOLFIRINOX were thus continued with irinotecan and oxaliplatin being administered only on day 1 (Fig. 1b). After 2 weeks of treatment, CEA and CA19-9 levels decreased to 32.69 ng/mL and 25.57 U/mL, respectively (Fig. 1c). A CT scan performed in June 2019 showed a significant size reduction in the primary and metastatic tumors, which indicated a partial response (PR, Fig. 1a). Since the patient experienced severe marrow suppression during treatment, only olaparib monotherapy was administered since July 2019 to reduce adverse effects (Fig. 1b). Stable disease (SD) was subsequently observed in August 2019 (Fig. 1a). In September 2019, aside from an increase in CEA and CA19-9 levels (Fig. 1c), laboratory blood tests demonstrated that the patient underwent acquired granulocytopenia, anemia, and thrombocytopenia. Consequently, G-CSF, thrombopoietin, and erythropoietin were administered for symptom management. After olaparib treatment for another 1.5 months, PD was indicated by a CT scan (Fig. 1a). The patient achieved a PFS for ~ 6.5 months following olaparib combination and monotherapy.
Discussion and conclusions
Neoplastic cells lacking a functional homologous recombination repair system, such as those carrying BRCA mutations, are sensitive to PARP inhibition through accumulated DNA damage via multiple mechanisms [6]. As a new therapeutic concept, maintenance olaparib has shown promising results in the treatment of germline BRCA-mutated breast, ovarian, and metastatic pancreatic cancer [7, 10, 11]. To date, the majority of BRCA2 mutations identified in pancreatic cancer were frame-shifting indels (e.g., c.6174delT, c.6158insT) and splice-site mutations. In contrast, single point mutations have been rarely reported [4, 5, 12]. Mesman [13] recently assessed the potential pathogenic impact of a large set of BRCA2 missense variants using a mouse embryonic stem cell (mESC)-based functional assay, and found that BRCA2 missense mutations, such as c.93G > T (p. W31C) and c.8351G > A (p. R2784Q), were able to increase susceptibility to PARP inhibitor treatment.
The patient in our report harbored an unreported BRCA2 point mutation [c.6944T > C (p. I2315T)] located in exon 13 of BRCA2 between the G-CSF. Different germline BRCA2 mutations (e.g., p. I2315V, p. I2315L) at the same site have been documented with unknown functional significance [14, 15]. Although the underlying molecular mechanism(s) by which this novel BRCA2 p. I2315T mutation impairs DNA repair and sensitizes tumor cells to PARP inhibition remains to be elucidated. We postulate that it may be related to a change in the polarity of amino acid residues since isoleucine (I), valine (V) and leucine (L) are all non-polar and hydrophobic, while threonine (T) is hydrophilic. Thus, we hypothesize that the p. I2315T mutation is likely to cause a structural abnormality in the BRCA2 protein, which results in defective DNA double strand break (DSB) repair by homologous recombination (HR) and its sensitivity to olaparib. To test this hypothesis, we attempted to generate a three dimensional (3D) structural model of the BRCA2 p. I2315T mutation, but failed due to the absence of an established crystal structure of the full-length human BRCA2 due to its size and segmental nature [16].
In summary, we report a metastatic pancreatic cancer patient carrying a novel somatic BRCA2 p. I2315T point mutation. Furthermore, advances in NGS technology have provided a solid basis for precise detection of well-known driver mutations, and rare or novel mutations. Thus, NGS may provide clinicians with invaluable information (e.g., BRCA1/2 status of tumors) that can be leveraged for therapeutic decision making, and perform better evaluations of patients’ responses during the course of treatment.
Abbreviations
PARPPoly(ADP-ribose) polymerase
PFSProgression-free survival
PDProgressive disease
DNADeoxyribonucleic acid
POLOPancreas cancer olaparib ongoing
CTComputed tomography
NCCNThe National Comprehensive Cancer Network
CEACarcinoembryonic antigen
CA19-9Carbohydrate antigen 19-9
NGSNext-generation sequencing
MAFMutant allele frequency
FOLFIRINOXFOL-folinic acid, F-fluorouracil, IRIN-irinotecan, OX-oxaliplatin
G-CSFGranulocyte-colony stimulating factor
PRPartial response
mESCMouse embryonic stem cell
DSBsDouble strand breaks
HRHomologous recombination
3DThree dimensional
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Acknowledgements
We would like to thank the patient for providing written informed consent for publication.
Authors' contributions
XL conceptualized and designed the manuscript. QT and DW carried out patient clinical management, sample collection and drafted the manuscript. RG analyzed the data. SL and MY revised the manuscript. All authors read and approved the final manuscript.
Funding
Supported by the Key Project of Zhenjiang City for Health Science and Technology (SH2016038 and SH2019046), and the Project of Young Medical Talents in Jiangsu Province (QNRC2016829), China. The funding body did not have any role in the study design, data collection and analysis, decision to publish, or preparation of the manuscript.
Availability of data and materials
The datasets generated and/or analysed during the current study are not publicly available in order to protect participant confidentiality but are available from the corresponding author on reasonable request.
Ethics approval and consent to participate
The study protocol was approved by the ethical committee of the Affiliated Hospital of Jiangsu University. Written informed consent was provided by the patient.
Consent for publication
Written informed consent was obtained from the patient for publication of the case and all accompanying tables/images. A copy of the written consent is available for review by the Editor of this journal.
Competing interests
Ruting Guan and Sisi Liu are the employees of Nanjing Geneseeq Technology Inc., China; Man Yu is an employee of Geneseeq Technology Inc., Canada. The remaining authors declare no conflicts of interest. | 150 mg (milligrams). | DrugDosage | CC BY | 33407459 | 19,274,581 | 2021-01-06 |
Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Gastrointestinal haemorrhage'. | Gastrointestinal perforation in anti-NXP2 antibody-associated juvenile dermatomyositis: case reports and a review of the literature.
BACKGROUND
To summarize the characteristics of gastrointestinal (GI) perforation in anti-nuclear matrix protein 2 (NXP2) antibody-associated juvenile dermatomyositis (JDM).
METHODS
Five patients with GI perforation from a JDM cohort of 120 cases are described. Relevant literature was reviewed.
RESULTS
Five patients, including four females and one male, were included in the study. The age of onset of these patients ranged from 3.3 to 9.5 years with the median age of 5.0 years. When these patients were complicated by GI perforation, childhood myositis assessment score (CMAS) ranged from 1 to 5 with the median score of 2. Myositis-specific antibody (MSA) spectrum analysis indicated that the five patients were anti-NXP2 antibody positive. The initial symptoms of GI perforation were progressive abdominal pain and intermittent fever. Two patients also presented with ureteral calculus with hydronephrosis and ureteral stricture. Surgery was performed in four patients. One patient failed to undergo a repair as the perforation was high in position. For the other three patients, perforation repair was successful, of which two patients failed due to recurrent perforation. At 24 months postoperative follow-up, one patient was in complete remission on prednisone (Pred) and methotrexate (MTX) treatment, and her ureteral stricture had disappeared. The other four patients died. Adding these cases with 16 other patients described in the literature, the symptom at onset was progressive abdominal pain, which often occurred within 10 months after JDM was diagnosed. Perforation most commonly occurred in the duodenum, although it also occurred at multiple sites or was recurrent. The mortality rate of GI perforation in JDM was 38% (8/21).
CONCLUSIONS
All the five perforation cases in our study subjected to MSA analysis were anti-NXP2 antibody positive. The symptom at onset was abdominal pain. The most common site of perforation was the duodenum in the retroperitoneum, and the lack of acute abdominal manifestations prevented early diagnosis. GI perforation may be a fatal complication in JDM, and early diagnosis is very important. More research is needed to determine the pathogenesis and predictive factors of GI perforation in JDM.
Background
Juvenile dermatomyositis (JDM) is an autoimmune disease characterized by proximal myopathy and a characteristic rash. However, multiple systems, including the digestive system, can also be involved. The occurrence of gastrointestinal (GI) perforation is rare, but a high mortality rate has been reported due to atypical symptoms and difficulty in early diagnosis [1]. Myositis-specific autoantibodies (MSAs) are increasingly used to delineate distinct subgroups of JDM [2, 3]. The presence of anti-nuclear matrix protein 2 (NXP2) autoantibodies substantially increases the risk of calcinosis across all ages and is associated with disease severity [4]. The role of MSAs in cases of JDM complicated by GI perforation has not been reported. Here, from among 120 patients with JDM, we report five cases complicated by GI perforation. All five patients had anti-NXP2 antibody-associated JDM. In addition, we reviewed the other JDM cases with GI perforation reported in the literature to improve our recognition of this disease. Anti-NXP2 autoantibodies may facilitate early diagnosis of the disease.
Methods
We described five patients with GI perforation from a JDM cohort who were admitted to the Children’s Hospital affiliated with the Capital Institute of Pediatrics, China, from January 2016 to December 2019. The inclusion criteria were: (1) age < 18 years old; (2) diagnosis of JDM based on the Bohan and Peter criteria for myositis [5]; and (3) GI perforation. Patients with other diseases that cause weakness or rash, or a clear alternative diagnosis were excluded from the study. Sixteen MSAs (MDA-5, NXP2, Jo-1, PM-SCL100, PL-7, PL-12, EJ, OJ, anti-Ro52, Ku, PM-Scl, SRP, SAE1, TIF1γ, Mi-2α and Mi-2β) were tested by immune dot blot hybridization using a commercial kit based on goat anti-human IgG antibodies (BlueDot Myositis 12 IgG, #MYO12D-24, D-TEK, Belgium). The study was approved by the Ethics Committee of Capital Institute of Pediatrics. We searched PubMed, Medline and Scopus using the keywords “juvenile dermatomyositis”, “gastrointestinal perforation”, and “perforation”. These literatures with detailed cases which clearly diagnosed JDM and excluded Degos-like presentation with GI perforation were reviewed.
Results (Table 1)
Table 1 Clinical data of JDM patients with GI perforation
Patient
/Year Gender Age at onset (y) CMAS score CAT-A
score CAT-D
score Positive for MSA Treatment before
GI perforation Symptoms of GI perforation Duration from onset to perforation (m) Site of perforation Surgical
treatment Histopathology of perforation site Medical Treatment Follow-up(m)
/Outcome
P1 F 3.4 5 2 3 Anti-NXP2 Pred+MTX + IVIG Abdominal pain/
bloody stools
4/9 Duodenum/ colon Transverse colon ostomyv
duodenostomy
Inflammatory cells infiltrate/
No vasculitis
Pred+Mp pulse+CsA+
IVIG→Pred+Thal+CYC→
Pred+CYC (Po) + MTX → Pred+MTX
24/Remission
P2 F 5.0 1 7 5 Anti-NXP2 MP + MP Pulse+CYC
HCQ/MP + MP Pulse+MTX
Abdominal pain/
bloody stools
10 Duodenum/
Duodenal bulb hepatic
artery rupture
Vessel sutured/
placement of duodenal
jejunal tube (failed)
ND Pred+MP Pulse+CYC+
IVIG
Death/Infection
P3 M 3.3 5 6 5 Anti-NXP2 Pred+MTX + IVIG/
Pred+IVIG +RTX
Abdominal pain
and distention bloody stools
10 Unknown No surgery ND MP pulse+CYC + IVIG Death/Abdominal bleeding
P4 F 6 2 6 6 Anti-NXP2 Pred+ MTX/CsA
→MP pulse+IVIG+CYC
Abdominal pain/
bloody stools
13 Duodenum×2 Perforation repair×2 ND CYC → MP pulse +IVIG+PE Death/Shock
P5 F 9.5 2 6 4 Anti-NXP2 Pred+ MTX/CsA Abdominal pain/ fever and bloody stools 6 Duodenum×2 Perforation repair ND MP pulse+ RTX Death/Abandon treatment
P6 [6]
/2016
F 7.0 ND ND ND ND Pred+MTX Abdominal pain vomiting and fever 6 Duodenal retroperitoneum Perforation repair No vasculitis ND ND/Improved
P7 [7]
/1997
M 7.0 ND ND ND ND Pred Abdominal pain /vomit 24 Duodenum Jejunum Perforation repair ND PE
Pred+MP pulse+CYC
12/Stable
P8 [8]
/1988
F 5.0 ND ND ND ND Pred Abdominal pain 3 Colon Perforation repair ND ND 12/Stable
P9 [8]
/1988
F 7.0 ND ND ND ND Pred +MTX Abdominal pain 6 The third duodenum ND ND ND 3/ND
P10 [8]
/1988
M 8.0 ND ND ND ND Pred+MTX Abdominal pain/
fever
6 Esophagus/
duodenum/ colon
Mesenteric arterial rupture
Perforation repair ND ND ND/Improved
P11 [8]
/1988
F 6.0 ND ND ND ND Pred+MTX Abdominal pain and distention/fever 5 Duodenum Perforation repair ND ND Death/unknown
P12 [9]
/2001
M 4.0 ND ND ND ND Pred+AZA Abdominal pain/
vomiting/fever
2 Duodenum Perforation repair Mucosal ischemia Pred+MP pulse 19/ND
P13 [10]
/2014
M 2.0 ND ND ND ND ND Abdominal pain 108 Unknown ND ND ND Death/unknown
P14 [11]
/1985
F 4.0 ND ND ND ND ND ND 48 Gastric pylorus Partial gastrectomy and gastrojejunostomy ND ND ND/Stable.
P15 [11]
/1985
F 5.0 ND ND ND ND ND ND 3 Middle transverse colon Loop transverse colon fistula ND ND Death/ARDS
P16 [11]
/1985
F 6.0 ND ND ND ND Pred+MTX/Pred+AZA/
Pre + CYC
Abdominal pain/
vomiting/fever
10 Duodenum colon transverse colon Multiple perforation repair ND ND 7/Stable.
P17 [11]
/1985
M 9.0 ND ND ND ND Pred/Pred+MTX/
Pred+AZA
Abdominal pain/ fever 13 Duodenum Perforation repair ND ND ND/Stable.
P18 [12]
/1984
M 7.0 ND ND ND ND Pred+MTX Abdominal pain 10 Duodenal perforation/
colon perforations
Perforation repair ND ND 48/Stable.
P19 [13]
/2019
F 6.0 ND ND ND ND Pred+MTX Abdominal pain/fever 1 transverse colon, Perforation repair
and loop colostomy.
No vasculitis and vasculopathy/
CMV colitis
Steroid+IVIG+Ganciclovir 12/Remission
P20 [14]
/2020
ND 10.5 16 ND ND ND ND Abdominal pain/ GI hemorrhage/ severe bowel obstruction 8/20 Duodenal Perforation/
Jejunal perforation
Jejunal resection/ exclusive parenteral
nutrition/ antibiotics,
ND Steroid+CsA 108/Remission
P21 [14]
/2020
ND 10.7 5 ND ND ND ND Abdominal pain/
severe bowel obstruction
7/9 Esophageal perforation/
Cecal perforation
Colostomy ND Steroid+ RTX+ PE 84/Death/Hepatitis
F is female, M is male, ND is no data, y is year, CMAS is child myositis assessment score, MSA is myositis-specific antibody, m is month, Pred is prednisone, CYC is cyclophosphamide, IVIG is intravenous immunoglobulin, MTX is methotrexate, MP is methylprednisol, CsA is cyclosporine A, RTX is rituximab, AZA is azathioprine, Thal is thalidomide, HCQ is hydroxychloroquine, Po is peros, CMV is Cytomegalovirus, PE is plasma exchanges, ARDS is acute respiratory distresssyndrome, CAT-A is cutaneous assessment tool activity, CAT-D is cutaneous assessment tool damage
The general data of the 5 patients
Five patients with GI perforation were identified from 120 cases in a JDM cohort (4.17%). Four of these were females, with the age at onset ranging from 3.3 to 9.5 years (median age − 5.0 years). All five patients showed severe rashes, skin ulcers, and weakness of the skeletal muscles (ranging from power 3/5 to 1/5). When these patients were complicated by GI perforation, childhood myositis assessment score (CMAS) ranged from 1 to 5 with the median score of 2, cutaneous assessment tool (CAT) activity score ranged from 2 to 7 with the median score of 6, CAT damage score ranged from 3 to 6 with the median score of 5. No calcification was observed. Two patients also presented with ureteral calculus with hydronephrosis and ureteral stricture. Analysis of MSAs showed that the five patients were anti-NXP2 antibody positive. There are 31 patients with anti-NXP2 antibody positive in the cohort. The incidence of GI perforation in anti-NXP2 antibody positive patients in our study was 16.13% (5/31). One patient had increased level of cytomegalovirus (CMV)-DNA copies in blood. GI perforation occurred from 4 to 13 months after JDM was diagnosed. The symptoms at onset were severe abdominal pain, fever, GI bleeding and vomiting. Perforations occurred in the duodenum (3 patients), duodenum and colon (1 patient), and an unclear location (1 patient), and perforations at multiple sites or at recurrent times occurred in four patients. All patients were treated with corticosteroids and immunosuppressant agents [cyclophosphamide (CYC)/methotrexate (MTX)/cyclosporine A (CsA)]. One patient was treated with plasma exchange (PE) therapy, and two patients received rituximab (RTX). All five patients were given proton-pump inhibitors (omeprazole). Surgery was performed in four patients, of which one patient failed to undergo repair due to the high position of perforation. For the other three patients, perforation repair was successful, of which two patients failed due to recurrent perforation. At 24 months postoperative follow-up, one patient was in complete remission under Pred and MTX treatment, and her ureteral stricture had disappeared. The other four patients died.
Case 1
A 3.4-year-old girl, suffering from characteristic skin rash and muscle weakness was diagnosed with JDM in a local hospital and was treated with Pred(2 mg/kg/d) and MTX (12 mg/m2/wk). Muscle weakness improved after 3 months of treatment, following which the dosage of Pred was reduced. When Pred was reduced to 10 mg/d, the girl developed infection in the lungs, skin ulcers around the anus and abdominal pain. One month later, a perforation in the transverse colon was confirmed, and colostomy was performed in a local hospital. She received Pred, CYC, intravenous immunoglobulin (IVIG) and MTX, after which her abdominal pain disappeared, and her muscle strength improved. Seven months after JDM diagnosis, ureteral calculus with hydronephrosis and ureteral stricture were diagnosed and treated via ureteroscopy. Nine months after JDM diagnosis, she developed severe abdominal pain and worsening muscle weakness, for which pulse methylprednisolone (MP) and CsA were given. Later, GI bleeding and fever recurred. She was transferred to our emergency department. She had shock, and her contrast-enhanced computed tomography (CT) abdomen indicated encapsulated effusion and pneumatosis, duodenal perforation and an abscess, which were confirmed during surgery. After duodenostomy, Pred, pulse CYC and thalidomide were given, and when her condition stabilized, we switched to oral Pred, CYC and MTX. At 24 months postoperative follow-up, she was in complete remission with Pred and MTX treatment, and her ureteral stricture had disappeared.
Case 2
A 5-year-old girl suffering from characteristic skin rash and muscle weakness was diagnosed with JDM in a local hospital and treated with Pred, MTX and hydroxychloroquine (HCQ), after which her muscle strength improved. But her parents stopped the treatment. Twelve months after JDM diagnosis, she was admitted to our emergency department due to abdominal pain, vomiting, and dark coloured stools. Physical examination showed a poor mental response, painful expression, severe malnutrition, High spring sign (+), partially scabbed skin ulcers in the lower jaw, popliteal fossa and axillae and muscle weakness. A contrast-enhanced CT abdomen indicated peritonitis, intestinal perforation and a right renal-ureteral calculus with pelvicalyceal-ureteral dilation. During surgery, multiple perforations of the duodenum and ruptured right hepatic artery were found. The ruptured blood vessel was sutured, but duodeno jejunal tube placement was unsuccessful. The patient subsequently died of infections and haemorrhagic shock.
Case 3
A 3.3-year-old boy suffering from characteristic skin rash and muscle weakness was diagnosed with JDM and treated with Pred, MTX and IVIG in a local hospital. His symptoms improved after treatment; the dosage of Pred was reduced, and MTX was stopped due to cataracts and abnormal liver function. The rash and muscle weakness worsened. Nine months after JDM diagnosis, physical examination revealed that severe proximal muscle weakness (power 3/5) and numerous purplish red rashes and ulcerative scabs which could be seen on the face and limbs. MP, RTX and IVIG were administered in our hospital. Two weeks later, he gradually developed abdominal pain, bloating, low back pain, right lower quadrant tenderness and rebound pain. Localized colitis was suspected based on a CT scan. His abdominal pain and distension were relieved after the administration of antibiotics, MP (20 mg/kg/d for 2 days) and IVIG. Four days later, he developed fever, abdominal pain and distension, and an ultrasound showed echoic enhancement in the omentum of the right lower quadrant with weak peristalsis and ascites. MP, pulse CYC and IVIG were continued, and his temperature returned to normal with improved abdominal pain. However, 7 days later, he experienced severe abdominal pain and distension with a rapid decrease in his haemoglobin (Hb) level (from 112 g/L to 67 g/L). Ultrasound showed abdominal muscle inflammation with haemorrhage, and contrast-enhanced CT showed generalized retroperitoneal infection with abdominal wall haemorrhage and intestinal perforation (Fig. 1). Surgical intervention was not possible in view of unstable vital signs, severe infection, and severe and extensive intestinal lesions that could not be surgically repaired. Repeated blood transfusions, anti-microbial agents, and treatment for the primary disease were given. He persisted to have abdominal pain and bloating. A slight change in body position caused massive abdominal wall bleeding. He died after returning home.
Fig. 1 a The thigh skin ulcers accompanied by swelling of the ipsilateral testis on Case 3(arrow) b. Contrast-enhanced CT showed retroperitoneal effusion (arrow 1), retroperitoneal gas (arrow 2) and abdominal wall hemorrhage (arrow 3) on Case 3. c Contrast-enhanced CT showed retroperitoneal effusion (arrow 1) and retroperitoneal gas (arrow 2) on Case 3
Case 4
A 7-year-old girl with a past history of JDM was treated 1 year earlier with MP and an immunosuppressant. She presented with progressive proximal muscle weakness, skin ulcers and intermittent abdominal pain for 1 month. Physical examination showed severe malnutrition, anemia, maculopapular rashes symmetrically distributed over the extensor sides of the joints of all extremities, partially scabbing skin ulcers on the extensor side of the left elbow and in both axilla, proximal muscle weakness and edema in both upper limbs. Her Hb level was 59 g/L. Abdominal contrast-enhanced CT did not indicate obvious abnormalities. Ultrasound of the abdomen suggested thickening of the abdominal bowel wall and poor bowel motility. After treatment with blood transfusion, MP and CYC were given. Her symptoms improved, and abdominal pain disappeared. Hb decreased again after 2 weeks, and fever and abdominal pain reappeared again after 4 weeks. Abdominal CT revealed bowel perforation. She immediately underwent surgical repair (Fig. 2). One week later, abdominal pain appeared again. Abdominal CT showed another intestinal perforation. Surgical repair and PE therapy were performed. Her abdominal pain was relieved, but she developed severe pulmonary infection. Three days later, she had manifestations of peritonitis and then developed seizures. Her blood pressure was normal, cerebrospinal fluid tests were negative, but her magnetic resonance imaging (MRI) brain showed that the right temporal lobe and bilateral parieto-occipital lobes were swollen with abnormal signals; patchy abnormal signals were observed in the right thalamus, showing long T2 signal, high T2 FLAIR signal, limited dispersion, and reduced ADC value. We speculated primary disease involving the nervous system. Seizures did not recur after treatment of the primary disease. A repeat MRI brain was not done. Pulse MP and anti-microbial agents were given. Surgical intervention was not possible. The patient died due to uncontrolled bleeding and refractory shock.
Fig.2 a Contrast leakage seen at the junction of the descending and horizontal segments of the duodenum on Case 4 (arrow). b Contrast-enhanced CT showed retroperitoneal gas on Case 4 (arrow). c Duodenal perforation can be seen at surgery on Case 4 (arrow)
Case 5
A 10-year-old girl had been diagnosed with JDM 6 months earlier and received Pred and immunosuppressants. She presented with intermittent abdominal pain and fever for 1 month. She was initially treated with pulse MP and IVIG. But her muscle weakness and rash did not improve. She was admitted to our hospital with GI haemorrhage for 3 days. Physical examination showed a poor mental response, painful expression, severe malnutrition, anemia, scattered maculopapular rashes and ulcers distributed in the neck, axillae, buttocks, and extendible joints, and severe proximal muscle weakness. Her Hb level was 54 g/L. Ultrasound of the abdomen suggested thickening of the abdominal bowel wall and poor bowel movements. Pulse RTX and MP were given. Three days later, her abdominal pain worsened. Ultrasound of the abdomen showed intestinal perforation. During surgery, a 5-cm perforation of the transverse part of the duodenum was observed, the perforation was repaired and a double cavity jejunal fistula was performed. Her abdominal pain was relieved. CMV-DNA was detected in the blood, and she was given ganciclovir treatment. Four days later, she again experienced abdominal pain and muscle spasms. Considering the necrosis and perforation of the lower part of the duodenum, her parents withdrew treatment, and the patient died.
Results of the literature review
Sixteen patients of JDM with GI perforation were identified in PubMed, Medline and Scopus [6–18] which were published between 1984 and 2020. Eight patients were female (50%), six patients were male (37.5%), and the sex of two patients was not recorded (12.5%). The age of onset of these patients ranged from 2 to 10.5 years with the median age of 6.5 years. No clear MSA results were recorded in any case. Primary treatment with Pred and immunosuppressants did not have a significant effect. GI symptoms occurred from one to 108 months after treatment, most of which occurred within 10 months. The initial GI symptoms were severe abdominal pain with fever or vomiting. Perforations were reported in the duodenum (10/16, 62.5%), colon (6/16, 37.5%), jejunum (2/16, 12.5%), oesophagus (2/16, 12.5%), gastric pylorus (1/16, 6.25%), caecum (1/16, 6.25%) and an unclear location (1/16, 6.25%); perforations at multiple sites or recurrent perforations were reported in six patients (6/16, 37.5%). Only five patients had records regarding treatment of the initial disease, and they were treated with Pred or MP and an immunosuppressant (CYC/CsA). One patient underwent PE therapy, one patient received PE therapy with RTX and surgery was performed in 14 patients. In particular, one patient was treated with ganciclovir for CMV infection. Four patients died (25%), and the others were discharged from the hospital after they experienced relief of their symptoms. The clinical data of all 16 patients taken from the literature and the five patients in our study is summarized in Table 1.
Discussion
JDM, the most common inflammatory myopathy of childhood, is a rare systemic autoimmune vasculopathy that is characterized by weakness in proximal muscles and pathognomonic skin rashes [19]. Multiple systems can be involved, but GI perforations in anti-NXP2 antibody-associated JDM are rarely reported. From among 120 patients with JDM, we report five anti-NXP2 antibody-associated JDM complicated by GI perforation. Most patients in our study were females, with a proportion that was significantly higher than that for the other patients reported in the literature. At the age of onset of these five patients ranged from 3.3 to 9.5 years with the median age of 5.0 years, and GI perforations appeared between 4 and 13 months post diagnosis, which was similar to the 16 cases reported in the literature. When our patients were complicated by GI perforation, CMAS were very low, CAT activity score indicated moderate activity, which suggest that GI perforations may be associated with disease severity and activity. The initial symptoms of JDM with GI perforation were severe abdominal pain, abdominal distention, vomiting, fever and bloody stools. Early identification of perforation was very difficult. With regard to patient (P) 1 and P2, the doctors did not recognize that GI perforation had occurred after persistent abdominal pain for more than 1 month. The perforation in P3 occurred during hospitalization in our hospital and manifested as severe abdominal pain and distension with decreased bowel sounds. Repeated abdominal ultrasounds, X-rays and contrast-enhanced CTs indicated the presence of a low-signal mass in the right lower quadrant with bowel distension, thinning of the intestinal wall and local colitis without pneumoperitoneum or subphrenic pneumatosis. Transitory relief of symptoms occurred after treatment, but severe abdominal pain quickly reappeared, and contrast-enhanced CT and ultrasound showed intestinal perforation, diffuse abdominal wall bleeding and infection. We did not know the precise time when the perforation occurred, suggesting that once abdominal pain appears, perforation should be strongly suspected, and imaging should be performed. Perforation should be considered when abdominal pain is not relieved by active treatment in patients with JDM, and it can be diagnosed early with contrast-enhanced CT scans [6]. We also suggest that repeated scanning and GI angiograms are essential, if the diagnosis cannot be confirmed during the first scan. In the 16 patients in the literature, perforation often occurred in the duodenum (partially in the retroperitoneal area in P6) and the colon. In addition, multi-site or recurrent perforations were also observed in some patients (P7,P10,P16,P18,P20,P21), similar to the results of our study. Furthermore, arterial rupture near the perforation site often occurs, as observed in P2, who had ruptured hepatic arteries, and in P10, who had a ruptured duodenal proximal mesenteric artery; therefore, haemorrhage may also be considered when an unexplained decrease in the Hb level occurs in JDM patients. In addition, several patients have been described in literature with Degos-like lesions linked to GI perforation [20, 21]. A similar deposit complex and pattern of vasculopathy has been found in patients suffering from Degos disease and JDM [22]. We should pay attention to the identification of Degos-like disease. Degos - like skin lesions were initially pale red papules followed by enlarged lesions, showing a characteristic pitting center with a concave navel porcelain white center and a red halo around the periphery. After the rash subsided, there was a white superficial scar. The rash is more common on the trunk and extremities, less common on the palms and feet, and often occurs in batches, old and new. The appearance and location of the rash in five patients of our study were different from Degos-like disease. Further hisopathological identification may be performed if necessary.
In addition, two patients (P1, P2) had urinary system involvement in this group of cases, including ureteral stones, uretero-pelvic dilation and ureteral stenosis. With remission of the primary disease, ureteral stenosis disappeared in P1. This leads us to speculate that ureteral stenosis may be related to vasculopathy involving the urinary system. Morita et al. [23] reported a case of dermatomyositis who developed duodenal perforation as well as ureteral stenosis, with biopsy of stenotic ureter showing calcification with granulomatous tissue without any vasculitic lesion. Ruby Haviv et al. [24] reported a case of juvenile polymyositis (JPM) with right ureteral obstruction secondary to necrosis. The histopathology report of the resected ureter revealed moderate, acute, and chronic inflammatory infiltrates within the ureter wall, urothelial erosions, superficial granulation tissue, and degenerated smooth muscle fibres within the muscularis propria; some of which were infiltrated with lymphocytes and plasma cells, and multiple calcifications within the lamina propria. It also showed fragments of gross calcifications, similar calcifications in other parts of the ureter and obstructing calcifications within small blood vessels. Ruby Haviv et al. considered calcified ureteral necrosis to be a feature of visceral vasculopathy, related to both JDM and JPM. The mechanism is obscure, and the presence of calcifications within visceral tissues might suggest the pathogenesis of the typical calcinosis related to these diseases [24]. Considering that NXP-2 is a type prone to calcification, it was not clear whether ureteral calculi and ureteral stenosis in P1 and P2 were related to vasculopathy with calcification, which needs further studies of visceral calcinosis.
The underlying mechanisms of GI perforation in JDM are still obscure. Some researchers have reported glucocorticoids, non-steroidal anti inflammatory drugs and MTX to be risk factors for GI ulceration and perforation, especially at 1 month post-treatment or with an accumulated dose of steroids higher than 1 g [17]. In our study, Pred was reduced to a small dose before GI symptoms appeared in P1. After perforation was identified, pulse MP pulse and CYC were given, and the patient’s condition improved; thus, the perforation was not attributed to drug factors. Schneider et al. [6] assumed that ulceration in the proximal region and bulb of the duodenum was related to medication, while perforation in the descending part was related to vasculitis, causing intestinal ischemia and necrosis due to thrombogenesis and vascular occlusion. Recent researchers [16, 17] reported that perforated sites showed chronic vasculopathy rather than acute vasculitis. This chronic vasculopathy is characterized by narrowing or complete occlusion of multiple small and medium arteries, subintimal foam cells, fibromyxoid neointimal expansion, and significant luminal compromise with infiltration of macrophages through the muscle layers into the intima. Histopathology at the perforation site was recorded in three patients (P6, P12, P19) in the literature [6, 9, 13], and no vasculitis was noted. P12 exhibited mucosal ischemia, and P19 exhibited vasculopathy and CMV colitis. No manifestation of vasculitis was observed in the histopathology of the fistula. Histopathology of perforation site in P1 of our study showed inflammatory cells infiltrate and no vasculitic lesion was observed in the tissue. The other three patients were unable to undergo histopathology due to erosion of the perforation site. Therefore, whether chronic non-inflammatory vasculopathy causes ischemia and perforation must be considered. Bhaskaran et al. [13] reported a case of intestinal perforation in a child with JDM caused by CMV colitis. CMV-DNA was also detected in the blood of P5. No relevant pathological tests were performed. The other four patients did not undergo blood CMV-DNA tests. The role of CMV colitis in perforation requires further study.
The 120 patients in the JDM cohort were all tested by MSAs analysis, all five patients with GI perforation had strong positivity for anti-NXP2 antibody (3+), and no GI perforation was noted in other MSA patients, which led us question whether anti-NXP2 antibody is associated with GI perforation. After reviewing 16 cases in the literature, Besnard et al. [13] reported that most patients with severe GI manifestations were positive for anti-NXP2 antibody or anti-TIF-1γ antibody. Unfortunately, no specific antibody type was recorded in two patients with GI perforation in this study. The other patients described in the literature had not been tested for MSAs. In 2017, Tansley et al. [25] mentioned that 14 children who were positive for anti-NXP2 antibody had ulcers. Aouizerate et al. [26] reported that anti-NXP2 antibody had a positive association with GI involvement in JDM. The study evaluated the clinical, biological, and histological manifestations of 23 JDM patients and performed a multivariate analysis of 26 histopathological parameters. A case-control study can be performed to further uncover the relationship between anti-NXP2 antibody and GI perforation, which may further reveal the pathological mechanism of GI perforation. Based on our experience in this study, or even early in disease, clinicians should be highly alert to the possibility of GI perforation when abdominal pain occurs on anti-NXP2 antibody-positive patients with JDM.
The mortality rate among our patients was higher than that reported in the literature, which might be due to their severe condition and poor response to various therapeutic drugs, delayed surgery, surgical difficulties at the perforation site, economic reasons and the deficient number of cases. When a patient has intermittent abdominal pain and GI ulcers, the primary disease should be treated more actively to prevent GI perforation. Once GI perforation occurs, the primary disease is not well controlled, and the prognosis is poor. We need more research to choose appropriate treatment strategy for these diseases.
Conclusion
In this study, the clinical details of five cases of anti-NXP2 antibody-associated JDM complicated by GI perforation were summarized for the first time. Based on the these cases combined with a literature review, we suggest that once JDM patients present with abdominal pain, especially anti-NXP2 antibody-positive patients, GI perforation should be considered. For timely diagnosis, dynamic imaging is important. GI perforation may be a fatal complication of JDM, more research is needed to determine the pathogenesis and predictive factors of GI perforation in JDM.
Abbreviations
JDMJuvenile dermatomyositis
NXP2Nuclear matrix protein 2
GIGastrointestinal
MSAMyositis-specific antibody
CMASChild myositis assessment score
PredPrednisone
CYCCyclophosphamide
IVIGIntravenous immunoglobulin
MTXMethotrexate
MPMethylprednisolone
CsACyclosporine A
RTXRituximab
AZAAzathioprine
ThalThalidomide
PEPlasma exchanges
CMVCytomegalovirus
CTComputed tomography
HCQHydroxychloroquine
HbHaemoglobin
MRIMagnetic resonance imaging
JPMJuvenile polymyositis
CATCutaneous assessment tool
PPatient
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Acknowledgement
We would like to thank the Department of General Surgery, the Department of Intensive Medicine and the Department of Radiology of the Children’'s Hospital Affiliated to the Capital Institute of Pediatrics for their contributions to the treatment of patients in our study.
Authors’ contributions
YX wrote the first draft of the manuscript, contributed to patient management and to the literature review. XM made many contributions in the process of writing and revising the manuscript. ZZ supervised patient management. JL critically revised the manuscript and supervised patient management. JH, JZ, MK and JL contributed to patient management. XL revised the manuscript. All the authors read and approved the final version of the manuscript.
Funding
This work was supported by Beijing Municipal Administration of Hospitals Clinical Medicine Development of Special Funding Support (code: XMLX201813) and Capital Funds for Health Improvement and Research (code:2020–2-2102).
Availability of data and materials
The datasets during and/or analyzed during the current study available from the corresponding author on reasonable request.
Ethics approval and consent to participate
Parental informed consent for publication was obtained. This study was approved by the Ethics Committee of Capital Institute of Pediatrics.
Consent for publication
Written informed consent was obtained from the patient’s legal guardians for publication of this case report and any accompanying images.
Competing interests
The authors declare that they have no competing interests. | CYCLOSPORINE, METHYLPREDNISOLONE SODIUM SUCCINATE | DrugsGivenReaction | CC BY | 33407602 | 18,840,448 | 2021-01-06 |
Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Pyrexia'. | Gastrointestinal perforation in anti-NXP2 antibody-associated juvenile dermatomyositis: case reports and a review of the literature.
BACKGROUND
To summarize the characteristics of gastrointestinal (GI) perforation in anti-nuclear matrix protein 2 (NXP2) antibody-associated juvenile dermatomyositis (JDM).
METHODS
Five patients with GI perforation from a JDM cohort of 120 cases are described. Relevant literature was reviewed.
RESULTS
Five patients, including four females and one male, were included in the study. The age of onset of these patients ranged from 3.3 to 9.5 years with the median age of 5.0 years. When these patients were complicated by GI perforation, childhood myositis assessment score (CMAS) ranged from 1 to 5 with the median score of 2. Myositis-specific antibody (MSA) spectrum analysis indicated that the five patients were anti-NXP2 antibody positive. The initial symptoms of GI perforation were progressive abdominal pain and intermittent fever. Two patients also presented with ureteral calculus with hydronephrosis and ureteral stricture. Surgery was performed in four patients. One patient failed to undergo a repair as the perforation was high in position. For the other three patients, perforation repair was successful, of which two patients failed due to recurrent perforation. At 24 months postoperative follow-up, one patient was in complete remission on prednisone (Pred) and methotrexate (MTX) treatment, and her ureteral stricture had disappeared. The other four patients died. Adding these cases with 16 other patients described in the literature, the symptom at onset was progressive abdominal pain, which often occurred within 10 months after JDM was diagnosed. Perforation most commonly occurred in the duodenum, although it also occurred at multiple sites or was recurrent. The mortality rate of GI perforation in JDM was 38% (8/21).
CONCLUSIONS
All the five perforation cases in our study subjected to MSA analysis were anti-NXP2 antibody positive. The symptom at onset was abdominal pain. The most common site of perforation was the duodenum in the retroperitoneum, and the lack of acute abdominal manifestations prevented early diagnosis. GI perforation may be a fatal complication in JDM, and early diagnosis is very important. More research is needed to determine the pathogenesis and predictive factors of GI perforation in JDM.
Background
Juvenile dermatomyositis (JDM) is an autoimmune disease characterized by proximal myopathy and a characteristic rash. However, multiple systems, including the digestive system, can also be involved. The occurrence of gastrointestinal (GI) perforation is rare, but a high mortality rate has been reported due to atypical symptoms and difficulty in early diagnosis [1]. Myositis-specific autoantibodies (MSAs) are increasingly used to delineate distinct subgroups of JDM [2, 3]. The presence of anti-nuclear matrix protein 2 (NXP2) autoantibodies substantially increases the risk of calcinosis across all ages and is associated with disease severity [4]. The role of MSAs in cases of JDM complicated by GI perforation has not been reported. Here, from among 120 patients with JDM, we report five cases complicated by GI perforation. All five patients had anti-NXP2 antibody-associated JDM. In addition, we reviewed the other JDM cases with GI perforation reported in the literature to improve our recognition of this disease. Anti-NXP2 autoantibodies may facilitate early diagnosis of the disease.
Methods
We described five patients with GI perforation from a JDM cohort who were admitted to the Children’s Hospital affiliated with the Capital Institute of Pediatrics, China, from January 2016 to December 2019. The inclusion criteria were: (1) age < 18 years old; (2) diagnosis of JDM based on the Bohan and Peter criteria for myositis [5]; and (3) GI perforation. Patients with other diseases that cause weakness or rash, or a clear alternative diagnosis were excluded from the study. Sixteen MSAs (MDA-5, NXP2, Jo-1, PM-SCL100, PL-7, PL-12, EJ, OJ, anti-Ro52, Ku, PM-Scl, SRP, SAE1, TIF1γ, Mi-2α and Mi-2β) were tested by immune dot blot hybridization using a commercial kit based on goat anti-human IgG antibodies (BlueDot Myositis 12 IgG, #MYO12D-24, D-TEK, Belgium). The study was approved by the Ethics Committee of Capital Institute of Pediatrics. We searched PubMed, Medline and Scopus using the keywords “juvenile dermatomyositis”, “gastrointestinal perforation”, and “perforation”. These literatures with detailed cases which clearly diagnosed JDM and excluded Degos-like presentation with GI perforation were reviewed.
Results (Table 1)
Table 1 Clinical data of JDM patients with GI perforation
Patient
/Year Gender Age at onset (y) CMAS score CAT-A
score CAT-D
score Positive for MSA Treatment before
GI perforation Symptoms of GI perforation Duration from onset to perforation (m) Site of perforation Surgical
treatment Histopathology of perforation site Medical Treatment Follow-up(m)
/Outcome
P1 F 3.4 5 2 3 Anti-NXP2 Pred+MTX + IVIG Abdominal pain/
bloody stools
4/9 Duodenum/ colon Transverse colon ostomyv
duodenostomy
Inflammatory cells infiltrate/
No vasculitis
Pred+Mp pulse+CsA+
IVIG→Pred+Thal+CYC→
Pred+CYC (Po) + MTX → Pred+MTX
24/Remission
P2 F 5.0 1 7 5 Anti-NXP2 MP + MP Pulse+CYC
HCQ/MP + MP Pulse+MTX
Abdominal pain/
bloody stools
10 Duodenum/
Duodenal bulb hepatic
artery rupture
Vessel sutured/
placement of duodenal
jejunal tube (failed)
ND Pred+MP Pulse+CYC+
IVIG
Death/Infection
P3 M 3.3 5 6 5 Anti-NXP2 Pred+MTX + IVIG/
Pred+IVIG +RTX
Abdominal pain
and distention bloody stools
10 Unknown No surgery ND MP pulse+CYC + IVIG Death/Abdominal bleeding
P4 F 6 2 6 6 Anti-NXP2 Pred+ MTX/CsA
→MP pulse+IVIG+CYC
Abdominal pain/
bloody stools
13 Duodenum×2 Perforation repair×2 ND CYC → MP pulse +IVIG+PE Death/Shock
P5 F 9.5 2 6 4 Anti-NXP2 Pred+ MTX/CsA Abdominal pain/ fever and bloody stools 6 Duodenum×2 Perforation repair ND MP pulse+ RTX Death/Abandon treatment
P6 [6]
/2016
F 7.0 ND ND ND ND Pred+MTX Abdominal pain vomiting and fever 6 Duodenal retroperitoneum Perforation repair No vasculitis ND ND/Improved
P7 [7]
/1997
M 7.0 ND ND ND ND Pred Abdominal pain /vomit 24 Duodenum Jejunum Perforation repair ND PE
Pred+MP pulse+CYC
12/Stable
P8 [8]
/1988
F 5.0 ND ND ND ND Pred Abdominal pain 3 Colon Perforation repair ND ND 12/Stable
P9 [8]
/1988
F 7.0 ND ND ND ND Pred +MTX Abdominal pain 6 The third duodenum ND ND ND 3/ND
P10 [8]
/1988
M 8.0 ND ND ND ND Pred+MTX Abdominal pain/
fever
6 Esophagus/
duodenum/ colon
Mesenteric arterial rupture
Perforation repair ND ND ND/Improved
P11 [8]
/1988
F 6.0 ND ND ND ND Pred+MTX Abdominal pain and distention/fever 5 Duodenum Perforation repair ND ND Death/unknown
P12 [9]
/2001
M 4.0 ND ND ND ND Pred+AZA Abdominal pain/
vomiting/fever
2 Duodenum Perforation repair Mucosal ischemia Pred+MP pulse 19/ND
P13 [10]
/2014
M 2.0 ND ND ND ND ND Abdominal pain 108 Unknown ND ND ND Death/unknown
P14 [11]
/1985
F 4.0 ND ND ND ND ND ND 48 Gastric pylorus Partial gastrectomy and gastrojejunostomy ND ND ND/Stable.
P15 [11]
/1985
F 5.0 ND ND ND ND ND ND 3 Middle transverse colon Loop transverse colon fistula ND ND Death/ARDS
P16 [11]
/1985
F 6.0 ND ND ND ND Pred+MTX/Pred+AZA/
Pre + CYC
Abdominal pain/
vomiting/fever
10 Duodenum colon transverse colon Multiple perforation repair ND ND 7/Stable.
P17 [11]
/1985
M 9.0 ND ND ND ND Pred/Pred+MTX/
Pred+AZA
Abdominal pain/ fever 13 Duodenum Perforation repair ND ND ND/Stable.
P18 [12]
/1984
M 7.0 ND ND ND ND Pred+MTX Abdominal pain 10 Duodenal perforation/
colon perforations
Perforation repair ND ND 48/Stable.
P19 [13]
/2019
F 6.0 ND ND ND ND Pred+MTX Abdominal pain/fever 1 transverse colon, Perforation repair
and loop colostomy.
No vasculitis and vasculopathy/
CMV colitis
Steroid+IVIG+Ganciclovir 12/Remission
P20 [14]
/2020
ND 10.5 16 ND ND ND ND Abdominal pain/ GI hemorrhage/ severe bowel obstruction 8/20 Duodenal Perforation/
Jejunal perforation
Jejunal resection/ exclusive parenteral
nutrition/ antibiotics,
ND Steroid+CsA 108/Remission
P21 [14]
/2020
ND 10.7 5 ND ND ND ND Abdominal pain/
severe bowel obstruction
7/9 Esophageal perforation/
Cecal perforation
Colostomy ND Steroid+ RTX+ PE 84/Death/Hepatitis
F is female, M is male, ND is no data, y is year, CMAS is child myositis assessment score, MSA is myositis-specific antibody, m is month, Pred is prednisone, CYC is cyclophosphamide, IVIG is intravenous immunoglobulin, MTX is methotrexate, MP is methylprednisol, CsA is cyclosporine A, RTX is rituximab, AZA is azathioprine, Thal is thalidomide, HCQ is hydroxychloroquine, Po is peros, CMV is Cytomegalovirus, PE is plasma exchanges, ARDS is acute respiratory distresssyndrome, CAT-A is cutaneous assessment tool activity, CAT-D is cutaneous assessment tool damage
The general data of the 5 patients
Five patients with GI perforation were identified from 120 cases in a JDM cohort (4.17%). Four of these were females, with the age at onset ranging from 3.3 to 9.5 years (median age − 5.0 years). All five patients showed severe rashes, skin ulcers, and weakness of the skeletal muscles (ranging from power 3/5 to 1/5). When these patients were complicated by GI perforation, childhood myositis assessment score (CMAS) ranged from 1 to 5 with the median score of 2, cutaneous assessment tool (CAT) activity score ranged from 2 to 7 with the median score of 6, CAT damage score ranged from 3 to 6 with the median score of 5. No calcification was observed. Two patients also presented with ureteral calculus with hydronephrosis and ureteral stricture. Analysis of MSAs showed that the five patients were anti-NXP2 antibody positive. There are 31 patients with anti-NXP2 antibody positive in the cohort. The incidence of GI perforation in anti-NXP2 antibody positive patients in our study was 16.13% (5/31). One patient had increased level of cytomegalovirus (CMV)-DNA copies in blood. GI perforation occurred from 4 to 13 months after JDM was diagnosed. The symptoms at onset were severe abdominal pain, fever, GI bleeding and vomiting. Perforations occurred in the duodenum (3 patients), duodenum and colon (1 patient), and an unclear location (1 patient), and perforations at multiple sites or at recurrent times occurred in four patients. All patients were treated with corticosteroids and immunosuppressant agents [cyclophosphamide (CYC)/methotrexate (MTX)/cyclosporine A (CsA)]. One patient was treated with plasma exchange (PE) therapy, and two patients received rituximab (RTX). All five patients were given proton-pump inhibitors (omeprazole). Surgery was performed in four patients, of which one patient failed to undergo repair due to the high position of perforation. For the other three patients, perforation repair was successful, of which two patients failed due to recurrent perforation. At 24 months postoperative follow-up, one patient was in complete remission under Pred and MTX treatment, and her ureteral stricture had disappeared. The other four patients died.
Case 1
A 3.4-year-old girl, suffering from characteristic skin rash and muscle weakness was diagnosed with JDM in a local hospital and was treated with Pred(2 mg/kg/d) and MTX (12 mg/m2/wk). Muscle weakness improved after 3 months of treatment, following which the dosage of Pred was reduced. When Pred was reduced to 10 mg/d, the girl developed infection in the lungs, skin ulcers around the anus and abdominal pain. One month later, a perforation in the transverse colon was confirmed, and colostomy was performed in a local hospital. She received Pred, CYC, intravenous immunoglobulin (IVIG) and MTX, after which her abdominal pain disappeared, and her muscle strength improved. Seven months after JDM diagnosis, ureteral calculus with hydronephrosis and ureteral stricture were diagnosed and treated via ureteroscopy. Nine months after JDM diagnosis, she developed severe abdominal pain and worsening muscle weakness, for which pulse methylprednisolone (MP) and CsA were given. Later, GI bleeding and fever recurred. She was transferred to our emergency department. She had shock, and her contrast-enhanced computed tomography (CT) abdomen indicated encapsulated effusion and pneumatosis, duodenal perforation and an abscess, which were confirmed during surgery. After duodenostomy, Pred, pulse CYC and thalidomide were given, and when her condition stabilized, we switched to oral Pred, CYC and MTX. At 24 months postoperative follow-up, she was in complete remission with Pred and MTX treatment, and her ureteral stricture had disappeared.
Case 2
A 5-year-old girl suffering from characteristic skin rash and muscle weakness was diagnosed with JDM in a local hospital and treated with Pred, MTX and hydroxychloroquine (HCQ), after which her muscle strength improved. But her parents stopped the treatment. Twelve months after JDM diagnosis, she was admitted to our emergency department due to abdominal pain, vomiting, and dark coloured stools. Physical examination showed a poor mental response, painful expression, severe malnutrition, High spring sign (+), partially scabbed skin ulcers in the lower jaw, popliteal fossa and axillae and muscle weakness. A contrast-enhanced CT abdomen indicated peritonitis, intestinal perforation and a right renal-ureteral calculus with pelvicalyceal-ureteral dilation. During surgery, multiple perforations of the duodenum and ruptured right hepatic artery were found. The ruptured blood vessel was sutured, but duodeno jejunal tube placement was unsuccessful. The patient subsequently died of infections and haemorrhagic shock.
Case 3
A 3.3-year-old boy suffering from characteristic skin rash and muscle weakness was diagnosed with JDM and treated with Pred, MTX and IVIG in a local hospital. His symptoms improved after treatment; the dosage of Pred was reduced, and MTX was stopped due to cataracts and abnormal liver function. The rash and muscle weakness worsened. Nine months after JDM diagnosis, physical examination revealed that severe proximal muscle weakness (power 3/5) and numerous purplish red rashes and ulcerative scabs which could be seen on the face and limbs. MP, RTX and IVIG were administered in our hospital. Two weeks later, he gradually developed abdominal pain, bloating, low back pain, right lower quadrant tenderness and rebound pain. Localized colitis was suspected based on a CT scan. His abdominal pain and distension were relieved after the administration of antibiotics, MP (20 mg/kg/d for 2 days) and IVIG. Four days later, he developed fever, abdominal pain and distension, and an ultrasound showed echoic enhancement in the omentum of the right lower quadrant with weak peristalsis and ascites. MP, pulse CYC and IVIG were continued, and his temperature returned to normal with improved abdominal pain. However, 7 days later, he experienced severe abdominal pain and distension with a rapid decrease in his haemoglobin (Hb) level (from 112 g/L to 67 g/L). Ultrasound showed abdominal muscle inflammation with haemorrhage, and contrast-enhanced CT showed generalized retroperitoneal infection with abdominal wall haemorrhage and intestinal perforation (Fig. 1). Surgical intervention was not possible in view of unstable vital signs, severe infection, and severe and extensive intestinal lesions that could not be surgically repaired. Repeated blood transfusions, anti-microbial agents, and treatment for the primary disease were given. He persisted to have abdominal pain and bloating. A slight change in body position caused massive abdominal wall bleeding. He died after returning home.
Fig. 1 a The thigh skin ulcers accompanied by swelling of the ipsilateral testis on Case 3(arrow) b. Contrast-enhanced CT showed retroperitoneal effusion (arrow 1), retroperitoneal gas (arrow 2) and abdominal wall hemorrhage (arrow 3) on Case 3. c Contrast-enhanced CT showed retroperitoneal effusion (arrow 1) and retroperitoneal gas (arrow 2) on Case 3
Case 4
A 7-year-old girl with a past history of JDM was treated 1 year earlier with MP and an immunosuppressant. She presented with progressive proximal muscle weakness, skin ulcers and intermittent abdominal pain for 1 month. Physical examination showed severe malnutrition, anemia, maculopapular rashes symmetrically distributed over the extensor sides of the joints of all extremities, partially scabbing skin ulcers on the extensor side of the left elbow and in both axilla, proximal muscle weakness and edema in both upper limbs. Her Hb level was 59 g/L. Abdominal contrast-enhanced CT did not indicate obvious abnormalities. Ultrasound of the abdomen suggested thickening of the abdominal bowel wall and poor bowel motility. After treatment with blood transfusion, MP and CYC were given. Her symptoms improved, and abdominal pain disappeared. Hb decreased again after 2 weeks, and fever and abdominal pain reappeared again after 4 weeks. Abdominal CT revealed bowel perforation. She immediately underwent surgical repair (Fig. 2). One week later, abdominal pain appeared again. Abdominal CT showed another intestinal perforation. Surgical repair and PE therapy were performed. Her abdominal pain was relieved, but she developed severe pulmonary infection. Three days later, she had manifestations of peritonitis and then developed seizures. Her blood pressure was normal, cerebrospinal fluid tests were negative, but her magnetic resonance imaging (MRI) brain showed that the right temporal lobe and bilateral parieto-occipital lobes were swollen with abnormal signals; patchy abnormal signals were observed in the right thalamus, showing long T2 signal, high T2 FLAIR signal, limited dispersion, and reduced ADC value. We speculated primary disease involving the nervous system. Seizures did not recur after treatment of the primary disease. A repeat MRI brain was not done. Pulse MP and anti-microbial agents were given. Surgical intervention was not possible. The patient died due to uncontrolled bleeding and refractory shock.
Fig.2 a Contrast leakage seen at the junction of the descending and horizontal segments of the duodenum on Case 4 (arrow). b Contrast-enhanced CT showed retroperitoneal gas on Case 4 (arrow). c Duodenal perforation can be seen at surgery on Case 4 (arrow)
Case 5
A 10-year-old girl had been diagnosed with JDM 6 months earlier and received Pred and immunosuppressants. She presented with intermittent abdominal pain and fever for 1 month. She was initially treated with pulse MP and IVIG. But her muscle weakness and rash did not improve. She was admitted to our hospital with GI haemorrhage for 3 days. Physical examination showed a poor mental response, painful expression, severe malnutrition, anemia, scattered maculopapular rashes and ulcers distributed in the neck, axillae, buttocks, and extendible joints, and severe proximal muscle weakness. Her Hb level was 54 g/L. Ultrasound of the abdomen suggested thickening of the abdominal bowel wall and poor bowel movements. Pulse RTX and MP were given. Three days later, her abdominal pain worsened. Ultrasound of the abdomen showed intestinal perforation. During surgery, a 5-cm perforation of the transverse part of the duodenum was observed, the perforation was repaired and a double cavity jejunal fistula was performed. Her abdominal pain was relieved. CMV-DNA was detected in the blood, and she was given ganciclovir treatment. Four days later, she again experienced abdominal pain and muscle spasms. Considering the necrosis and perforation of the lower part of the duodenum, her parents withdrew treatment, and the patient died.
Results of the literature review
Sixteen patients of JDM with GI perforation were identified in PubMed, Medline and Scopus [6–18] which were published between 1984 and 2020. Eight patients were female (50%), six patients were male (37.5%), and the sex of two patients was not recorded (12.5%). The age of onset of these patients ranged from 2 to 10.5 years with the median age of 6.5 years. No clear MSA results were recorded in any case. Primary treatment with Pred and immunosuppressants did not have a significant effect. GI symptoms occurred from one to 108 months after treatment, most of which occurred within 10 months. The initial GI symptoms were severe abdominal pain with fever or vomiting. Perforations were reported in the duodenum (10/16, 62.5%), colon (6/16, 37.5%), jejunum (2/16, 12.5%), oesophagus (2/16, 12.5%), gastric pylorus (1/16, 6.25%), caecum (1/16, 6.25%) and an unclear location (1/16, 6.25%); perforations at multiple sites or recurrent perforations were reported in six patients (6/16, 37.5%). Only five patients had records regarding treatment of the initial disease, and they were treated with Pred or MP and an immunosuppressant (CYC/CsA). One patient underwent PE therapy, one patient received PE therapy with RTX and surgery was performed in 14 patients. In particular, one patient was treated with ganciclovir for CMV infection. Four patients died (25%), and the others were discharged from the hospital after they experienced relief of their symptoms. The clinical data of all 16 patients taken from the literature and the five patients in our study is summarized in Table 1.
Discussion
JDM, the most common inflammatory myopathy of childhood, is a rare systemic autoimmune vasculopathy that is characterized by weakness in proximal muscles and pathognomonic skin rashes [19]. Multiple systems can be involved, but GI perforations in anti-NXP2 antibody-associated JDM are rarely reported. From among 120 patients with JDM, we report five anti-NXP2 antibody-associated JDM complicated by GI perforation. Most patients in our study were females, with a proportion that was significantly higher than that for the other patients reported in the literature. At the age of onset of these five patients ranged from 3.3 to 9.5 years with the median age of 5.0 years, and GI perforations appeared between 4 and 13 months post diagnosis, which was similar to the 16 cases reported in the literature. When our patients were complicated by GI perforation, CMAS were very low, CAT activity score indicated moderate activity, which suggest that GI perforations may be associated with disease severity and activity. The initial symptoms of JDM with GI perforation were severe abdominal pain, abdominal distention, vomiting, fever and bloody stools. Early identification of perforation was very difficult. With regard to patient (P) 1 and P2, the doctors did not recognize that GI perforation had occurred after persistent abdominal pain for more than 1 month. The perforation in P3 occurred during hospitalization in our hospital and manifested as severe abdominal pain and distension with decreased bowel sounds. Repeated abdominal ultrasounds, X-rays and contrast-enhanced CTs indicated the presence of a low-signal mass in the right lower quadrant with bowel distension, thinning of the intestinal wall and local colitis without pneumoperitoneum or subphrenic pneumatosis. Transitory relief of symptoms occurred after treatment, but severe abdominal pain quickly reappeared, and contrast-enhanced CT and ultrasound showed intestinal perforation, diffuse abdominal wall bleeding and infection. We did not know the precise time when the perforation occurred, suggesting that once abdominal pain appears, perforation should be strongly suspected, and imaging should be performed. Perforation should be considered when abdominal pain is not relieved by active treatment in patients with JDM, and it can be diagnosed early with contrast-enhanced CT scans [6]. We also suggest that repeated scanning and GI angiograms are essential, if the diagnosis cannot be confirmed during the first scan. In the 16 patients in the literature, perforation often occurred in the duodenum (partially in the retroperitoneal area in P6) and the colon. In addition, multi-site or recurrent perforations were also observed in some patients (P7,P10,P16,P18,P20,P21), similar to the results of our study. Furthermore, arterial rupture near the perforation site often occurs, as observed in P2, who had ruptured hepatic arteries, and in P10, who had a ruptured duodenal proximal mesenteric artery; therefore, haemorrhage may also be considered when an unexplained decrease in the Hb level occurs in JDM patients. In addition, several patients have been described in literature with Degos-like lesions linked to GI perforation [20, 21]. A similar deposit complex and pattern of vasculopathy has been found in patients suffering from Degos disease and JDM [22]. We should pay attention to the identification of Degos-like disease. Degos - like skin lesions were initially pale red papules followed by enlarged lesions, showing a characteristic pitting center with a concave navel porcelain white center and a red halo around the periphery. After the rash subsided, there was a white superficial scar. The rash is more common on the trunk and extremities, less common on the palms and feet, and often occurs in batches, old and new. The appearance and location of the rash in five patients of our study were different from Degos-like disease. Further hisopathological identification may be performed if necessary.
In addition, two patients (P1, P2) had urinary system involvement in this group of cases, including ureteral stones, uretero-pelvic dilation and ureteral stenosis. With remission of the primary disease, ureteral stenosis disappeared in P1. This leads us to speculate that ureteral stenosis may be related to vasculopathy involving the urinary system. Morita et al. [23] reported a case of dermatomyositis who developed duodenal perforation as well as ureteral stenosis, with biopsy of stenotic ureter showing calcification with granulomatous tissue without any vasculitic lesion. Ruby Haviv et al. [24] reported a case of juvenile polymyositis (JPM) with right ureteral obstruction secondary to necrosis. The histopathology report of the resected ureter revealed moderate, acute, and chronic inflammatory infiltrates within the ureter wall, urothelial erosions, superficial granulation tissue, and degenerated smooth muscle fibres within the muscularis propria; some of which were infiltrated with lymphocytes and plasma cells, and multiple calcifications within the lamina propria. It also showed fragments of gross calcifications, similar calcifications in other parts of the ureter and obstructing calcifications within small blood vessels. Ruby Haviv et al. considered calcified ureteral necrosis to be a feature of visceral vasculopathy, related to both JDM and JPM. The mechanism is obscure, and the presence of calcifications within visceral tissues might suggest the pathogenesis of the typical calcinosis related to these diseases [24]. Considering that NXP-2 is a type prone to calcification, it was not clear whether ureteral calculi and ureteral stenosis in P1 and P2 were related to vasculopathy with calcification, which needs further studies of visceral calcinosis.
The underlying mechanisms of GI perforation in JDM are still obscure. Some researchers have reported glucocorticoids, non-steroidal anti inflammatory drugs and MTX to be risk factors for GI ulceration and perforation, especially at 1 month post-treatment or with an accumulated dose of steroids higher than 1 g [17]. In our study, Pred was reduced to a small dose before GI symptoms appeared in P1. After perforation was identified, pulse MP pulse and CYC were given, and the patient’s condition improved; thus, the perforation was not attributed to drug factors. Schneider et al. [6] assumed that ulceration in the proximal region and bulb of the duodenum was related to medication, while perforation in the descending part was related to vasculitis, causing intestinal ischemia and necrosis due to thrombogenesis and vascular occlusion. Recent researchers [16, 17] reported that perforated sites showed chronic vasculopathy rather than acute vasculitis. This chronic vasculopathy is characterized by narrowing or complete occlusion of multiple small and medium arteries, subintimal foam cells, fibromyxoid neointimal expansion, and significant luminal compromise with infiltration of macrophages through the muscle layers into the intima. Histopathology at the perforation site was recorded in three patients (P6, P12, P19) in the literature [6, 9, 13], and no vasculitis was noted. P12 exhibited mucosal ischemia, and P19 exhibited vasculopathy and CMV colitis. No manifestation of vasculitis was observed in the histopathology of the fistula. Histopathology of perforation site in P1 of our study showed inflammatory cells infiltrate and no vasculitic lesion was observed in the tissue. The other three patients were unable to undergo histopathology due to erosion of the perforation site. Therefore, whether chronic non-inflammatory vasculopathy causes ischemia and perforation must be considered. Bhaskaran et al. [13] reported a case of intestinal perforation in a child with JDM caused by CMV colitis. CMV-DNA was also detected in the blood of P5. No relevant pathological tests were performed. The other four patients did not undergo blood CMV-DNA tests. The role of CMV colitis in perforation requires further study.
The 120 patients in the JDM cohort were all tested by MSAs analysis, all five patients with GI perforation had strong positivity for anti-NXP2 antibody (3+), and no GI perforation was noted in other MSA patients, which led us question whether anti-NXP2 antibody is associated with GI perforation. After reviewing 16 cases in the literature, Besnard et al. [13] reported that most patients with severe GI manifestations were positive for anti-NXP2 antibody or anti-TIF-1γ antibody. Unfortunately, no specific antibody type was recorded in two patients with GI perforation in this study. The other patients described in the literature had not been tested for MSAs. In 2017, Tansley et al. [25] mentioned that 14 children who were positive for anti-NXP2 antibody had ulcers. Aouizerate et al. [26] reported that anti-NXP2 antibody had a positive association with GI involvement in JDM. The study evaluated the clinical, biological, and histological manifestations of 23 JDM patients and performed a multivariate analysis of 26 histopathological parameters. A case-control study can be performed to further uncover the relationship between anti-NXP2 antibody and GI perforation, which may further reveal the pathological mechanism of GI perforation. Based on our experience in this study, or even early in disease, clinicians should be highly alert to the possibility of GI perforation when abdominal pain occurs on anti-NXP2 antibody-positive patients with JDM.
The mortality rate among our patients was higher than that reported in the literature, which might be due to their severe condition and poor response to various therapeutic drugs, delayed surgery, surgical difficulties at the perforation site, economic reasons and the deficient number of cases. When a patient has intermittent abdominal pain and GI ulcers, the primary disease should be treated more actively to prevent GI perforation. Once GI perforation occurs, the primary disease is not well controlled, and the prognosis is poor. We need more research to choose appropriate treatment strategy for these diseases.
Conclusion
In this study, the clinical details of five cases of anti-NXP2 antibody-associated JDM complicated by GI perforation were summarized for the first time. Based on the these cases combined with a literature review, we suggest that once JDM patients present with abdominal pain, especially anti-NXP2 antibody-positive patients, GI perforation should be considered. For timely diagnosis, dynamic imaging is important. GI perforation may be a fatal complication of JDM, more research is needed to determine the pathogenesis and predictive factors of GI perforation in JDM.
Abbreviations
JDMJuvenile dermatomyositis
NXP2Nuclear matrix protein 2
GIGastrointestinal
MSAMyositis-specific antibody
CMASChild myositis assessment score
PredPrednisone
CYCCyclophosphamide
IVIGIntravenous immunoglobulin
MTXMethotrexate
MPMethylprednisolone
CsACyclosporine A
RTXRituximab
AZAAzathioprine
ThalThalidomide
PEPlasma exchanges
CMVCytomegalovirus
CTComputed tomography
HCQHydroxychloroquine
HbHaemoglobin
MRIMagnetic resonance imaging
JPMJuvenile polymyositis
CATCutaneous assessment tool
PPatient
Publisher’s Note
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Acknowledgement
We would like to thank the Department of General Surgery, the Department of Intensive Medicine and the Department of Radiology of the Children’'s Hospital Affiliated to the Capital Institute of Pediatrics for their contributions to the treatment of patients in our study.
Authors’ contributions
YX wrote the first draft of the manuscript, contributed to patient management and to the literature review. XM made many contributions in the process of writing and revising the manuscript. ZZ supervised patient management. JL critically revised the manuscript and supervised patient management. JH, JZ, MK and JL contributed to patient management. XL revised the manuscript. All the authors read and approved the final version of the manuscript.
Funding
This work was supported by Beijing Municipal Administration of Hospitals Clinical Medicine Development of Special Funding Support (code: XMLX201813) and Capital Funds for Health Improvement and Research (code:2020–2-2102).
Availability of data and materials
The datasets during and/or analyzed during the current study available from the corresponding author on reasonable request.
Ethics approval and consent to participate
Parental informed consent for publication was obtained. This study was approved by the Ethics Committee of Capital Institute of Pediatrics.
Consent for publication
Written informed consent was obtained from the patient’s legal guardians for publication of this case report and any accompanying images.
Competing interests
The authors declare that they have no competing interests. | CYCLOSPORINE, METHYLPREDNISOLONE SODIUM SUCCINATE | DrugsGivenReaction | CC BY | 33407602 | 18,840,448 | 2021-01-06 |
What was the administration route of drug 'HUMAN IMMUNOGLOBULIN G'? | Gastrointestinal perforation in anti-NXP2 antibody-associated juvenile dermatomyositis: case reports and a review of the literature.
BACKGROUND
To summarize the characteristics of gastrointestinal (GI) perforation in anti-nuclear matrix protein 2 (NXP2) antibody-associated juvenile dermatomyositis (JDM).
METHODS
Five patients with GI perforation from a JDM cohort of 120 cases are described. Relevant literature was reviewed.
RESULTS
Five patients, including four females and one male, were included in the study. The age of onset of these patients ranged from 3.3 to 9.5 years with the median age of 5.0 years. When these patients were complicated by GI perforation, childhood myositis assessment score (CMAS) ranged from 1 to 5 with the median score of 2. Myositis-specific antibody (MSA) spectrum analysis indicated that the five patients were anti-NXP2 antibody positive. The initial symptoms of GI perforation were progressive abdominal pain and intermittent fever. Two patients also presented with ureteral calculus with hydronephrosis and ureteral stricture. Surgery was performed in four patients. One patient failed to undergo a repair as the perforation was high in position. For the other three patients, perforation repair was successful, of which two patients failed due to recurrent perforation. At 24 months postoperative follow-up, one patient was in complete remission on prednisone (Pred) and methotrexate (MTX) treatment, and her ureteral stricture had disappeared. The other four patients died. Adding these cases with 16 other patients described in the literature, the symptom at onset was progressive abdominal pain, which often occurred within 10 months after JDM was diagnosed. Perforation most commonly occurred in the duodenum, although it also occurred at multiple sites or was recurrent. The mortality rate of GI perforation in JDM was 38% (8/21).
CONCLUSIONS
All the five perforation cases in our study subjected to MSA analysis were anti-NXP2 antibody positive. The symptom at onset was abdominal pain. The most common site of perforation was the duodenum in the retroperitoneum, and the lack of acute abdominal manifestations prevented early diagnosis. GI perforation may be a fatal complication in JDM, and early diagnosis is very important. More research is needed to determine the pathogenesis and predictive factors of GI perforation in JDM.
Background
Juvenile dermatomyositis (JDM) is an autoimmune disease characterized by proximal myopathy and a characteristic rash. However, multiple systems, including the digestive system, can also be involved. The occurrence of gastrointestinal (GI) perforation is rare, but a high mortality rate has been reported due to atypical symptoms and difficulty in early diagnosis [1]. Myositis-specific autoantibodies (MSAs) are increasingly used to delineate distinct subgroups of JDM [2, 3]. The presence of anti-nuclear matrix protein 2 (NXP2) autoantibodies substantially increases the risk of calcinosis across all ages and is associated with disease severity [4]. The role of MSAs in cases of JDM complicated by GI perforation has not been reported. Here, from among 120 patients with JDM, we report five cases complicated by GI perforation. All five patients had anti-NXP2 antibody-associated JDM. In addition, we reviewed the other JDM cases with GI perforation reported in the literature to improve our recognition of this disease. Anti-NXP2 autoantibodies may facilitate early diagnosis of the disease.
Methods
We described five patients with GI perforation from a JDM cohort who were admitted to the Children’s Hospital affiliated with the Capital Institute of Pediatrics, China, from January 2016 to December 2019. The inclusion criteria were: (1) age < 18 years old; (2) diagnosis of JDM based on the Bohan and Peter criteria for myositis [5]; and (3) GI perforation. Patients with other diseases that cause weakness or rash, or a clear alternative diagnosis were excluded from the study. Sixteen MSAs (MDA-5, NXP2, Jo-1, PM-SCL100, PL-7, PL-12, EJ, OJ, anti-Ro52, Ku, PM-Scl, SRP, SAE1, TIF1γ, Mi-2α and Mi-2β) were tested by immune dot blot hybridization using a commercial kit based on goat anti-human IgG antibodies (BlueDot Myositis 12 IgG, #MYO12D-24, D-TEK, Belgium). The study was approved by the Ethics Committee of Capital Institute of Pediatrics. We searched PubMed, Medline and Scopus using the keywords “juvenile dermatomyositis”, “gastrointestinal perforation”, and “perforation”. These literatures with detailed cases which clearly diagnosed JDM and excluded Degos-like presentation with GI perforation were reviewed.
Results (Table 1)
Table 1 Clinical data of JDM patients with GI perforation
Patient
/Year Gender Age at onset (y) CMAS score CAT-A
score CAT-D
score Positive for MSA Treatment before
GI perforation Symptoms of GI perforation Duration from onset to perforation (m) Site of perforation Surgical
treatment Histopathology of perforation site Medical Treatment Follow-up(m)
/Outcome
P1 F 3.4 5 2 3 Anti-NXP2 Pred+MTX + IVIG Abdominal pain/
bloody stools
4/9 Duodenum/ colon Transverse colon ostomyv
duodenostomy
Inflammatory cells infiltrate/
No vasculitis
Pred+Mp pulse+CsA+
IVIG→Pred+Thal+CYC→
Pred+CYC (Po) + MTX → Pred+MTX
24/Remission
P2 F 5.0 1 7 5 Anti-NXP2 MP + MP Pulse+CYC
HCQ/MP + MP Pulse+MTX
Abdominal pain/
bloody stools
10 Duodenum/
Duodenal bulb hepatic
artery rupture
Vessel sutured/
placement of duodenal
jejunal tube (failed)
ND Pred+MP Pulse+CYC+
IVIG
Death/Infection
P3 M 3.3 5 6 5 Anti-NXP2 Pred+MTX + IVIG/
Pred+IVIG +RTX
Abdominal pain
and distention bloody stools
10 Unknown No surgery ND MP pulse+CYC + IVIG Death/Abdominal bleeding
P4 F 6 2 6 6 Anti-NXP2 Pred+ MTX/CsA
→MP pulse+IVIG+CYC
Abdominal pain/
bloody stools
13 Duodenum×2 Perforation repair×2 ND CYC → MP pulse +IVIG+PE Death/Shock
P5 F 9.5 2 6 4 Anti-NXP2 Pred+ MTX/CsA Abdominal pain/ fever and bloody stools 6 Duodenum×2 Perforation repair ND MP pulse+ RTX Death/Abandon treatment
P6 [6]
/2016
F 7.0 ND ND ND ND Pred+MTX Abdominal pain vomiting and fever 6 Duodenal retroperitoneum Perforation repair No vasculitis ND ND/Improved
P7 [7]
/1997
M 7.0 ND ND ND ND Pred Abdominal pain /vomit 24 Duodenum Jejunum Perforation repair ND PE
Pred+MP pulse+CYC
12/Stable
P8 [8]
/1988
F 5.0 ND ND ND ND Pred Abdominal pain 3 Colon Perforation repair ND ND 12/Stable
P9 [8]
/1988
F 7.0 ND ND ND ND Pred +MTX Abdominal pain 6 The third duodenum ND ND ND 3/ND
P10 [8]
/1988
M 8.0 ND ND ND ND Pred+MTX Abdominal pain/
fever
6 Esophagus/
duodenum/ colon
Mesenteric arterial rupture
Perforation repair ND ND ND/Improved
P11 [8]
/1988
F 6.0 ND ND ND ND Pred+MTX Abdominal pain and distention/fever 5 Duodenum Perforation repair ND ND Death/unknown
P12 [9]
/2001
M 4.0 ND ND ND ND Pred+AZA Abdominal pain/
vomiting/fever
2 Duodenum Perforation repair Mucosal ischemia Pred+MP pulse 19/ND
P13 [10]
/2014
M 2.0 ND ND ND ND ND Abdominal pain 108 Unknown ND ND ND Death/unknown
P14 [11]
/1985
F 4.0 ND ND ND ND ND ND 48 Gastric pylorus Partial gastrectomy and gastrojejunostomy ND ND ND/Stable.
P15 [11]
/1985
F 5.0 ND ND ND ND ND ND 3 Middle transverse colon Loop transverse colon fistula ND ND Death/ARDS
P16 [11]
/1985
F 6.0 ND ND ND ND Pred+MTX/Pred+AZA/
Pre + CYC
Abdominal pain/
vomiting/fever
10 Duodenum colon transverse colon Multiple perforation repair ND ND 7/Stable.
P17 [11]
/1985
M 9.0 ND ND ND ND Pred/Pred+MTX/
Pred+AZA
Abdominal pain/ fever 13 Duodenum Perforation repair ND ND ND/Stable.
P18 [12]
/1984
M 7.0 ND ND ND ND Pred+MTX Abdominal pain 10 Duodenal perforation/
colon perforations
Perforation repair ND ND 48/Stable.
P19 [13]
/2019
F 6.0 ND ND ND ND Pred+MTX Abdominal pain/fever 1 transverse colon, Perforation repair
and loop colostomy.
No vasculitis and vasculopathy/
CMV colitis
Steroid+IVIG+Ganciclovir 12/Remission
P20 [14]
/2020
ND 10.5 16 ND ND ND ND Abdominal pain/ GI hemorrhage/ severe bowel obstruction 8/20 Duodenal Perforation/
Jejunal perforation
Jejunal resection/ exclusive parenteral
nutrition/ antibiotics,
ND Steroid+CsA 108/Remission
P21 [14]
/2020
ND 10.7 5 ND ND ND ND Abdominal pain/
severe bowel obstruction
7/9 Esophageal perforation/
Cecal perforation
Colostomy ND Steroid+ RTX+ PE 84/Death/Hepatitis
F is female, M is male, ND is no data, y is year, CMAS is child myositis assessment score, MSA is myositis-specific antibody, m is month, Pred is prednisone, CYC is cyclophosphamide, IVIG is intravenous immunoglobulin, MTX is methotrexate, MP is methylprednisol, CsA is cyclosporine A, RTX is rituximab, AZA is azathioprine, Thal is thalidomide, HCQ is hydroxychloroquine, Po is peros, CMV is Cytomegalovirus, PE is plasma exchanges, ARDS is acute respiratory distresssyndrome, CAT-A is cutaneous assessment tool activity, CAT-D is cutaneous assessment tool damage
The general data of the 5 patients
Five patients with GI perforation were identified from 120 cases in a JDM cohort (4.17%). Four of these were females, with the age at onset ranging from 3.3 to 9.5 years (median age − 5.0 years). All five patients showed severe rashes, skin ulcers, and weakness of the skeletal muscles (ranging from power 3/5 to 1/5). When these patients were complicated by GI perforation, childhood myositis assessment score (CMAS) ranged from 1 to 5 with the median score of 2, cutaneous assessment tool (CAT) activity score ranged from 2 to 7 with the median score of 6, CAT damage score ranged from 3 to 6 with the median score of 5. No calcification was observed. Two patients also presented with ureteral calculus with hydronephrosis and ureteral stricture. Analysis of MSAs showed that the five patients were anti-NXP2 antibody positive. There are 31 patients with anti-NXP2 antibody positive in the cohort. The incidence of GI perforation in anti-NXP2 antibody positive patients in our study was 16.13% (5/31). One patient had increased level of cytomegalovirus (CMV)-DNA copies in blood. GI perforation occurred from 4 to 13 months after JDM was diagnosed. The symptoms at onset were severe abdominal pain, fever, GI bleeding and vomiting. Perforations occurred in the duodenum (3 patients), duodenum and colon (1 patient), and an unclear location (1 patient), and perforations at multiple sites or at recurrent times occurred in four patients. All patients were treated with corticosteroids and immunosuppressant agents [cyclophosphamide (CYC)/methotrexate (MTX)/cyclosporine A (CsA)]. One patient was treated with plasma exchange (PE) therapy, and two patients received rituximab (RTX). All five patients were given proton-pump inhibitors (omeprazole). Surgery was performed in four patients, of which one patient failed to undergo repair due to the high position of perforation. For the other three patients, perforation repair was successful, of which two patients failed due to recurrent perforation. At 24 months postoperative follow-up, one patient was in complete remission under Pred and MTX treatment, and her ureteral stricture had disappeared. The other four patients died.
Case 1
A 3.4-year-old girl, suffering from characteristic skin rash and muscle weakness was diagnosed with JDM in a local hospital and was treated with Pred(2 mg/kg/d) and MTX (12 mg/m2/wk). Muscle weakness improved after 3 months of treatment, following which the dosage of Pred was reduced. When Pred was reduced to 10 mg/d, the girl developed infection in the lungs, skin ulcers around the anus and abdominal pain. One month later, a perforation in the transverse colon was confirmed, and colostomy was performed in a local hospital. She received Pred, CYC, intravenous immunoglobulin (IVIG) and MTX, after which her abdominal pain disappeared, and her muscle strength improved. Seven months after JDM diagnosis, ureteral calculus with hydronephrosis and ureteral stricture were diagnosed and treated via ureteroscopy. Nine months after JDM diagnosis, she developed severe abdominal pain and worsening muscle weakness, for which pulse methylprednisolone (MP) and CsA were given. Later, GI bleeding and fever recurred. She was transferred to our emergency department. She had shock, and her contrast-enhanced computed tomography (CT) abdomen indicated encapsulated effusion and pneumatosis, duodenal perforation and an abscess, which were confirmed during surgery. After duodenostomy, Pred, pulse CYC and thalidomide were given, and when her condition stabilized, we switched to oral Pred, CYC and MTX. At 24 months postoperative follow-up, she was in complete remission with Pred and MTX treatment, and her ureteral stricture had disappeared.
Case 2
A 5-year-old girl suffering from characteristic skin rash and muscle weakness was diagnosed with JDM in a local hospital and treated with Pred, MTX and hydroxychloroquine (HCQ), after which her muscle strength improved. But her parents stopped the treatment. Twelve months after JDM diagnosis, she was admitted to our emergency department due to abdominal pain, vomiting, and dark coloured stools. Physical examination showed a poor mental response, painful expression, severe malnutrition, High spring sign (+), partially scabbed skin ulcers in the lower jaw, popliteal fossa and axillae and muscle weakness. A contrast-enhanced CT abdomen indicated peritonitis, intestinal perforation and a right renal-ureteral calculus with pelvicalyceal-ureteral dilation. During surgery, multiple perforations of the duodenum and ruptured right hepatic artery were found. The ruptured blood vessel was sutured, but duodeno jejunal tube placement was unsuccessful. The patient subsequently died of infections and haemorrhagic shock.
Case 3
A 3.3-year-old boy suffering from characteristic skin rash and muscle weakness was diagnosed with JDM and treated with Pred, MTX and IVIG in a local hospital. His symptoms improved after treatment; the dosage of Pred was reduced, and MTX was stopped due to cataracts and abnormal liver function. The rash and muscle weakness worsened. Nine months after JDM diagnosis, physical examination revealed that severe proximal muscle weakness (power 3/5) and numerous purplish red rashes and ulcerative scabs which could be seen on the face and limbs. MP, RTX and IVIG were administered in our hospital. Two weeks later, he gradually developed abdominal pain, bloating, low back pain, right lower quadrant tenderness and rebound pain. Localized colitis was suspected based on a CT scan. His abdominal pain and distension were relieved after the administration of antibiotics, MP (20 mg/kg/d for 2 days) and IVIG. Four days later, he developed fever, abdominal pain and distension, and an ultrasound showed echoic enhancement in the omentum of the right lower quadrant with weak peristalsis and ascites. MP, pulse CYC and IVIG were continued, and his temperature returned to normal with improved abdominal pain. However, 7 days later, he experienced severe abdominal pain and distension with a rapid decrease in his haemoglobin (Hb) level (from 112 g/L to 67 g/L). Ultrasound showed abdominal muscle inflammation with haemorrhage, and contrast-enhanced CT showed generalized retroperitoneal infection with abdominal wall haemorrhage and intestinal perforation (Fig. 1). Surgical intervention was not possible in view of unstable vital signs, severe infection, and severe and extensive intestinal lesions that could not be surgically repaired. Repeated blood transfusions, anti-microbial agents, and treatment for the primary disease were given. He persisted to have abdominal pain and bloating. A slight change in body position caused massive abdominal wall bleeding. He died after returning home.
Fig. 1 a The thigh skin ulcers accompanied by swelling of the ipsilateral testis on Case 3(arrow) b. Contrast-enhanced CT showed retroperitoneal effusion (arrow 1), retroperitoneal gas (arrow 2) and abdominal wall hemorrhage (arrow 3) on Case 3. c Contrast-enhanced CT showed retroperitoneal effusion (arrow 1) and retroperitoneal gas (arrow 2) on Case 3
Case 4
A 7-year-old girl with a past history of JDM was treated 1 year earlier with MP and an immunosuppressant. She presented with progressive proximal muscle weakness, skin ulcers and intermittent abdominal pain for 1 month. Physical examination showed severe malnutrition, anemia, maculopapular rashes symmetrically distributed over the extensor sides of the joints of all extremities, partially scabbing skin ulcers on the extensor side of the left elbow and in both axilla, proximal muscle weakness and edema in both upper limbs. Her Hb level was 59 g/L. Abdominal contrast-enhanced CT did not indicate obvious abnormalities. Ultrasound of the abdomen suggested thickening of the abdominal bowel wall and poor bowel motility. After treatment with blood transfusion, MP and CYC were given. Her symptoms improved, and abdominal pain disappeared. Hb decreased again after 2 weeks, and fever and abdominal pain reappeared again after 4 weeks. Abdominal CT revealed bowel perforation. She immediately underwent surgical repair (Fig. 2). One week later, abdominal pain appeared again. Abdominal CT showed another intestinal perforation. Surgical repair and PE therapy were performed. Her abdominal pain was relieved, but she developed severe pulmonary infection. Three days later, she had manifestations of peritonitis and then developed seizures. Her blood pressure was normal, cerebrospinal fluid tests were negative, but her magnetic resonance imaging (MRI) brain showed that the right temporal lobe and bilateral parieto-occipital lobes were swollen with abnormal signals; patchy abnormal signals were observed in the right thalamus, showing long T2 signal, high T2 FLAIR signal, limited dispersion, and reduced ADC value. We speculated primary disease involving the nervous system. Seizures did not recur after treatment of the primary disease. A repeat MRI brain was not done. Pulse MP and anti-microbial agents were given. Surgical intervention was not possible. The patient died due to uncontrolled bleeding and refractory shock.
Fig.2 a Contrast leakage seen at the junction of the descending and horizontal segments of the duodenum on Case 4 (arrow). b Contrast-enhanced CT showed retroperitoneal gas on Case 4 (arrow). c Duodenal perforation can be seen at surgery on Case 4 (arrow)
Case 5
A 10-year-old girl had been diagnosed with JDM 6 months earlier and received Pred and immunosuppressants. She presented with intermittent abdominal pain and fever for 1 month. She was initially treated with pulse MP and IVIG. But her muscle weakness and rash did not improve. She was admitted to our hospital with GI haemorrhage for 3 days. Physical examination showed a poor mental response, painful expression, severe malnutrition, anemia, scattered maculopapular rashes and ulcers distributed in the neck, axillae, buttocks, and extendible joints, and severe proximal muscle weakness. Her Hb level was 54 g/L. Ultrasound of the abdomen suggested thickening of the abdominal bowel wall and poor bowel movements. Pulse RTX and MP were given. Three days later, her abdominal pain worsened. Ultrasound of the abdomen showed intestinal perforation. During surgery, a 5-cm perforation of the transverse part of the duodenum was observed, the perforation was repaired and a double cavity jejunal fistula was performed. Her abdominal pain was relieved. CMV-DNA was detected in the blood, and she was given ganciclovir treatment. Four days later, she again experienced abdominal pain and muscle spasms. Considering the necrosis and perforation of the lower part of the duodenum, her parents withdrew treatment, and the patient died.
Results of the literature review
Sixteen patients of JDM with GI perforation were identified in PubMed, Medline and Scopus [6–18] which were published between 1984 and 2020. Eight patients were female (50%), six patients were male (37.5%), and the sex of two patients was not recorded (12.5%). The age of onset of these patients ranged from 2 to 10.5 years with the median age of 6.5 years. No clear MSA results were recorded in any case. Primary treatment with Pred and immunosuppressants did not have a significant effect. GI symptoms occurred from one to 108 months after treatment, most of which occurred within 10 months. The initial GI symptoms were severe abdominal pain with fever or vomiting. Perforations were reported in the duodenum (10/16, 62.5%), colon (6/16, 37.5%), jejunum (2/16, 12.5%), oesophagus (2/16, 12.5%), gastric pylorus (1/16, 6.25%), caecum (1/16, 6.25%) and an unclear location (1/16, 6.25%); perforations at multiple sites or recurrent perforations were reported in six patients (6/16, 37.5%). Only five patients had records regarding treatment of the initial disease, and they were treated with Pred or MP and an immunosuppressant (CYC/CsA). One patient underwent PE therapy, one patient received PE therapy with RTX and surgery was performed in 14 patients. In particular, one patient was treated with ganciclovir for CMV infection. Four patients died (25%), and the others were discharged from the hospital after they experienced relief of their symptoms. The clinical data of all 16 patients taken from the literature and the five patients in our study is summarized in Table 1.
Discussion
JDM, the most common inflammatory myopathy of childhood, is a rare systemic autoimmune vasculopathy that is characterized by weakness in proximal muscles and pathognomonic skin rashes [19]. Multiple systems can be involved, but GI perforations in anti-NXP2 antibody-associated JDM are rarely reported. From among 120 patients with JDM, we report five anti-NXP2 antibody-associated JDM complicated by GI perforation. Most patients in our study were females, with a proportion that was significantly higher than that for the other patients reported in the literature. At the age of onset of these five patients ranged from 3.3 to 9.5 years with the median age of 5.0 years, and GI perforations appeared between 4 and 13 months post diagnosis, which was similar to the 16 cases reported in the literature. When our patients were complicated by GI perforation, CMAS were very low, CAT activity score indicated moderate activity, which suggest that GI perforations may be associated with disease severity and activity. The initial symptoms of JDM with GI perforation were severe abdominal pain, abdominal distention, vomiting, fever and bloody stools. Early identification of perforation was very difficult. With regard to patient (P) 1 and P2, the doctors did not recognize that GI perforation had occurred after persistent abdominal pain for more than 1 month. The perforation in P3 occurred during hospitalization in our hospital and manifested as severe abdominal pain and distension with decreased bowel sounds. Repeated abdominal ultrasounds, X-rays and contrast-enhanced CTs indicated the presence of a low-signal mass in the right lower quadrant with bowel distension, thinning of the intestinal wall and local colitis without pneumoperitoneum or subphrenic pneumatosis. Transitory relief of symptoms occurred after treatment, but severe abdominal pain quickly reappeared, and contrast-enhanced CT and ultrasound showed intestinal perforation, diffuse abdominal wall bleeding and infection. We did not know the precise time when the perforation occurred, suggesting that once abdominal pain appears, perforation should be strongly suspected, and imaging should be performed. Perforation should be considered when abdominal pain is not relieved by active treatment in patients with JDM, and it can be diagnosed early with contrast-enhanced CT scans [6]. We also suggest that repeated scanning and GI angiograms are essential, if the diagnosis cannot be confirmed during the first scan. In the 16 patients in the literature, perforation often occurred in the duodenum (partially in the retroperitoneal area in P6) and the colon. In addition, multi-site or recurrent perforations were also observed in some patients (P7,P10,P16,P18,P20,P21), similar to the results of our study. Furthermore, arterial rupture near the perforation site often occurs, as observed in P2, who had ruptured hepatic arteries, and in P10, who had a ruptured duodenal proximal mesenteric artery; therefore, haemorrhage may also be considered when an unexplained decrease in the Hb level occurs in JDM patients. In addition, several patients have been described in literature with Degos-like lesions linked to GI perforation [20, 21]. A similar deposit complex and pattern of vasculopathy has been found in patients suffering from Degos disease and JDM [22]. We should pay attention to the identification of Degos-like disease. Degos - like skin lesions were initially pale red papules followed by enlarged lesions, showing a characteristic pitting center with a concave navel porcelain white center and a red halo around the periphery. After the rash subsided, there was a white superficial scar. The rash is more common on the trunk and extremities, less common on the palms and feet, and often occurs in batches, old and new. The appearance and location of the rash in five patients of our study were different from Degos-like disease. Further hisopathological identification may be performed if necessary.
In addition, two patients (P1, P2) had urinary system involvement in this group of cases, including ureteral stones, uretero-pelvic dilation and ureteral stenosis. With remission of the primary disease, ureteral stenosis disappeared in P1. This leads us to speculate that ureteral stenosis may be related to vasculopathy involving the urinary system. Morita et al. [23] reported a case of dermatomyositis who developed duodenal perforation as well as ureteral stenosis, with biopsy of stenotic ureter showing calcification with granulomatous tissue without any vasculitic lesion. Ruby Haviv et al. [24] reported a case of juvenile polymyositis (JPM) with right ureteral obstruction secondary to necrosis. The histopathology report of the resected ureter revealed moderate, acute, and chronic inflammatory infiltrates within the ureter wall, urothelial erosions, superficial granulation tissue, and degenerated smooth muscle fibres within the muscularis propria; some of which were infiltrated with lymphocytes and plasma cells, and multiple calcifications within the lamina propria. It also showed fragments of gross calcifications, similar calcifications in other parts of the ureter and obstructing calcifications within small blood vessels. Ruby Haviv et al. considered calcified ureteral necrosis to be a feature of visceral vasculopathy, related to both JDM and JPM. The mechanism is obscure, and the presence of calcifications within visceral tissues might suggest the pathogenesis of the typical calcinosis related to these diseases [24]. Considering that NXP-2 is a type prone to calcification, it was not clear whether ureteral calculi and ureteral stenosis in P1 and P2 were related to vasculopathy with calcification, which needs further studies of visceral calcinosis.
The underlying mechanisms of GI perforation in JDM are still obscure. Some researchers have reported glucocorticoids, non-steroidal anti inflammatory drugs and MTX to be risk factors for GI ulceration and perforation, especially at 1 month post-treatment or with an accumulated dose of steroids higher than 1 g [17]. In our study, Pred was reduced to a small dose before GI symptoms appeared in P1. After perforation was identified, pulse MP pulse and CYC were given, and the patient’s condition improved; thus, the perforation was not attributed to drug factors. Schneider et al. [6] assumed that ulceration in the proximal region and bulb of the duodenum was related to medication, while perforation in the descending part was related to vasculitis, causing intestinal ischemia and necrosis due to thrombogenesis and vascular occlusion. Recent researchers [16, 17] reported that perforated sites showed chronic vasculopathy rather than acute vasculitis. This chronic vasculopathy is characterized by narrowing or complete occlusion of multiple small and medium arteries, subintimal foam cells, fibromyxoid neointimal expansion, and significant luminal compromise with infiltration of macrophages through the muscle layers into the intima. Histopathology at the perforation site was recorded in three patients (P6, P12, P19) in the literature [6, 9, 13], and no vasculitis was noted. P12 exhibited mucosal ischemia, and P19 exhibited vasculopathy and CMV colitis. No manifestation of vasculitis was observed in the histopathology of the fistula. Histopathology of perforation site in P1 of our study showed inflammatory cells infiltrate and no vasculitic lesion was observed in the tissue. The other three patients were unable to undergo histopathology due to erosion of the perforation site. Therefore, whether chronic non-inflammatory vasculopathy causes ischemia and perforation must be considered. Bhaskaran et al. [13] reported a case of intestinal perforation in a child with JDM caused by CMV colitis. CMV-DNA was also detected in the blood of P5. No relevant pathological tests were performed. The other four patients did not undergo blood CMV-DNA tests. The role of CMV colitis in perforation requires further study.
The 120 patients in the JDM cohort were all tested by MSAs analysis, all five patients with GI perforation had strong positivity for anti-NXP2 antibody (3+), and no GI perforation was noted in other MSA patients, which led us question whether anti-NXP2 antibody is associated with GI perforation. After reviewing 16 cases in the literature, Besnard et al. [13] reported that most patients with severe GI manifestations were positive for anti-NXP2 antibody or anti-TIF-1γ antibody. Unfortunately, no specific antibody type was recorded in two patients with GI perforation in this study. The other patients described in the literature had not been tested for MSAs. In 2017, Tansley et al. [25] mentioned that 14 children who were positive for anti-NXP2 antibody had ulcers. Aouizerate et al. [26] reported that anti-NXP2 antibody had a positive association with GI involvement in JDM. The study evaluated the clinical, biological, and histological manifestations of 23 JDM patients and performed a multivariate analysis of 26 histopathological parameters. A case-control study can be performed to further uncover the relationship between anti-NXP2 antibody and GI perforation, which may further reveal the pathological mechanism of GI perforation. Based on our experience in this study, or even early in disease, clinicians should be highly alert to the possibility of GI perforation when abdominal pain occurs on anti-NXP2 antibody-positive patients with JDM.
The mortality rate among our patients was higher than that reported in the literature, which might be due to their severe condition and poor response to various therapeutic drugs, delayed surgery, surgical difficulties at the perforation site, economic reasons and the deficient number of cases. When a patient has intermittent abdominal pain and GI ulcers, the primary disease should be treated more actively to prevent GI perforation. Once GI perforation occurs, the primary disease is not well controlled, and the prognosis is poor. We need more research to choose appropriate treatment strategy for these diseases.
Conclusion
In this study, the clinical details of five cases of anti-NXP2 antibody-associated JDM complicated by GI perforation were summarized for the first time. Based on the these cases combined with a literature review, we suggest that once JDM patients present with abdominal pain, especially anti-NXP2 antibody-positive patients, GI perforation should be considered. For timely diagnosis, dynamic imaging is important. GI perforation may be a fatal complication of JDM, more research is needed to determine the pathogenesis and predictive factors of GI perforation in JDM.
Abbreviations
JDMJuvenile dermatomyositis
NXP2Nuclear matrix protein 2
GIGastrointestinal
MSAMyositis-specific antibody
CMASChild myositis assessment score
PredPrednisone
CYCCyclophosphamide
IVIGIntravenous immunoglobulin
MTXMethotrexate
MPMethylprednisolone
CsACyclosporine A
RTXRituximab
AZAAzathioprine
ThalThalidomide
PEPlasma exchanges
CMVCytomegalovirus
CTComputed tomography
HCQHydroxychloroquine
HbHaemoglobin
MRIMagnetic resonance imaging
JPMJuvenile polymyositis
CATCutaneous assessment tool
PPatient
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Acknowledgement
We would like to thank the Department of General Surgery, the Department of Intensive Medicine and the Department of Radiology of the Children’'s Hospital Affiliated to the Capital Institute of Pediatrics for their contributions to the treatment of patients in our study.
Authors’ contributions
YX wrote the first draft of the manuscript, contributed to patient management and to the literature review. XM made many contributions in the process of writing and revising the manuscript. ZZ supervised patient management. JL critically revised the manuscript and supervised patient management. JH, JZ, MK and JL contributed to patient management. XL revised the manuscript. All the authors read and approved the final version of the manuscript.
Funding
This work was supported by Beijing Municipal Administration of Hospitals Clinical Medicine Development of Special Funding Support (code: XMLX201813) and Capital Funds for Health Improvement and Research (code:2020–2-2102).
Availability of data and materials
The datasets during and/or analyzed during the current study available from the corresponding author on reasonable request.
Ethics approval and consent to participate
Parental informed consent for publication was obtained. This study was approved by the Ethics Committee of Capital Institute of Pediatrics.
Consent for publication
Written informed consent was obtained from the patient’s legal guardians for publication of this case report and any accompanying images.
Competing interests
The authors declare that they have no competing interests. | Intravenous (not otherwise specified) | DrugAdministrationRoute | CC BY | 33407602 | 18,785,322 | 2021-01-06 |
What was the administration route of drug 'METHYLPREDNISOLONE SODIUM SUCCINATE'? | Gastrointestinal perforation in anti-NXP2 antibody-associated juvenile dermatomyositis: case reports and a review of the literature.
BACKGROUND
To summarize the characteristics of gastrointestinal (GI) perforation in anti-nuclear matrix protein 2 (NXP2) antibody-associated juvenile dermatomyositis (JDM).
METHODS
Five patients with GI perforation from a JDM cohort of 120 cases are described. Relevant literature was reviewed.
RESULTS
Five patients, including four females and one male, were included in the study. The age of onset of these patients ranged from 3.3 to 9.5 years with the median age of 5.0 years. When these patients were complicated by GI perforation, childhood myositis assessment score (CMAS) ranged from 1 to 5 with the median score of 2. Myositis-specific antibody (MSA) spectrum analysis indicated that the five patients were anti-NXP2 antibody positive. The initial symptoms of GI perforation were progressive abdominal pain and intermittent fever. Two patients also presented with ureteral calculus with hydronephrosis and ureteral stricture. Surgery was performed in four patients. One patient failed to undergo a repair as the perforation was high in position. For the other three patients, perforation repair was successful, of which two patients failed due to recurrent perforation. At 24 months postoperative follow-up, one patient was in complete remission on prednisone (Pred) and methotrexate (MTX) treatment, and her ureteral stricture had disappeared. The other four patients died. Adding these cases with 16 other patients described in the literature, the symptom at onset was progressive abdominal pain, which often occurred within 10 months after JDM was diagnosed. Perforation most commonly occurred in the duodenum, although it also occurred at multiple sites or was recurrent. The mortality rate of GI perforation in JDM was 38% (8/21).
CONCLUSIONS
All the five perforation cases in our study subjected to MSA analysis were anti-NXP2 antibody positive. The symptom at onset was abdominal pain. The most common site of perforation was the duodenum in the retroperitoneum, and the lack of acute abdominal manifestations prevented early diagnosis. GI perforation may be a fatal complication in JDM, and early diagnosis is very important. More research is needed to determine the pathogenesis and predictive factors of GI perforation in JDM.
Background
Juvenile dermatomyositis (JDM) is an autoimmune disease characterized by proximal myopathy and a characteristic rash. However, multiple systems, including the digestive system, can also be involved. The occurrence of gastrointestinal (GI) perforation is rare, but a high mortality rate has been reported due to atypical symptoms and difficulty in early diagnosis [1]. Myositis-specific autoantibodies (MSAs) are increasingly used to delineate distinct subgroups of JDM [2, 3]. The presence of anti-nuclear matrix protein 2 (NXP2) autoantibodies substantially increases the risk of calcinosis across all ages and is associated with disease severity [4]. The role of MSAs in cases of JDM complicated by GI perforation has not been reported. Here, from among 120 patients with JDM, we report five cases complicated by GI perforation. All five patients had anti-NXP2 antibody-associated JDM. In addition, we reviewed the other JDM cases with GI perforation reported in the literature to improve our recognition of this disease. Anti-NXP2 autoantibodies may facilitate early diagnosis of the disease.
Methods
We described five patients with GI perforation from a JDM cohort who were admitted to the Children’s Hospital affiliated with the Capital Institute of Pediatrics, China, from January 2016 to December 2019. The inclusion criteria were: (1) age < 18 years old; (2) diagnosis of JDM based on the Bohan and Peter criteria for myositis [5]; and (3) GI perforation. Patients with other diseases that cause weakness or rash, or a clear alternative diagnosis were excluded from the study. Sixteen MSAs (MDA-5, NXP2, Jo-1, PM-SCL100, PL-7, PL-12, EJ, OJ, anti-Ro52, Ku, PM-Scl, SRP, SAE1, TIF1γ, Mi-2α and Mi-2β) were tested by immune dot blot hybridization using a commercial kit based on goat anti-human IgG antibodies (BlueDot Myositis 12 IgG, #MYO12D-24, D-TEK, Belgium). The study was approved by the Ethics Committee of Capital Institute of Pediatrics. We searched PubMed, Medline and Scopus using the keywords “juvenile dermatomyositis”, “gastrointestinal perforation”, and “perforation”. These literatures with detailed cases which clearly diagnosed JDM and excluded Degos-like presentation with GI perforation were reviewed.
Results (Table 1)
Table 1 Clinical data of JDM patients with GI perforation
Patient
/Year Gender Age at onset (y) CMAS score CAT-A
score CAT-D
score Positive for MSA Treatment before
GI perforation Symptoms of GI perforation Duration from onset to perforation (m) Site of perforation Surgical
treatment Histopathology of perforation site Medical Treatment Follow-up(m)
/Outcome
P1 F 3.4 5 2 3 Anti-NXP2 Pred+MTX + IVIG Abdominal pain/
bloody stools
4/9 Duodenum/ colon Transverse colon ostomyv
duodenostomy
Inflammatory cells infiltrate/
No vasculitis
Pred+Mp pulse+CsA+
IVIG→Pred+Thal+CYC→
Pred+CYC (Po) + MTX → Pred+MTX
24/Remission
P2 F 5.0 1 7 5 Anti-NXP2 MP + MP Pulse+CYC
HCQ/MP + MP Pulse+MTX
Abdominal pain/
bloody stools
10 Duodenum/
Duodenal bulb hepatic
artery rupture
Vessel sutured/
placement of duodenal
jejunal tube (failed)
ND Pred+MP Pulse+CYC+
IVIG
Death/Infection
P3 M 3.3 5 6 5 Anti-NXP2 Pred+MTX + IVIG/
Pred+IVIG +RTX
Abdominal pain
and distention bloody stools
10 Unknown No surgery ND MP pulse+CYC + IVIG Death/Abdominal bleeding
P4 F 6 2 6 6 Anti-NXP2 Pred+ MTX/CsA
→MP pulse+IVIG+CYC
Abdominal pain/
bloody stools
13 Duodenum×2 Perforation repair×2 ND CYC → MP pulse +IVIG+PE Death/Shock
P5 F 9.5 2 6 4 Anti-NXP2 Pred+ MTX/CsA Abdominal pain/ fever and bloody stools 6 Duodenum×2 Perforation repair ND MP pulse+ RTX Death/Abandon treatment
P6 [6]
/2016
F 7.0 ND ND ND ND Pred+MTX Abdominal pain vomiting and fever 6 Duodenal retroperitoneum Perforation repair No vasculitis ND ND/Improved
P7 [7]
/1997
M 7.0 ND ND ND ND Pred Abdominal pain /vomit 24 Duodenum Jejunum Perforation repair ND PE
Pred+MP pulse+CYC
12/Stable
P8 [8]
/1988
F 5.0 ND ND ND ND Pred Abdominal pain 3 Colon Perforation repair ND ND 12/Stable
P9 [8]
/1988
F 7.0 ND ND ND ND Pred +MTX Abdominal pain 6 The third duodenum ND ND ND 3/ND
P10 [8]
/1988
M 8.0 ND ND ND ND Pred+MTX Abdominal pain/
fever
6 Esophagus/
duodenum/ colon
Mesenteric arterial rupture
Perforation repair ND ND ND/Improved
P11 [8]
/1988
F 6.0 ND ND ND ND Pred+MTX Abdominal pain and distention/fever 5 Duodenum Perforation repair ND ND Death/unknown
P12 [9]
/2001
M 4.0 ND ND ND ND Pred+AZA Abdominal pain/
vomiting/fever
2 Duodenum Perforation repair Mucosal ischemia Pred+MP pulse 19/ND
P13 [10]
/2014
M 2.0 ND ND ND ND ND Abdominal pain 108 Unknown ND ND ND Death/unknown
P14 [11]
/1985
F 4.0 ND ND ND ND ND ND 48 Gastric pylorus Partial gastrectomy and gastrojejunostomy ND ND ND/Stable.
P15 [11]
/1985
F 5.0 ND ND ND ND ND ND 3 Middle transverse colon Loop transverse colon fistula ND ND Death/ARDS
P16 [11]
/1985
F 6.0 ND ND ND ND Pred+MTX/Pred+AZA/
Pre + CYC
Abdominal pain/
vomiting/fever
10 Duodenum colon transverse colon Multiple perforation repair ND ND 7/Stable.
P17 [11]
/1985
M 9.0 ND ND ND ND Pred/Pred+MTX/
Pred+AZA
Abdominal pain/ fever 13 Duodenum Perforation repair ND ND ND/Stable.
P18 [12]
/1984
M 7.0 ND ND ND ND Pred+MTX Abdominal pain 10 Duodenal perforation/
colon perforations
Perforation repair ND ND 48/Stable.
P19 [13]
/2019
F 6.0 ND ND ND ND Pred+MTX Abdominal pain/fever 1 transverse colon, Perforation repair
and loop colostomy.
No vasculitis and vasculopathy/
CMV colitis
Steroid+IVIG+Ganciclovir 12/Remission
P20 [14]
/2020
ND 10.5 16 ND ND ND ND Abdominal pain/ GI hemorrhage/ severe bowel obstruction 8/20 Duodenal Perforation/
Jejunal perforation
Jejunal resection/ exclusive parenteral
nutrition/ antibiotics,
ND Steroid+CsA 108/Remission
P21 [14]
/2020
ND 10.7 5 ND ND ND ND Abdominal pain/
severe bowel obstruction
7/9 Esophageal perforation/
Cecal perforation
Colostomy ND Steroid+ RTX+ PE 84/Death/Hepatitis
F is female, M is male, ND is no data, y is year, CMAS is child myositis assessment score, MSA is myositis-specific antibody, m is month, Pred is prednisone, CYC is cyclophosphamide, IVIG is intravenous immunoglobulin, MTX is methotrexate, MP is methylprednisol, CsA is cyclosporine A, RTX is rituximab, AZA is azathioprine, Thal is thalidomide, HCQ is hydroxychloroquine, Po is peros, CMV is Cytomegalovirus, PE is plasma exchanges, ARDS is acute respiratory distresssyndrome, CAT-A is cutaneous assessment tool activity, CAT-D is cutaneous assessment tool damage
The general data of the 5 patients
Five patients with GI perforation were identified from 120 cases in a JDM cohort (4.17%). Four of these were females, with the age at onset ranging from 3.3 to 9.5 years (median age − 5.0 years). All five patients showed severe rashes, skin ulcers, and weakness of the skeletal muscles (ranging from power 3/5 to 1/5). When these patients were complicated by GI perforation, childhood myositis assessment score (CMAS) ranged from 1 to 5 with the median score of 2, cutaneous assessment tool (CAT) activity score ranged from 2 to 7 with the median score of 6, CAT damage score ranged from 3 to 6 with the median score of 5. No calcification was observed. Two patients also presented with ureteral calculus with hydronephrosis and ureteral stricture. Analysis of MSAs showed that the five patients were anti-NXP2 antibody positive. There are 31 patients with anti-NXP2 antibody positive in the cohort. The incidence of GI perforation in anti-NXP2 antibody positive patients in our study was 16.13% (5/31). One patient had increased level of cytomegalovirus (CMV)-DNA copies in blood. GI perforation occurred from 4 to 13 months after JDM was diagnosed. The symptoms at onset were severe abdominal pain, fever, GI bleeding and vomiting. Perforations occurred in the duodenum (3 patients), duodenum and colon (1 patient), and an unclear location (1 patient), and perforations at multiple sites or at recurrent times occurred in four patients. All patients were treated with corticosteroids and immunosuppressant agents [cyclophosphamide (CYC)/methotrexate (MTX)/cyclosporine A (CsA)]. One patient was treated with plasma exchange (PE) therapy, and two patients received rituximab (RTX). All five patients were given proton-pump inhibitors (omeprazole). Surgery was performed in four patients, of which one patient failed to undergo repair due to the high position of perforation. For the other three patients, perforation repair was successful, of which two patients failed due to recurrent perforation. At 24 months postoperative follow-up, one patient was in complete remission under Pred and MTX treatment, and her ureteral stricture had disappeared. The other four patients died.
Case 1
A 3.4-year-old girl, suffering from characteristic skin rash and muscle weakness was diagnosed with JDM in a local hospital and was treated with Pred(2 mg/kg/d) and MTX (12 mg/m2/wk). Muscle weakness improved after 3 months of treatment, following which the dosage of Pred was reduced. When Pred was reduced to 10 mg/d, the girl developed infection in the lungs, skin ulcers around the anus and abdominal pain. One month later, a perforation in the transverse colon was confirmed, and colostomy was performed in a local hospital. She received Pred, CYC, intravenous immunoglobulin (IVIG) and MTX, after which her abdominal pain disappeared, and her muscle strength improved. Seven months after JDM diagnosis, ureteral calculus with hydronephrosis and ureteral stricture were diagnosed and treated via ureteroscopy. Nine months after JDM diagnosis, she developed severe abdominal pain and worsening muscle weakness, for which pulse methylprednisolone (MP) and CsA were given. Later, GI bleeding and fever recurred. She was transferred to our emergency department. She had shock, and her contrast-enhanced computed tomography (CT) abdomen indicated encapsulated effusion and pneumatosis, duodenal perforation and an abscess, which were confirmed during surgery. After duodenostomy, Pred, pulse CYC and thalidomide were given, and when her condition stabilized, we switched to oral Pred, CYC and MTX. At 24 months postoperative follow-up, she was in complete remission with Pred and MTX treatment, and her ureteral stricture had disappeared.
Case 2
A 5-year-old girl suffering from characteristic skin rash and muscle weakness was diagnosed with JDM in a local hospital and treated with Pred, MTX and hydroxychloroquine (HCQ), after which her muscle strength improved. But her parents stopped the treatment. Twelve months after JDM diagnosis, she was admitted to our emergency department due to abdominal pain, vomiting, and dark coloured stools. Physical examination showed a poor mental response, painful expression, severe malnutrition, High spring sign (+), partially scabbed skin ulcers in the lower jaw, popliteal fossa and axillae and muscle weakness. A contrast-enhanced CT abdomen indicated peritonitis, intestinal perforation and a right renal-ureteral calculus with pelvicalyceal-ureteral dilation. During surgery, multiple perforations of the duodenum and ruptured right hepatic artery were found. The ruptured blood vessel was sutured, but duodeno jejunal tube placement was unsuccessful. The patient subsequently died of infections and haemorrhagic shock.
Case 3
A 3.3-year-old boy suffering from characteristic skin rash and muscle weakness was diagnosed with JDM and treated with Pred, MTX and IVIG in a local hospital. His symptoms improved after treatment; the dosage of Pred was reduced, and MTX was stopped due to cataracts and abnormal liver function. The rash and muscle weakness worsened. Nine months after JDM diagnosis, physical examination revealed that severe proximal muscle weakness (power 3/5) and numerous purplish red rashes and ulcerative scabs which could be seen on the face and limbs. MP, RTX and IVIG were administered in our hospital. Two weeks later, he gradually developed abdominal pain, bloating, low back pain, right lower quadrant tenderness and rebound pain. Localized colitis was suspected based on a CT scan. His abdominal pain and distension were relieved after the administration of antibiotics, MP (20 mg/kg/d for 2 days) and IVIG. Four days later, he developed fever, abdominal pain and distension, and an ultrasound showed echoic enhancement in the omentum of the right lower quadrant with weak peristalsis and ascites. MP, pulse CYC and IVIG were continued, and his temperature returned to normal with improved abdominal pain. However, 7 days later, he experienced severe abdominal pain and distension with a rapid decrease in his haemoglobin (Hb) level (from 112 g/L to 67 g/L). Ultrasound showed abdominal muscle inflammation with haemorrhage, and contrast-enhanced CT showed generalized retroperitoneal infection with abdominal wall haemorrhage and intestinal perforation (Fig. 1). Surgical intervention was not possible in view of unstable vital signs, severe infection, and severe and extensive intestinal lesions that could not be surgically repaired. Repeated blood transfusions, anti-microbial agents, and treatment for the primary disease were given. He persisted to have abdominal pain and bloating. A slight change in body position caused massive abdominal wall bleeding. He died after returning home.
Fig. 1 a The thigh skin ulcers accompanied by swelling of the ipsilateral testis on Case 3(arrow) b. Contrast-enhanced CT showed retroperitoneal effusion (arrow 1), retroperitoneal gas (arrow 2) and abdominal wall hemorrhage (arrow 3) on Case 3. c Contrast-enhanced CT showed retroperitoneal effusion (arrow 1) and retroperitoneal gas (arrow 2) on Case 3
Case 4
A 7-year-old girl with a past history of JDM was treated 1 year earlier with MP and an immunosuppressant. She presented with progressive proximal muscle weakness, skin ulcers and intermittent abdominal pain for 1 month. Physical examination showed severe malnutrition, anemia, maculopapular rashes symmetrically distributed over the extensor sides of the joints of all extremities, partially scabbing skin ulcers on the extensor side of the left elbow and in both axilla, proximal muscle weakness and edema in both upper limbs. Her Hb level was 59 g/L. Abdominal contrast-enhanced CT did not indicate obvious abnormalities. Ultrasound of the abdomen suggested thickening of the abdominal bowel wall and poor bowel motility. After treatment with blood transfusion, MP and CYC were given. Her symptoms improved, and abdominal pain disappeared. Hb decreased again after 2 weeks, and fever and abdominal pain reappeared again after 4 weeks. Abdominal CT revealed bowel perforation. She immediately underwent surgical repair (Fig. 2). One week later, abdominal pain appeared again. Abdominal CT showed another intestinal perforation. Surgical repair and PE therapy were performed. Her abdominal pain was relieved, but she developed severe pulmonary infection. Three days later, she had manifestations of peritonitis and then developed seizures. Her blood pressure was normal, cerebrospinal fluid tests were negative, but her magnetic resonance imaging (MRI) brain showed that the right temporal lobe and bilateral parieto-occipital lobes were swollen with abnormal signals; patchy abnormal signals were observed in the right thalamus, showing long T2 signal, high T2 FLAIR signal, limited dispersion, and reduced ADC value. We speculated primary disease involving the nervous system. Seizures did not recur after treatment of the primary disease. A repeat MRI brain was not done. Pulse MP and anti-microbial agents were given. Surgical intervention was not possible. The patient died due to uncontrolled bleeding and refractory shock.
Fig.2 a Contrast leakage seen at the junction of the descending and horizontal segments of the duodenum on Case 4 (arrow). b Contrast-enhanced CT showed retroperitoneal gas on Case 4 (arrow). c Duodenal perforation can be seen at surgery on Case 4 (arrow)
Case 5
A 10-year-old girl had been diagnosed with JDM 6 months earlier and received Pred and immunosuppressants. She presented with intermittent abdominal pain and fever for 1 month. She was initially treated with pulse MP and IVIG. But her muscle weakness and rash did not improve. She was admitted to our hospital with GI haemorrhage for 3 days. Physical examination showed a poor mental response, painful expression, severe malnutrition, anemia, scattered maculopapular rashes and ulcers distributed in the neck, axillae, buttocks, and extendible joints, and severe proximal muscle weakness. Her Hb level was 54 g/L. Ultrasound of the abdomen suggested thickening of the abdominal bowel wall and poor bowel movements. Pulse RTX and MP were given. Three days later, her abdominal pain worsened. Ultrasound of the abdomen showed intestinal perforation. During surgery, a 5-cm perforation of the transverse part of the duodenum was observed, the perforation was repaired and a double cavity jejunal fistula was performed. Her abdominal pain was relieved. CMV-DNA was detected in the blood, and she was given ganciclovir treatment. Four days later, she again experienced abdominal pain and muscle spasms. Considering the necrosis and perforation of the lower part of the duodenum, her parents withdrew treatment, and the patient died.
Results of the literature review
Sixteen patients of JDM with GI perforation were identified in PubMed, Medline and Scopus [6–18] which were published between 1984 and 2020. Eight patients were female (50%), six patients were male (37.5%), and the sex of two patients was not recorded (12.5%). The age of onset of these patients ranged from 2 to 10.5 years with the median age of 6.5 years. No clear MSA results were recorded in any case. Primary treatment with Pred and immunosuppressants did not have a significant effect. GI symptoms occurred from one to 108 months after treatment, most of which occurred within 10 months. The initial GI symptoms were severe abdominal pain with fever or vomiting. Perforations were reported in the duodenum (10/16, 62.5%), colon (6/16, 37.5%), jejunum (2/16, 12.5%), oesophagus (2/16, 12.5%), gastric pylorus (1/16, 6.25%), caecum (1/16, 6.25%) and an unclear location (1/16, 6.25%); perforations at multiple sites or recurrent perforations were reported in six patients (6/16, 37.5%). Only five patients had records regarding treatment of the initial disease, and they were treated with Pred or MP and an immunosuppressant (CYC/CsA). One patient underwent PE therapy, one patient received PE therapy with RTX and surgery was performed in 14 patients. In particular, one patient was treated with ganciclovir for CMV infection. Four patients died (25%), and the others were discharged from the hospital after they experienced relief of their symptoms. The clinical data of all 16 patients taken from the literature and the five patients in our study is summarized in Table 1.
Discussion
JDM, the most common inflammatory myopathy of childhood, is a rare systemic autoimmune vasculopathy that is characterized by weakness in proximal muscles and pathognomonic skin rashes [19]. Multiple systems can be involved, but GI perforations in anti-NXP2 antibody-associated JDM are rarely reported. From among 120 patients with JDM, we report five anti-NXP2 antibody-associated JDM complicated by GI perforation. Most patients in our study were females, with a proportion that was significantly higher than that for the other patients reported in the literature. At the age of onset of these five patients ranged from 3.3 to 9.5 years with the median age of 5.0 years, and GI perforations appeared between 4 and 13 months post diagnosis, which was similar to the 16 cases reported in the literature. When our patients were complicated by GI perforation, CMAS were very low, CAT activity score indicated moderate activity, which suggest that GI perforations may be associated with disease severity and activity. The initial symptoms of JDM with GI perforation were severe abdominal pain, abdominal distention, vomiting, fever and bloody stools. Early identification of perforation was very difficult. With regard to patient (P) 1 and P2, the doctors did not recognize that GI perforation had occurred after persistent abdominal pain for more than 1 month. The perforation in P3 occurred during hospitalization in our hospital and manifested as severe abdominal pain and distension with decreased bowel sounds. Repeated abdominal ultrasounds, X-rays and contrast-enhanced CTs indicated the presence of a low-signal mass in the right lower quadrant with bowel distension, thinning of the intestinal wall and local colitis without pneumoperitoneum or subphrenic pneumatosis. Transitory relief of symptoms occurred after treatment, but severe abdominal pain quickly reappeared, and contrast-enhanced CT and ultrasound showed intestinal perforation, diffuse abdominal wall bleeding and infection. We did not know the precise time when the perforation occurred, suggesting that once abdominal pain appears, perforation should be strongly suspected, and imaging should be performed. Perforation should be considered when abdominal pain is not relieved by active treatment in patients with JDM, and it can be diagnosed early with contrast-enhanced CT scans [6]. We also suggest that repeated scanning and GI angiograms are essential, if the diagnosis cannot be confirmed during the first scan. In the 16 patients in the literature, perforation often occurred in the duodenum (partially in the retroperitoneal area in P6) and the colon. In addition, multi-site or recurrent perforations were also observed in some patients (P7,P10,P16,P18,P20,P21), similar to the results of our study. Furthermore, arterial rupture near the perforation site often occurs, as observed in P2, who had ruptured hepatic arteries, and in P10, who had a ruptured duodenal proximal mesenteric artery; therefore, haemorrhage may also be considered when an unexplained decrease in the Hb level occurs in JDM patients. In addition, several patients have been described in literature with Degos-like lesions linked to GI perforation [20, 21]. A similar deposit complex and pattern of vasculopathy has been found in patients suffering from Degos disease and JDM [22]. We should pay attention to the identification of Degos-like disease. Degos - like skin lesions were initially pale red papules followed by enlarged lesions, showing a characteristic pitting center with a concave navel porcelain white center and a red halo around the periphery. After the rash subsided, there was a white superficial scar. The rash is more common on the trunk and extremities, less common on the palms and feet, and often occurs in batches, old and new. The appearance and location of the rash in five patients of our study were different from Degos-like disease. Further hisopathological identification may be performed if necessary.
In addition, two patients (P1, P2) had urinary system involvement in this group of cases, including ureteral stones, uretero-pelvic dilation and ureteral stenosis. With remission of the primary disease, ureteral stenosis disappeared in P1. This leads us to speculate that ureteral stenosis may be related to vasculopathy involving the urinary system. Morita et al. [23] reported a case of dermatomyositis who developed duodenal perforation as well as ureteral stenosis, with biopsy of stenotic ureter showing calcification with granulomatous tissue without any vasculitic lesion. Ruby Haviv et al. [24] reported a case of juvenile polymyositis (JPM) with right ureteral obstruction secondary to necrosis. The histopathology report of the resected ureter revealed moderate, acute, and chronic inflammatory infiltrates within the ureter wall, urothelial erosions, superficial granulation tissue, and degenerated smooth muscle fibres within the muscularis propria; some of which were infiltrated with lymphocytes and plasma cells, and multiple calcifications within the lamina propria. It also showed fragments of gross calcifications, similar calcifications in other parts of the ureter and obstructing calcifications within small blood vessels. Ruby Haviv et al. considered calcified ureteral necrosis to be a feature of visceral vasculopathy, related to both JDM and JPM. The mechanism is obscure, and the presence of calcifications within visceral tissues might suggest the pathogenesis of the typical calcinosis related to these diseases [24]. Considering that NXP-2 is a type prone to calcification, it was not clear whether ureteral calculi and ureteral stenosis in P1 and P2 were related to vasculopathy with calcification, which needs further studies of visceral calcinosis.
The underlying mechanisms of GI perforation in JDM are still obscure. Some researchers have reported glucocorticoids, non-steroidal anti inflammatory drugs and MTX to be risk factors for GI ulceration and perforation, especially at 1 month post-treatment or with an accumulated dose of steroids higher than 1 g [17]. In our study, Pred was reduced to a small dose before GI symptoms appeared in P1. After perforation was identified, pulse MP pulse and CYC were given, and the patient’s condition improved; thus, the perforation was not attributed to drug factors. Schneider et al. [6] assumed that ulceration in the proximal region and bulb of the duodenum was related to medication, while perforation in the descending part was related to vasculitis, causing intestinal ischemia and necrosis due to thrombogenesis and vascular occlusion. Recent researchers [16, 17] reported that perforated sites showed chronic vasculopathy rather than acute vasculitis. This chronic vasculopathy is characterized by narrowing or complete occlusion of multiple small and medium arteries, subintimal foam cells, fibromyxoid neointimal expansion, and significant luminal compromise with infiltration of macrophages through the muscle layers into the intima. Histopathology at the perforation site was recorded in three patients (P6, P12, P19) in the literature [6, 9, 13], and no vasculitis was noted. P12 exhibited mucosal ischemia, and P19 exhibited vasculopathy and CMV colitis. No manifestation of vasculitis was observed in the histopathology of the fistula. Histopathology of perforation site in P1 of our study showed inflammatory cells infiltrate and no vasculitic lesion was observed in the tissue. The other three patients were unable to undergo histopathology due to erosion of the perforation site. Therefore, whether chronic non-inflammatory vasculopathy causes ischemia and perforation must be considered. Bhaskaran et al. [13] reported a case of intestinal perforation in a child with JDM caused by CMV colitis. CMV-DNA was also detected in the blood of P5. No relevant pathological tests were performed. The other four patients did not undergo blood CMV-DNA tests. The role of CMV colitis in perforation requires further study.
The 120 patients in the JDM cohort were all tested by MSAs analysis, all five patients with GI perforation had strong positivity for anti-NXP2 antibody (3+), and no GI perforation was noted in other MSA patients, which led us question whether anti-NXP2 antibody is associated with GI perforation. After reviewing 16 cases in the literature, Besnard et al. [13] reported that most patients with severe GI manifestations were positive for anti-NXP2 antibody or anti-TIF-1γ antibody. Unfortunately, no specific antibody type was recorded in two patients with GI perforation in this study. The other patients described in the literature had not been tested for MSAs. In 2017, Tansley et al. [25] mentioned that 14 children who were positive for anti-NXP2 antibody had ulcers. Aouizerate et al. [26] reported that anti-NXP2 antibody had a positive association with GI involvement in JDM. The study evaluated the clinical, biological, and histological manifestations of 23 JDM patients and performed a multivariate analysis of 26 histopathological parameters. A case-control study can be performed to further uncover the relationship between anti-NXP2 antibody and GI perforation, which may further reveal the pathological mechanism of GI perforation. Based on our experience in this study, or even early in disease, clinicians should be highly alert to the possibility of GI perforation when abdominal pain occurs on anti-NXP2 antibody-positive patients with JDM.
The mortality rate among our patients was higher than that reported in the literature, which might be due to their severe condition and poor response to various therapeutic drugs, delayed surgery, surgical difficulties at the perforation site, economic reasons and the deficient number of cases. When a patient has intermittent abdominal pain and GI ulcers, the primary disease should be treated more actively to prevent GI perforation. Once GI perforation occurs, the primary disease is not well controlled, and the prognosis is poor. We need more research to choose appropriate treatment strategy for these diseases.
Conclusion
In this study, the clinical details of five cases of anti-NXP2 antibody-associated JDM complicated by GI perforation were summarized for the first time. Based on the these cases combined with a literature review, we suggest that once JDM patients present with abdominal pain, especially anti-NXP2 antibody-positive patients, GI perforation should be considered. For timely diagnosis, dynamic imaging is important. GI perforation may be a fatal complication of JDM, more research is needed to determine the pathogenesis and predictive factors of GI perforation in JDM.
Abbreviations
JDMJuvenile dermatomyositis
NXP2Nuclear matrix protein 2
GIGastrointestinal
MSAMyositis-specific antibody
CMASChild myositis assessment score
PredPrednisone
CYCCyclophosphamide
IVIGIntravenous immunoglobulin
MTXMethotrexate
MPMethylprednisolone
CsACyclosporine A
RTXRituximab
AZAAzathioprine
ThalThalidomide
PEPlasma exchanges
CMVCytomegalovirus
CTComputed tomography
HCQHydroxychloroquine
HbHaemoglobin
MRIMagnetic resonance imaging
JPMJuvenile polymyositis
CATCutaneous assessment tool
PPatient
Publisher’s Note
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Acknowledgement
We would like to thank the Department of General Surgery, the Department of Intensive Medicine and the Department of Radiology of the Children’'s Hospital Affiliated to the Capital Institute of Pediatrics for their contributions to the treatment of patients in our study.
Authors’ contributions
YX wrote the first draft of the manuscript, contributed to patient management and to the literature review. XM made many contributions in the process of writing and revising the manuscript. ZZ supervised patient management. JL critically revised the manuscript and supervised patient management. JH, JZ, MK and JL contributed to patient management. XL revised the manuscript. All the authors read and approved the final version of the manuscript.
Funding
This work was supported by Beijing Municipal Administration of Hospitals Clinical Medicine Development of Special Funding Support (code: XMLX201813) and Capital Funds for Health Improvement and Research (code:2020–2-2102).
Availability of data and materials
The datasets during and/or analyzed during the current study available from the corresponding author on reasonable request.
Ethics approval and consent to participate
Parental informed consent for publication was obtained. This study was approved by the Ethics Committee of Capital Institute of Pediatrics.
Consent for publication
Written informed consent was obtained from the patient’s legal guardians for publication of this case report and any accompanying images.
Competing interests
The authors declare that they have no competing interests. | Intravenous (not otherwise specified) | DrugAdministrationRoute | CC BY | 33407602 | 18,840,448 | 2021-01-06 |
What was the outcome of reaction 'Gastrointestinal haemorrhage'? | Gastrointestinal perforation in anti-NXP2 antibody-associated juvenile dermatomyositis: case reports and a review of the literature.
BACKGROUND
To summarize the characteristics of gastrointestinal (GI) perforation in anti-nuclear matrix protein 2 (NXP2) antibody-associated juvenile dermatomyositis (JDM).
METHODS
Five patients with GI perforation from a JDM cohort of 120 cases are described. Relevant literature was reviewed.
RESULTS
Five patients, including four females and one male, were included in the study. The age of onset of these patients ranged from 3.3 to 9.5 years with the median age of 5.0 years. When these patients were complicated by GI perforation, childhood myositis assessment score (CMAS) ranged from 1 to 5 with the median score of 2. Myositis-specific antibody (MSA) spectrum analysis indicated that the five patients were anti-NXP2 antibody positive. The initial symptoms of GI perforation were progressive abdominal pain and intermittent fever. Two patients also presented with ureteral calculus with hydronephrosis and ureteral stricture. Surgery was performed in four patients. One patient failed to undergo a repair as the perforation was high in position. For the other three patients, perforation repair was successful, of which two patients failed due to recurrent perforation. At 24 months postoperative follow-up, one patient was in complete remission on prednisone (Pred) and methotrexate (MTX) treatment, and her ureteral stricture had disappeared. The other four patients died. Adding these cases with 16 other patients described in the literature, the symptom at onset was progressive abdominal pain, which often occurred within 10 months after JDM was diagnosed. Perforation most commonly occurred in the duodenum, although it also occurred at multiple sites or was recurrent. The mortality rate of GI perforation in JDM was 38% (8/21).
CONCLUSIONS
All the five perforation cases in our study subjected to MSA analysis were anti-NXP2 antibody positive. The symptom at onset was abdominal pain. The most common site of perforation was the duodenum in the retroperitoneum, and the lack of acute abdominal manifestations prevented early diagnosis. GI perforation may be a fatal complication in JDM, and early diagnosis is very important. More research is needed to determine the pathogenesis and predictive factors of GI perforation in JDM.
Background
Juvenile dermatomyositis (JDM) is an autoimmune disease characterized by proximal myopathy and a characteristic rash. However, multiple systems, including the digestive system, can also be involved. The occurrence of gastrointestinal (GI) perforation is rare, but a high mortality rate has been reported due to atypical symptoms and difficulty in early diagnosis [1]. Myositis-specific autoantibodies (MSAs) are increasingly used to delineate distinct subgroups of JDM [2, 3]. The presence of anti-nuclear matrix protein 2 (NXP2) autoantibodies substantially increases the risk of calcinosis across all ages and is associated with disease severity [4]. The role of MSAs in cases of JDM complicated by GI perforation has not been reported. Here, from among 120 patients with JDM, we report five cases complicated by GI perforation. All five patients had anti-NXP2 antibody-associated JDM. In addition, we reviewed the other JDM cases with GI perforation reported in the literature to improve our recognition of this disease. Anti-NXP2 autoantibodies may facilitate early diagnosis of the disease.
Methods
We described five patients with GI perforation from a JDM cohort who were admitted to the Children’s Hospital affiliated with the Capital Institute of Pediatrics, China, from January 2016 to December 2019. The inclusion criteria were: (1) age < 18 years old; (2) diagnosis of JDM based on the Bohan and Peter criteria for myositis [5]; and (3) GI perforation. Patients with other diseases that cause weakness or rash, or a clear alternative diagnosis were excluded from the study. Sixteen MSAs (MDA-5, NXP2, Jo-1, PM-SCL100, PL-7, PL-12, EJ, OJ, anti-Ro52, Ku, PM-Scl, SRP, SAE1, TIF1γ, Mi-2α and Mi-2β) were tested by immune dot blot hybridization using a commercial kit based on goat anti-human IgG antibodies (BlueDot Myositis 12 IgG, #MYO12D-24, D-TEK, Belgium). The study was approved by the Ethics Committee of Capital Institute of Pediatrics. We searched PubMed, Medline and Scopus using the keywords “juvenile dermatomyositis”, “gastrointestinal perforation”, and “perforation”. These literatures with detailed cases which clearly diagnosed JDM and excluded Degos-like presentation with GI perforation were reviewed.
Results (Table 1)
Table 1 Clinical data of JDM patients with GI perforation
Patient
/Year Gender Age at onset (y) CMAS score CAT-A
score CAT-D
score Positive for MSA Treatment before
GI perforation Symptoms of GI perforation Duration from onset to perforation (m) Site of perforation Surgical
treatment Histopathology of perforation site Medical Treatment Follow-up(m)
/Outcome
P1 F 3.4 5 2 3 Anti-NXP2 Pred+MTX + IVIG Abdominal pain/
bloody stools
4/9 Duodenum/ colon Transverse colon ostomyv
duodenostomy
Inflammatory cells infiltrate/
No vasculitis
Pred+Mp pulse+CsA+
IVIG→Pred+Thal+CYC→
Pred+CYC (Po) + MTX → Pred+MTX
24/Remission
P2 F 5.0 1 7 5 Anti-NXP2 MP + MP Pulse+CYC
HCQ/MP + MP Pulse+MTX
Abdominal pain/
bloody stools
10 Duodenum/
Duodenal bulb hepatic
artery rupture
Vessel sutured/
placement of duodenal
jejunal tube (failed)
ND Pred+MP Pulse+CYC+
IVIG
Death/Infection
P3 M 3.3 5 6 5 Anti-NXP2 Pred+MTX + IVIG/
Pred+IVIG +RTX
Abdominal pain
and distention bloody stools
10 Unknown No surgery ND MP pulse+CYC + IVIG Death/Abdominal bleeding
P4 F 6 2 6 6 Anti-NXP2 Pred+ MTX/CsA
→MP pulse+IVIG+CYC
Abdominal pain/
bloody stools
13 Duodenum×2 Perforation repair×2 ND CYC → MP pulse +IVIG+PE Death/Shock
P5 F 9.5 2 6 4 Anti-NXP2 Pred+ MTX/CsA Abdominal pain/ fever and bloody stools 6 Duodenum×2 Perforation repair ND MP pulse+ RTX Death/Abandon treatment
P6 [6]
/2016
F 7.0 ND ND ND ND Pred+MTX Abdominal pain vomiting and fever 6 Duodenal retroperitoneum Perforation repair No vasculitis ND ND/Improved
P7 [7]
/1997
M 7.0 ND ND ND ND Pred Abdominal pain /vomit 24 Duodenum Jejunum Perforation repair ND PE
Pred+MP pulse+CYC
12/Stable
P8 [8]
/1988
F 5.0 ND ND ND ND Pred Abdominal pain 3 Colon Perforation repair ND ND 12/Stable
P9 [8]
/1988
F 7.0 ND ND ND ND Pred +MTX Abdominal pain 6 The third duodenum ND ND ND 3/ND
P10 [8]
/1988
M 8.0 ND ND ND ND Pred+MTX Abdominal pain/
fever
6 Esophagus/
duodenum/ colon
Mesenteric arterial rupture
Perforation repair ND ND ND/Improved
P11 [8]
/1988
F 6.0 ND ND ND ND Pred+MTX Abdominal pain and distention/fever 5 Duodenum Perforation repair ND ND Death/unknown
P12 [9]
/2001
M 4.0 ND ND ND ND Pred+AZA Abdominal pain/
vomiting/fever
2 Duodenum Perforation repair Mucosal ischemia Pred+MP pulse 19/ND
P13 [10]
/2014
M 2.0 ND ND ND ND ND Abdominal pain 108 Unknown ND ND ND Death/unknown
P14 [11]
/1985
F 4.0 ND ND ND ND ND ND 48 Gastric pylorus Partial gastrectomy and gastrojejunostomy ND ND ND/Stable.
P15 [11]
/1985
F 5.0 ND ND ND ND ND ND 3 Middle transverse colon Loop transverse colon fistula ND ND Death/ARDS
P16 [11]
/1985
F 6.0 ND ND ND ND Pred+MTX/Pred+AZA/
Pre + CYC
Abdominal pain/
vomiting/fever
10 Duodenum colon transverse colon Multiple perforation repair ND ND 7/Stable.
P17 [11]
/1985
M 9.0 ND ND ND ND Pred/Pred+MTX/
Pred+AZA
Abdominal pain/ fever 13 Duodenum Perforation repair ND ND ND/Stable.
P18 [12]
/1984
M 7.0 ND ND ND ND Pred+MTX Abdominal pain 10 Duodenal perforation/
colon perforations
Perforation repair ND ND 48/Stable.
P19 [13]
/2019
F 6.0 ND ND ND ND Pred+MTX Abdominal pain/fever 1 transverse colon, Perforation repair
and loop colostomy.
No vasculitis and vasculopathy/
CMV colitis
Steroid+IVIG+Ganciclovir 12/Remission
P20 [14]
/2020
ND 10.5 16 ND ND ND ND Abdominal pain/ GI hemorrhage/ severe bowel obstruction 8/20 Duodenal Perforation/
Jejunal perforation
Jejunal resection/ exclusive parenteral
nutrition/ antibiotics,
ND Steroid+CsA 108/Remission
P21 [14]
/2020
ND 10.7 5 ND ND ND ND Abdominal pain/
severe bowel obstruction
7/9 Esophageal perforation/
Cecal perforation
Colostomy ND Steroid+ RTX+ PE 84/Death/Hepatitis
F is female, M is male, ND is no data, y is year, CMAS is child myositis assessment score, MSA is myositis-specific antibody, m is month, Pred is prednisone, CYC is cyclophosphamide, IVIG is intravenous immunoglobulin, MTX is methotrexate, MP is methylprednisol, CsA is cyclosporine A, RTX is rituximab, AZA is azathioprine, Thal is thalidomide, HCQ is hydroxychloroquine, Po is peros, CMV is Cytomegalovirus, PE is plasma exchanges, ARDS is acute respiratory distresssyndrome, CAT-A is cutaneous assessment tool activity, CAT-D is cutaneous assessment tool damage
The general data of the 5 patients
Five patients with GI perforation were identified from 120 cases in a JDM cohort (4.17%). Four of these were females, with the age at onset ranging from 3.3 to 9.5 years (median age − 5.0 years). All five patients showed severe rashes, skin ulcers, and weakness of the skeletal muscles (ranging from power 3/5 to 1/5). When these patients were complicated by GI perforation, childhood myositis assessment score (CMAS) ranged from 1 to 5 with the median score of 2, cutaneous assessment tool (CAT) activity score ranged from 2 to 7 with the median score of 6, CAT damage score ranged from 3 to 6 with the median score of 5. No calcification was observed. Two patients also presented with ureteral calculus with hydronephrosis and ureteral stricture. Analysis of MSAs showed that the five patients were anti-NXP2 antibody positive. There are 31 patients with anti-NXP2 antibody positive in the cohort. The incidence of GI perforation in anti-NXP2 antibody positive patients in our study was 16.13% (5/31). One patient had increased level of cytomegalovirus (CMV)-DNA copies in blood. GI perforation occurred from 4 to 13 months after JDM was diagnosed. The symptoms at onset were severe abdominal pain, fever, GI bleeding and vomiting. Perforations occurred in the duodenum (3 patients), duodenum and colon (1 patient), and an unclear location (1 patient), and perforations at multiple sites or at recurrent times occurred in four patients. All patients were treated with corticosteroids and immunosuppressant agents [cyclophosphamide (CYC)/methotrexate (MTX)/cyclosporine A (CsA)]. One patient was treated with plasma exchange (PE) therapy, and two patients received rituximab (RTX). All five patients were given proton-pump inhibitors (omeprazole). Surgery was performed in four patients, of which one patient failed to undergo repair due to the high position of perforation. For the other three patients, perforation repair was successful, of which two patients failed due to recurrent perforation. At 24 months postoperative follow-up, one patient was in complete remission under Pred and MTX treatment, and her ureteral stricture had disappeared. The other four patients died.
Case 1
A 3.4-year-old girl, suffering from characteristic skin rash and muscle weakness was diagnosed with JDM in a local hospital and was treated with Pred(2 mg/kg/d) and MTX (12 mg/m2/wk). Muscle weakness improved after 3 months of treatment, following which the dosage of Pred was reduced. When Pred was reduced to 10 mg/d, the girl developed infection in the lungs, skin ulcers around the anus and abdominal pain. One month later, a perforation in the transverse colon was confirmed, and colostomy was performed in a local hospital. She received Pred, CYC, intravenous immunoglobulin (IVIG) and MTX, after which her abdominal pain disappeared, and her muscle strength improved. Seven months after JDM diagnosis, ureteral calculus with hydronephrosis and ureteral stricture were diagnosed and treated via ureteroscopy. Nine months after JDM diagnosis, she developed severe abdominal pain and worsening muscle weakness, for which pulse methylprednisolone (MP) and CsA were given. Later, GI bleeding and fever recurred. She was transferred to our emergency department. She had shock, and her contrast-enhanced computed tomography (CT) abdomen indicated encapsulated effusion and pneumatosis, duodenal perforation and an abscess, which were confirmed during surgery. After duodenostomy, Pred, pulse CYC and thalidomide were given, and when her condition stabilized, we switched to oral Pred, CYC and MTX. At 24 months postoperative follow-up, she was in complete remission with Pred and MTX treatment, and her ureteral stricture had disappeared.
Case 2
A 5-year-old girl suffering from characteristic skin rash and muscle weakness was diagnosed with JDM in a local hospital and treated with Pred, MTX and hydroxychloroquine (HCQ), after which her muscle strength improved. But her parents stopped the treatment. Twelve months after JDM diagnosis, she was admitted to our emergency department due to abdominal pain, vomiting, and dark coloured stools. Physical examination showed a poor mental response, painful expression, severe malnutrition, High spring sign (+), partially scabbed skin ulcers in the lower jaw, popliteal fossa and axillae and muscle weakness. A contrast-enhanced CT abdomen indicated peritonitis, intestinal perforation and a right renal-ureteral calculus with pelvicalyceal-ureteral dilation. During surgery, multiple perforations of the duodenum and ruptured right hepatic artery were found. The ruptured blood vessel was sutured, but duodeno jejunal tube placement was unsuccessful. The patient subsequently died of infections and haemorrhagic shock.
Case 3
A 3.3-year-old boy suffering from characteristic skin rash and muscle weakness was diagnosed with JDM and treated with Pred, MTX and IVIG in a local hospital. His symptoms improved after treatment; the dosage of Pred was reduced, and MTX was stopped due to cataracts and abnormal liver function. The rash and muscle weakness worsened. Nine months after JDM diagnosis, physical examination revealed that severe proximal muscle weakness (power 3/5) and numerous purplish red rashes and ulcerative scabs which could be seen on the face and limbs. MP, RTX and IVIG were administered in our hospital. Two weeks later, he gradually developed abdominal pain, bloating, low back pain, right lower quadrant tenderness and rebound pain. Localized colitis was suspected based on a CT scan. His abdominal pain and distension were relieved after the administration of antibiotics, MP (20 mg/kg/d for 2 days) and IVIG. Four days later, he developed fever, abdominal pain and distension, and an ultrasound showed echoic enhancement in the omentum of the right lower quadrant with weak peristalsis and ascites. MP, pulse CYC and IVIG were continued, and his temperature returned to normal with improved abdominal pain. However, 7 days later, he experienced severe abdominal pain and distension with a rapid decrease in his haemoglobin (Hb) level (from 112 g/L to 67 g/L). Ultrasound showed abdominal muscle inflammation with haemorrhage, and contrast-enhanced CT showed generalized retroperitoneal infection with abdominal wall haemorrhage and intestinal perforation (Fig. 1). Surgical intervention was not possible in view of unstable vital signs, severe infection, and severe and extensive intestinal lesions that could not be surgically repaired. Repeated blood transfusions, anti-microbial agents, and treatment for the primary disease were given. He persisted to have abdominal pain and bloating. A slight change in body position caused massive abdominal wall bleeding. He died after returning home.
Fig. 1 a The thigh skin ulcers accompanied by swelling of the ipsilateral testis on Case 3(arrow) b. Contrast-enhanced CT showed retroperitoneal effusion (arrow 1), retroperitoneal gas (arrow 2) and abdominal wall hemorrhage (arrow 3) on Case 3. c Contrast-enhanced CT showed retroperitoneal effusion (arrow 1) and retroperitoneal gas (arrow 2) on Case 3
Case 4
A 7-year-old girl with a past history of JDM was treated 1 year earlier with MP and an immunosuppressant. She presented with progressive proximal muscle weakness, skin ulcers and intermittent abdominal pain for 1 month. Physical examination showed severe malnutrition, anemia, maculopapular rashes symmetrically distributed over the extensor sides of the joints of all extremities, partially scabbing skin ulcers on the extensor side of the left elbow and in both axilla, proximal muscle weakness and edema in both upper limbs. Her Hb level was 59 g/L. Abdominal contrast-enhanced CT did not indicate obvious abnormalities. Ultrasound of the abdomen suggested thickening of the abdominal bowel wall and poor bowel motility. After treatment with blood transfusion, MP and CYC were given. Her symptoms improved, and abdominal pain disappeared. Hb decreased again after 2 weeks, and fever and abdominal pain reappeared again after 4 weeks. Abdominal CT revealed bowel perforation. She immediately underwent surgical repair (Fig. 2). One week later, abdominal pain appeared again. Abdominal CT showed another intestinal perforation. Surgical repair and PE therapy were performed. Her abdominal pain was relieved, but she developed severe pulmonary infection. Three days later, she had manifestations of peritonitis and then developed seizures. Her blood pressure was normal, cerebrospinal fluid tests were negative, but her magnetic resonance imaging (MRI) brain showed that the right temporal lobe and bilateral parieto-occipital lobes were swollen with abnormal signals; patchy abnormal signals were observed in the right thalamus, showing long T2 signal, high T2 FLAIR signal, limited dispersion, and reduced ADC value. We speculated primary disease involving the nervous system. Seizures did not recur after treatment of the primary disease. A repeat MRI brain was not done. Pulse MP and anti-microbial agents were given. Surgical intervention was not possible. The patient died due to uncontrolled bleeding and refractory shock.
Fig.2 a Contrast leakage seen at the junction of the descending and horizontal segments of the duodenum on Case 4 (arrow). b Contrast-enhanced CT showed retroperitoneal gas on Case 4 (arrow). c Duodenal perforation can be seen at surgery on Case 4 (arrow)
Case 5
A 10-year-old girl had been diagnosed with JDM 6 months earlier and received Pred and immunosuppressants. She presented with intermittent abdominal pain and fever for 1 month. She was initially treated with pulse MP and IVIG. But her muscle weakness and rash did not improve. She was admitted to our hospital with GI haemorrhage for 3 days. Physical examination showed a poor mental response, painful expression, severe malnutrition, anemia, scattered maculopapular rashes and ulcers distributed in the neck, axillae, buttocks, and extendible joints, and severe proximal muscle weakness. Her Hb level was 54 g/L. Ultrasound of the abdomen suggested thickening of the abdominal bowel wall and poor bowel movements. Pulse RTX and MP were given. Three days later, her abdominal pain worsened. Ultrasound of the abdomen showed intestinal perforation. During surgery, a 5-cm perforation of the transverse part of the duodenum was observed, the perforation was repaired and a double cavity jejunal fistula was performed. Her abdominal pain was relieved. CMV-DNA was detected in the blood, and she was given ganciclovir treatment. Four days later, she again experienced abdominal pain and muscle spasms. Considering the necrosis and perforation of the lower part of the duodenum, her parents withdrew treatment, and the patient died.
Results of the literature review
Sixteen patients of JDM with GI perforation were identified in PubMed, Medline and Scopus [6–18] which were published between 1984 and 2020. Eight patients were female (50%), six patients were male (37.5%), and the sex of two patients was not recorded (12.5%). The age of onset of these patients ranged from 2 to 10.5 years with the median age of 6.5 years. No clear MSA results were recorded in any case. Primary treatment with Pred and immunosuppressants did not have a significant effect. GI symptoms occurred from one to 108 months after treatment, most of which occurred within 10 months. The initial GI symptoms were severe abdominal pain with fever or vomiting. Perforations were reported in the duodenum (10/16, 62.5%), colon (6/16, 37.5%), jejunum (2/16, 12.5%), oesophagus (2/16, 12.5%), gastric pylorus (1/16, 6.25%), caecum (1/16, 6.25%) and an unclear location (1/16, 6.25%); perforations at multiple sites or recurrent perforations were reported in six patients (6/16, 37.5%). Only five patients had records regarding treatment of the initial disease, and they were treated with Pred or MP and an immunosuppressant (CYC/CsA). One patient underwent PE therapy, one patient received PE therapy with RTX and surgery was performed in 14 patients. In particular, one patient was treated with ganciclovir for CMV infection. Four patients died (25%), and the others were discharged from the hospital after they experienced relief of their symptoms. The clinical data of all 16 patients taken from the literature and the five patients in our study is summarized in Table 1.
Discussion
JDM, the most common inflammatory myopathy of childhood, is a rare systemic autoimmune vasculopathy that is characterized by weakness in proximal muscles and pathognomonic skin rashes [19]. Multiple systems can be involved, but GI perforations in anti-NXP2 antibody-associated JDM are rarely reported. From among 120 patients with JDM, we report five anti-NXP2 antibody-associated JDM complicated by GI perforation. Most patients in our study were females, with a proportion that was significantly higher than that for the other patients reported in the literature. At the age of onset of these five patients ranged from 3.3 to 9.5 years with the median age of 5.0 years, and GI perforations appeared between 4 and 13 months post diagnosis, which was similar to the 16 cases reported in the literature. When our patients were complicated by GI perforation, CMAS were very low, CAT activity score indicated moderate activity, which suggest that GI perforations may be associated with disease severity and activity. The initial symptoms of JDM with GI perforation were severe abdominal pain, abdominal distention, vomiting, fever and bloody stools. Early identification of perforation was very difficult. With regard to patient (P) 1 and P2, the doctors did not recognize that GI perforation had occurred after persistent abdominal pain for more than 1 month. The perforation in P3 occurred during hospitalization in our hospital and manifested as severe abdominal pain and distension with decreased bowel sounds. Repeated abdominal ultrasounds, X-rays and contrast-enhanced CTs indicated the presence of a low-signal mass in the right lower quadrant with bowel distension, thinning of the intestinal wall and local colitis without pneumoperitoneum or subphrenic pneumatosis. Transitory relief of symptoms occurred after treatment, but severe abdominal pain quickly reappeared, and contrast-enhanced CT and ultrasound showed intestinal perforation, diffuse abdominal wall bleeding and infection. We did not know the precise time when the perforation occurred, suggesting that once abdominal pain appears, perforation should be strongly suspected, and imaging should be performed. Perforation should be considered when abdominal pain is not relieved by active treatment in patients with JDM, and it can be diagnosed early with contrast-enhanced CT scans [6]. We also suggest that repeated scanning and GI angiograms are essential, if the diagnosis cannot be confirmed during the first scan. In the 16 patients in the literature, perforation often occurred in the duodenum (partially in the retroperitoneal area in P6) and the colon. In addition, multi-site or recurrent perforations were also observed in some patients (P7,P10,P16,P18,P20,P21), similar to the results of our study. Furthermore, arterial rupture near the perforation site often occurs, as observed in P2, who had ruptured hepatic arteries, and in P10, who had a ruptured duodenal proximal mesenteric artery; therefore, haemorrhage may also be considered when an unexplained decrease in the Hb level occurs in JDM patients. In addition, several patients have been described in literature with Degos-like lesions linked to GI perforation [20, 21]. A similar deposit complex and pattern of vasculopathy has been found in patients suffering from Degos disease and JDM [22]. We should pay attention to the identification of Degos-like disease. Degos - like skin lesions were initially pale red papules followed by enlarged lesions, showing a characteristic pitting center with a concave navel porcelain white center and a red halo around the periphery. After the rash subsided, there was a white superficial scar. The rash is more common on the trunk and extremities, less common on the palms and feet, and often occurs in batches, old and new. The appearance and location of the rash in five patients of our study were different from Degos-like disease. Further hisopathological identification may be performed if necessary.
In addition, two patients (P1, P2) had urinary system involvement in this group of cases, including ureteral stones, uretero-pelvic dilation and ureteral stenosis. With remission of the primary disease, ureteral stenosis disappeared in P1. This leads us to speculate that ureteral stenosis may be related to vasculopathy involving the urinary system. Morita et al. [23] reported a case of dermatomyositis who developed duodenal perforation as well as ureteral stenosis, with biopsy of stenotic ureter showing calcification with granulomatous tissue without any vasculitic lesion. Ruby Haviv et al. [24] reported a case of juvenile polymyositis (JPM) with right ureteral obstruction secondary to necrosis. The histopathology report of the resected ureter revealed moderate, acute, and chronic inflammatory infiltrates within the ureter wall, urothelial erosions, superficial granulation tissue, and degenerated smooth muscle fibres within the muscularis propria; some of which were infiltrated with lymphocytes and plasma cells, and multiple calcifications within the lamina propria. It also showed fragments of gross calcifications, similar calcifications in other parts of the ureter and obstructing calcifications within small blood vessels. Ruby Haviv et al. considered calcified ureteral necrosis to be a feature of visceral vasculopathy, related to both JDM and JPM. The mechanism is obscure, and the presence of calcifications within visceral tissues might suggest the pathogenesis of the typical calcinosis related to these diseases [24]. Considering that NXP-2 is a type prone to calcification, it was not clear whether ureteral calculi and ureteral stenosis in P1 and P2 were related to vasculopathy with calcification, which needs further studies of visceral calcinosis.
The underlying mechanisms of GI perforation in JDM are still obscure. Some researchers have reported glucocorticoids, non-steroidal anti inflammatory drugs and MTX to be risk factors for GI ulceration and perforation, especially at 1 month post-treatment or with an accumulated dose of steroids higher than 1 g [17]. In our study, Pred was reduced to a small dose before GI symptoms appeared in P1. After perforation was identified, pulse MP pulse and CYC were given, and the patient’s condition improved; thus, the perforation was not attributed to drug factors. Schneider et al. [6] assumed that ulceration in the proximal region and bulb of the duodenum was related to medication, while perforation in the descending part was related to vasculitis, causing intestinal ischemia and necrosis due to thrombogenesis and vascular occlusion. Recent researchers [16, 17] reported that perforated sites showed chronic vasculopathy rather than acute vasculitis. This chronic vasculopathy is characterized by narrowing or complete occlusion of multiple small and medium arteries, subintimal foam cells, fibromyxoid neointimal expansion, and significant luminal compromise with infiltration of macrophages through the muscle layers into the intima. Histopathology at the perforation site was recorded in three patients (P6, P12, P19) in the literature [6, 9, 13], and no vasculitis was noted. P12 exhibited mucosal ischemia, and P19 exhibited vasculopathy and CMV colitis. No manifestation of vasculitis was observed in the histopathology of the fistula. Histopathology of perforation site in P1 of our study showed inflammatory cells infiltrate and no vasculitic lesion was observed in the tissue. The other three patients were unable to undergo histopathology due to erosion of the perforation site. Therefore, whether chronic non-inflammatory vasculopathy causes ischemia and perforation must be considered. Bhaskaran et al. [13] reported a case of intestinal perforation in a child with JDM caused by CMV colitis. CMV-DNA was also detected in the blood of P5. No relevant pathological tests were performed. The other four patients did not undergo blood CMV-DNA tests. The role of CMV colitis in perforation requires further study.
The 120 patients in the JDM cohort were all tested by MSAs analysis, all five patients with GI perforation had strong positivity for anti-NXP2 antibody (3+), and no GI perforation was noted in other MSA patients, which led us question whether anti-NXP2 antibody is associated with GI perforation. After reviewing 16 cases in the literature, Besnard et al. [13] reported that most patients with severe GI manifestations were positive for anti-NXP2 antibody or anti-TIF-1γ antibody. Unfortunately, no specific antibody type was recorded in two patients with GI perforation in this study. The other patients described in the literature had not been tested for MSAs. In 2017, Tansley et al. [25] mentioned that 14 children who were positive for anti-NXP2 antibody had ulcers. Aouizerate et al. [26] reported that anti-NXP2 antibody had a positive association with GI involvement in JDM. The study evaluated the clinical, biological, and histological manifestations of 23 JDM patients and performed a multivariate analysis of 26 histopathological parameters. A case-control study can be performed to further uncover the relationship between anti-NXP2 antibody and GI perforation, which may further reveal the pathological mechanism of GI perforation. Based on our experience in this study, or even early in disease, clinicians should be highly alert to the possibility of GI perforation when abdominal pain occurs on anti-NXP2 antibody-positive patients with JDM.
The mortality rate among our patients was higher than that reported in the literature, which might be due to their severe condition and poor response to various therapeutic drugs, delayed surgery, surgical difficulties at the perforation site, economic reasons and the deficient number of cases. When a patient has intermittent abdominal pain and GI ulcers, the primary disease should be treated more actively to prevent GI perforation. Once GI perforation occurs, the primary disease is not well controlled, and the prognosis is poor. We need more research to choose appropriate treatment strategy for these diseases.
Conclusion
In this study, the clinical details of five cases of anti-NXP2 antibody-associated JDM complicated by GI perforation were summarized for the first time. Based on the these cases combined with a literature review, we suggest that once JDM patients present with abdominal pain, especially anti-NXP2 antibody-positive patients, GI perforation should be considered. For timely diagnosis, dynamic imaging is important. GI perforation may be a fatal complication of JDM, more research is needed to determine the pathogenesis and predictive factors of GI perforation in JDM.
Abbreviations
JDMJuvenile dermatomyositis
NXP2Nuclear matrix protein 2
GIGastrointestinal
MSAMyositis-specific antibody
CMASChild myositis assessment score
PredPrednisone
CYCCyclophosphamide
IVIGIntravenous immunoglobulin
MTXMethotrexate
MPMethylprednisolone
CsACyclosporine A
RTXRituximab
AZAAzathioprine
ThalThalidomide
PEPlasma exchanges
CMVCytomegalovirus
CTComputed tomography
HCQHydroxychloroquine
HbHaemoglobin
MRIMagnetic resonance imaging
JPMJuvenile polymyositis
CATCutaneous assessment tool
PPatient
Publisher’s Note
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Acknowledgement
We would like to thank the Department of General Surgery, the Department of Intensive Medicine and the Department of Radiology of the Children’'s Hospital Affiliated to the Capital Institute of Pediatrics for their contributions to the treatment of patients in our study.
Authors’ contributions
YX wrote the first draft of the manuscript, contributed to patient management and to the literature review. XM made many contributions in the process of writing and revising the manuscript. ZZ supervised patient management. JL critically revised the manuscript and supervised patient management. JH, JZ, MK and JL contributed to patient management. XL revised the manuscript. All the authors read and approved the final version of the manuscript.
Funding
This work was supported by Beijing Municipal Administration of Hospitals Clinical Medicine Development of Special Funding Support (code: XMLX201813) and Capital Funds for Health Improvement and Research (code:2020–2-2102).
Availability of data and materials
The datasets during and/or analyzed during the current study available from the corresponding author on reasonable request.
Ethics approval and consent to participate
Parental informed consent for publication was obtained. This study was approved by the Ethics Committee of Capital Institute of Pediatrics.
Consent for publication
Written informed consent was obtained from the patient’s legal guardians for publication of this case report and any accompanying images.
Competing interests
The authors declare that they have no competing interests. | Recovered | ReactionOutcome | CC BY | 33407602 | 18,840,448 | 2021-01-06 |
What was the outcome of reaction 'Pyrexia'? | Gastrointestinal perforation in anti-NXP2 antibody-associated juvenile dermatomyositis: case reports and a review of the literature.
BACKGROUND
To summarize the characteristics of gastrointestinal (GI) perforation in anti-nuclear matrix protein 2 (NXP2) antibody-associated juvenile dermatomyositis (JDM).
METHODS
Five patients with GI perforation from a JDM cohort of 120 cases are described. Relevant literature was reviewed.
RESULTS
Five patients, including four females and one male, were included in the study. The age of onset of these patients ranged from 3.3 to 9.5 years with the median age of 5.0 years. When these patients were complicated by GI perforation, childhood myositis assessment score (CMAS) ranged from 1 to 5 with the median score of 2. Myositis-specific antibody (MSA) spectrum analysis indicated that the five patients were anti-NXP2 antibody positive. The initial symptoms of GI perforation were progressive abdominal pain and intermittent fever. Two patients also presented with ureteral calculus with hydronephrosis and ureteral stricture. Surgery was performed in four patients. One patient failed to undergo a repair as the perforation was high in position. For the other three patients, perforation repair was successful, of which two patients failed due to recurrent perforation. At 24 months postoperative follow-up, one patient was in complete remission on prednisone (Pred) and methotrexate (MTX) treatment, and her ureteral stricture had disappeared. The other four patients died. Adding these cases with 16 other patients described in the literature, the symptom at onset was progressive abdominal pain, which often occurred within 10 months after JDM was diagnosed. Perforation most commonly occurred in the duodenum, although it also occurred at multiple sites or was recurrent. The mortality rate of GI perforation in JDM was 38% (8/21).
CONCLUSIONS
All the five perforation cases in our study subjected to MSA analysis were anti-NXP2 antibody positive. The symptom at onset was abdominal pain. The most common site of perforation was the duodenum in the retroperitoneum, and the lack of acute abdominal manifestations prevented early diagnosis. GI perforation may be a fatal complication in JDM, and early diagnosis is very important. More research is needed to determine the pathogenesis and predictive factors of GI perforation in JDM.
Background
Juvenile dermatomyositis (JDM) is an autoimmune disease characterized by proximal myopathy and a characteristic rash. However, multiple systems, including the digestive system, can also be involved. The occurrence of gastrointestinal (GI) perforation is rare, but a high mortality rate has been reported due to atypical symptoms and difficulty in early diagnosis [1]. Myositis-specific autoantibodies (MSAs) are increasingly used to delineate distinct subgroups of JDM [2, 3]. The presence of anti-nuclear matrix protein 2 (NXP2) autoantibodies substantially increases the risk of calcinosis across all ages and is associated with disease severity [4]. The role of MSAs in cases of JDM complicated by GI perforation has not been reported. Here, from among 120 patients with JDM, we report five cases complicated by GI perforation. All five patients had anti-NXP2 antibody-associated JDM. In addition, we reviewed the other JDM cases with GI perforation reported in the literature to improve our recognition of this disease. Anti-NXP2 autoantibodies may facilitate early diagnosis of the disease.
Methods
We described five patients with GI perforation from a JDM cohort who were admitted to the Children’s Hospital affiliated with the Capital Institute of Pediatrics, China, from January 2016 to December 2019. The inclusion criteria were: (1) age < 18 years old; (2) diagnosis of JDM based on the Bohan and Peter criteria for myositis [5]; and (3) GI perforation. Patients with other diseases that cause weakness or rash, or a clear alternative diagnosis were excluded from the study. Sixteen MSAs (MDA-5, NXP2, Jo-1, PM-SCL100, PL-7, PL-12, EJ, OJ, anti-Ro52, Ku, PM-Scl, SRP, SAE1, TIF1γ, Mi-2α and Mi-2β) were tested by immune dot blot hybridization using a commercial kit based on goat anti-human IgG antibodies (BlueDot Myositis 12 IgG, #MYO12D-24, D-TEK, Belgium). The study was approved by the Ethics Committee of Capital Institute of Pediatrics. We searched PubMed, Medline and Scopus using the keywords “juvenile dermatomyositis”, “gastrointestinal perforation”, and “perforation”. These literatures with detailed cases which clearly diagnosed JDM and excluded Degos-like presentation with GI perforation were reviewed.
Results (Table 1)
Table 1 Clinical data of JDM patients with GI perforation
Patient
/Year Gender Age at onset (y) CMAS score CAT-A
score CAT-D
score Positive for MSA Treatment before
GI perforation Symptoms of GI perforation Duration from onset to perforation (m) Site of perforation Surgical
treatment Histopathology of perforation site Medical Treatment Follow-up(m)
/Outcome
P1 F 3.4 5 2 3 Anti-NXP2 Pred+MTX + IVIG Abdominal pain/
bloody stools
4/9 Duodenum/ colon Transverse colon ostomyv
duodenostomy
Inflammatory cells infiltrate/
No vasculitis
Pred+Mp pulse+CsA+
IVIG→Pred+Thal+CYC→
Pred+CYC (Po) + MTX → Pred+MTX
24/Remission
P2 F 5.0 1 7 5 Anti-NXP2 MP + MP Pulse+CYC
HCQ/MP + MP Pulse+MTX
Abdominal pain/
bloody stools
10 Duodenum/
Duodenal bulb hepatic
artery rupture
Vessel sutured/
placement of duodenal
jejunal tube (failed)
ND Pred+MP Pulse+CYC+
IVIG
Death/Infection
P3 M 3.3 5 6 5 Anti-NXP2 Pred+MTX + IVIG/
Pred+IVIG +RTX
Abdominal pain
and distention bloody stools
10 Unknown No surgery ND MP pulse+CYC + IVIG Death/Abdominal bleeding
P4 F 6 2 6 6 Anti-NXP2 Pred+ MTX/CsA
→MP pulse+IVIG+CYC
Abdominal pain/
bloody stools
13 Duodenum×2 Perforation repair×2 ND CYC → MP pulse +IVIG+PE Death/Shock
P5 F 9.5 2 6 4 Anti-NXP2 Pred+ MTX/CsA Abdominal pain/ fever and bloody stools 6 Duodenum×2 Perforation repair ND MP pulse+ RTX Death/Abandon treatment
P6 [6]
/2016
F 7.0 ND ND ND ND Pred+MTX Abdominal pain vomiting and fever 6 Duodenal retroperitoneum Perforation repair No vasculitis ND ND/Improved
P7 [7]
/1997
M 7.0 ND ND ND ND Pred Abdominal pain /vomit 24 Duodenum Jejunum Perforation repair ND PE
Pred+MP pulse+CYC
12/Stable
P8 [8]
/1988
F 5.0 ND ND ND ND Pred Abdominal pain 3 Colon Perforation repair ND ND 12/Stable
P9 [8]
/1988
F 7.0 ND ND ND ND Pred +MTX Abdominal pain 6 The third duodenum ND ND ND 3/ND
P10 [8]
/1988
M 8.0 ND ND ND ND Pred+MTX Abdominal pain/
fever
6 Esophagus/
duodenum/ colon
Mesenteric arterial rupture
Perforation repair ND ND ND/Improved
P11 [8]
/1988
F 6.0 ND ND ND ND Pred+MTX Abdominal pain and distention/fever 5 Duodenum Perforation repair ND ND Death/unknown
P12 [9]
/2001
M 4.0 ND ND ND ND Pred+AZA Abdominal pain/
vomiting/fever
2 Duodenum Perforation repair Mucosal ischemia Pred+MP pulse 19/ND
P13 [10]
/2014
M 2.0 ND ND ND ND ND Abdominal pain 108 Unknown ND ND ND Death/unknown
P14 [11]
/1985
F 4.0 ND ND ND ND ND ND 48 Gastric pylorus Partial gastrectomy and gastrojejunostomy ND ND ND/Stable.
P15 [11]
/1985
F 5.0 ND ND ND ND ND ND 3 Middle transverse colon Loop transverse colon fistula ND ND Death/ARDS
P16 [11]
/1985
F 6.0 ND ND ND ND Pred+MTX/Pred+AZA/
Pre + CYC
Abdominal pain/
vomiting/fever
10 Duodenum colon transverse colon Multiple perforation repair ND ND 7/Stable.
P17 [11]
/1985
M 9.0 ND ND ND ND Pred/Pred+MTX/
Pred+AZA
Abdominal pain/ fever 13 Duodenum Perforation repair ND ND ND/Stable.
P18 [12]
/1984
M 7.0 ND ND ND ND Pred+MTX Abdominal pain 10 Duodenal perforation/
colon perforations
Perforation repair ND ND 48/Stable.
P19 [13]
/2019
F 6.0 ND ND ND ND Pred+MTX Abdominal pain/fever 1 transverse colon, Perforation repair
and loop colostomy.
No vasculitis and vasculopathy/
CMV colitis
Steroid+IVIG+Ganciclovir 12/Remission
P20 [14]
/2020
ND 10.5 16 ND ND ND ND Abdominal pain/ GI hemorrhage/ severe bowel obstruction 8/20 Duodenal Perforation/
Jejunal perforation
Jejunal resection/ exclusive parenteral
nutrition/ antibiotics,
ND Steroid+CsA 108/Remission
P21 [14]
/2020
ND 10.7 5 ND ND ND ND Abdominal pain/
severe bowel obstruction
7/9 Esophageal perforation/
Cecal perforation
Colostomy ND Steroid+ RTX+ PE 84/Death/Hepatitis
F is female, M is male, ND is no data, y is year, CMAS is child myositis assessment score, MSA is myositis-specific antibody, m is month, Pred is prednisone, CYC is cyclophosphamide, IVIG is intravenous immunoglobulin, MTX is methotrexate, MP is methylprednisol, CsA is cyclosporine A, RTX is rituximab, AZA is azathioprine, Thal is thalidomide, HCQ is hydroxychloroquine, Po is peros, CMV is Cytomegalovirus, PE is plasma exchanges, ARDS is acute respiratory distresssyndrome, CAT-A is cutaneous assessment tool activity, CAT-D is cutaneous assessment tool damage
The general data of the 5 patients
Five patients with GI perforation were identified from 120 cases in a JDM cohort (4.17%). Four of these were females, with the age at onset ranging from 3.3 to 9.5 years (median age − 5.0 years). All five patients showed severe rashes, skin ulcers, and weakness of the skeletal muscles (ranging from power 3/5 to 1/5). When these patients were complicated by GI perforation, childhood myositis assessment score (CMAS) ranged from 1 to 5 with the median score of 2, cutaneous assessment tool (CAT) activity score ranged from 2 to 7 with the median score of 6, CAT damage score ranged from 3 to 6 with the median score of 5. No calcification was observed. Two patients also presented with ureteral calculus with hydronephrosis and ureteral stricture. Analysis of MSAs showed that the five patients were anti-NXP2 antibody positive. There are 31 patients with anti-NXP2 antibody positive in the cohort. The incidence of GI perforation in anti-NXP2 antibody positive patients in our study was 16.13% (5/31). One patient had increased level of cytomegalovirus (CMV)-DNA copies in blood. GI perforation occurred from 4 to 13 months after JDM was diagnosed. The symptoms at onset were severe abdominal pain, fever, GI bleeding and vomiting. Perforations occurred in the duodenum (3 patients), duodenum and colon (1 patient), and an unclear location (1 patient), and perforations at multiple sites or at recurrent times occurred in four patients. All patients were treated with corticosteroids and immunosuppressant agents [cyclophosphamide (CYC)/methotrexate (MTX)/cyclosporine A (CsA)]. One patient was treated with plasma exchange (PE) therapy, and two patients received rituximab (RTX). All five patients were given proton-pump inhibitors (omeprazole). Surgery was performed in four patients, of which one patient failed to undergo repair due to the high position of perforation. For the other three patients, perforation repair was successful, of which two patients failed due to recurrent perforation. At 24 months postoperative follow-up, one patient was in complete remission under Pred and MTX treatment, and her ureteral stricture had disappeared. The other four patients died.
Case 1
A 3.4-year-old girl, suffering from characteristic skin rash and muscle weakness was diagnosed with JDM in a local hospital and was treated with Pred(2 mg/kg/d) and MTX (12 mg/m2/wk). Muscle weakness improved after 3 months of treatment, following which the dosage of Pred was reduced. When Pred was reduced to 10 mg/d, the girl developed infection in the lungs, skin ulcers around the anus and abdominal pain. One month later, a perforation in the transverse colon was confirmed, and colostomy was performed in a local hospital. She received Pred, CYC, intravenous immunoglobulin (IVIG) and MTX, after which her abdominal pain disappeared, and her muscle strength improved. Seven months after JDM diagnosis, ureteral calculus with hydronephrosis and ureteral stricture were diagnosed and treated via ureteroscopy. Nine months after JDM diagnosis, she developed severe abdominal pain and worsening muscle weakness, for which pulse methylprednisolone (MP) and CsA were given. Later, GI bleeding and fever recurred. She was transferred to our emergency department. She had shock, and her contrast-enhanced computed tomography (CT) abdomen indicated encapsulated effusion and pneumatosis, duodenal perforation and an abscess, which were confirmed during surgery. After duodenostomy, Pred, pulse CYC and thalidomide were given, and when her condition stabilized, we switched to oral Pred, CYC and MTX. At 24 months postoperative follow-up, she was in complete remission with Pred and MTX treatment, and her ureteral stricture had disappeared.
Case 2
A 5-year-old girl suffering from characteristic skin rash and muscle weakness was diagnosed with JDM in a local hospital and treated with Pred, MTX and hydroxychloroquine (HCQ), after which her muscle strength improved. But her parents stopped the treatment. Twelve months after JDM diagnosis, she was admitted to our emergency department due to abdominal pain, vomiting, and dark coloured stools. Physical examination showed a poor mental response, painful expression, severe malnutrition, High spring sign (+), partially scabbed skin ulcers in the lower jaw, popliteal fossa and axillae and muscle weakness. A contrast-enhanced CT abdomen indicated peritonitis, intestinal perforation and a right renal-ureteral calculus with pelvicalyceal-ureteral dilation. During surgery, multiple perforations of the duodenum and ruptured right hepatic artery were found. The ruptured blood vessel was sutured, but duodeno jejunal tube placement was unsuccessful. The patient subsequently died of infections and haemorrhagic shock.
Case 3
A 3.3-year-old boy suffering from characteristic skin rash and muscle weakness was diagnosed with JDM and treated with Pred, MTX and IVIG in a local hospital. His symptoms improved after treatment; the dosage of Pred was reduced, and MTX was stopped due to cataracts and abnormal liver function. The rash and muscle weakness worsened. Nine months after JDM diagnosis, physical examination revealed that severe proximal muscle weakness (power 3/5) and numerous purplish red rashes and ulcerative scabs which could be seen on the face and limbs. MP, RTX and IVIG were administered in our hospital. Two weeks later, he gradually developed abdominal pain, bloating, low back pain, right lower quadrant tenderness and rebound pain. Localized colitis was suspected based on a CT scan. His abdominal pain and distension were relieved after the administration of antibiotics, MP (20 mg/kg/d for 2 days) and IVIG. Four days later, he developed fever, abdominal pain and distension, and an ultrasound showed echoic enhancement in the omentum of the right lower quadrant with weak peristalsis and ascites. MP, pulse CYC and IVIG were continued, and his temperature returned to normal with improved abdominal pain. However, 7 days later, he experienced severe abdominal pain and distension with a rapid decrease in his haemoglobin (Hb) level (from 112 g/L to 67 g/L). Ultrasound showed abdominal muscle inflammation with haemorrhage, and contrast-enhanced CT showed generalized retroperitoneal infection with abdominal wall haemorrhage and intestinal perforation (Fig. 1). Surgical intervention was not possible in view of unstable vital signs, severe infection, and severe and extensive intestinal lesions that could not be surgically repaired. Repeated blood transfusions, anti-microbial agents, and treatment for the primary disease were given. He persisted to have abdominal pain and bloating. A slight change in body position caused massive abdominal wall bleeding. He died after returning home.
Fig. 1 a The thigh skin ulcers accompanied by swelling of the ipsilateral testis on Case 3(arrow) b. Contrast-enhanced CT showed retroperitoneal effusion (arrow 1), retroperitoneal gas (arrow 2) and abdominal wall hemorrhage (arrow 3) on Case 3. c Contrast-enhanced CT showed retroperitoneal effusion (arrow 1) and retroperitoneal gas (arrow 2) on Case 3
Case 4
A 7-year-old girl with a past history of JDM was treated 1 year earlier with MP and an immunosuppressant. She presented with progressive proximal muscle weakness, skin ulcers and intermittent abdominal pain for 1 month. Physical examination showed severe malnutrition, anemia, maculopapular rashes symmetrically distributed over the extensor sides of the joints of all extremities, partially scabbing skin ulcers on the extensor side of the left elbow and in both axilla, proximal muscle weakness and edema in both upper limbs. Her Hb level was 59 g/L. Abdominal contrast-enhanced CT did not indicate obvious abnormalities. Ultrasound of the abdomen suggested thickening of the abdominal bowel wall and poor bowel motility. After treatment with blood transfusion, MP and CYC were given. Her symptoms improved, and abdominal pain disappeared. Hb decreased again after 2 weeks, and fever and abdominal pain reappeared again after 4 weeks. Abdominal CT revealed bowel perforation. She immediately underwent surgical repair (Fig. 2). One week later, abdominal pain appeared again. Abdominal CT showed another intestinal perforation. Surgical repair and PE therapy were performed. Her abdominal pain was relieved, but she developed severe pulmonary infection. Three days later, she had manifestations of peritonitis and then developed seizures. Her blood pressure was normal, cerebrospinal fluid tests were negative, but her magnetic resonance imaging (MRI) brain showed that the right temporal lobe and bilateral parieto-occipital lobes were swollen with abnormal signals; patchy abnormal signals were observed in the right thalamus, showing long T2 signal, high T2 FLAIR signal, limited dispersion, and reduced ADC value. We speculated primary disease involving the nervous system. Seizures did not recur after treatment of the primary disease. A repeat MRI brain was not done. Pulse MP and anti-microbial agents were given. Surgical intervention was not possible. The patient died due to uncontrolled bleeding and refractory shock.
Fig.2 a Contrast leakage seen at the junction of the descending and horizontal segments of the duodenum on Case 4 (arrow). b Contrast-enhanced CT showed retroperitoneal gas on Case 4 (arrow). c Duodenal perforation can be seen at surgery on Case 4 (arrow)
Case 5
A 10-year-old girl had been diagnosed with JDM 6 months earlier and received Pred and immunosuppressants. She presented with intermittent abdominal pain and fever for 1 month. She was initially treated with pulse MP and IVIG. But her muscle weakness and rash did not improve. She was admitted to our hospital with GI haemorrhage for 3 days. Physical examination showed a poor mental response, painful expression, severe malnutrition, anemia, scattered maculopapular rashes and ulcers distributed in the neck, axillae, buttocks, and extendible joints, and severe proximal muscle weakness. Her Hb level was 54 g/L. Ultrasound of the abdomen suggested thickening of the abdominal bowel wall and poor bowel movements. Pulse RTX and MP were given. Three days later, her abdominal pain worsened. Ultrasound of the abdomen showed intestinal perforation. During surgery, a 5-cm perforation of the transverse part of the duodenum was observed, the perforation was repaired and a double cavity jejunal fistula was performed. Her abdominal pain was relieved. CMV-DNA was detected in the blood, and she was given ganciclovir treatment. Four days later, she again experienced abdominal pain and muscle spasms. Considering the necrosis and perforation of the lower part of the duodenum, her parents withdrew treatment, and the patient died.
Results of the literature review
Sixteen patients of JDM with GI perforation were identified in PubMed, Medline and Scopus [6–18] which were published between 1984 and 2020. Eight patients were female (50%), six patients were male (37.5%), and the sex of two patients was not recorded (12.5%). The age of onset of these patients ranged from 2 to 10.5 years with the median age of 6.5 years. No clear MSA results were recorded in any case. Primary treatment with Pred and immunosuppressants did not have a significant effect. GI symptoms occurred from one to 108 months after treatment, most of which occurred within 10 months. The initial GI symptoms were severe abdominal pain with fever or vomiting. Perforations were reported in the duodenum (10/16, 62.5%), colon (6/16, 37.5%), jejunum (2/16, 12.5%), oesophagus (2/16, 12.5%), gastric pylorus (1/16, 6.25%), caecum (1/16, 6.25%) and an unclear location (1/16, 6.25%); perforations at multiple sites or recurrent perforations were reported in six patients (6/16, 37.5%). Only five patients had records regarding treatment of the initial disease, and they were treated with Pred or MP and an immunosuppressant (CYC/CsA). One patient underwent PE therapy, one patient received PE therapy with RTX and surgery was performed in 14 patients. In particular, one patient was treated with ganciclovir for CMV infection. Four patients died (25%), and the others were discharged from the hospital after they experienced relief of their symptoms. The clinical data of all 16 patients taken from the literature and the five patients in our study is summarized in Table 1.
Discussion
JDM, the most common inflammatory myopathy of childhood, is a rare systemic autoimmune vasculopathy that is characterized by weakness in proximal muscles and pathognomonic skin rashes [19]. Multiple systems can be involved, but GI perforations in anti-NXP2 antibody-associated JDM are rarely reported. From among 120 patients with JDM, we report five anti-NXP2 antibody-associated JDM complicated by GI perforation. Most patients in our study were females, with a proportion that was significantly higher than that for the other patients reported in the literature. At the age of onset of these five patients ranged from 3.3 to 9.5 years with the median age of 5.0 years, and GI perforations appeared between 4 and 13 months post diagnosis, which was similar to the 16 cases reported in the literature. When our patients were complicated by GI perforation, CMAS were very low, CAT activity score indicated moderate activity, which suggest that GI perforations may be associated with disease severity and activity. The initial symptoms of JDM with GI perforation were severe abdominal pain, abdominal distention, vomiting, fever and bloody stools. Early identification of perforation was very difficult. With regard to patient (P) 1 and P2, the doctors did not recognize that GI perforation had occurred after persistent abdominal pain for more than 1 month. The perforation in P3 occurred during hospitalization in our hospital and manifested as severe abdominal pain and distension with decreased bowel sounds. Repeated abdominal ultrasounds, X-rays and contrast-enhanced CTs indicated the presence of a low-signal mass in the right lower quadrant with bowel distension, thinning of the intestinal wall and local colitis without pneumoperitoneum or subphrenic pneumatosis. Transitory relief of symptoms occurred after treatment, but severe abdominal pain quickly reappeared, and contrast-enhanced CT and ultrasound showed intestinal perforation, diffuse abdominal wall bleeding and infection. We did not know the precise time when the perforation occurred, suggesting that once abdominal pain appears, perforation should be strongly suspected, and imaging should be performed. Perforation should be considered when abdominal pain is not relieved by active treatment in patients with JDM, and it can be diagnosed early with contrast-enhanced CT scans [6]. We also suggest that repeated scanning and GI angiograms are essential, if the diagnosis cannot be confirmed during the first scan. In the 16 patients in the literature, perforation often occurred in the duodenum (partially in the retroperitoneal area in P6) and the colon. In addition, multi-site or recurrent perforations were also observed in some patients (P7,P10,P16,P18,P20,P21), similar to the results of our study. Furthermore, arterial rupture near the perforation site often occurs, as observed in P2, who had ruptured hepatic arteries, and in P10, who had a ruptured duodenal proximal mesenteric artery; therefore, haemorrhage may also be considered when an unexplained decrease in the Hb level occurs in JDM patients. In addition, several patients have been described in literature with Degos-like lesions linked to GI perforation [20, 21]. A similar deposit complex and pattern of vasculopathy has been found in patients suffering from Degos disease and JDM [22]. We should pay attention to the identification of Degos-like disease. Degos - like skin lesions were initially pale red papules followed by enlarged lesions, showing a characteristic pitting center with a concave navel porcelain white center and a red halo around the periphery. After the rash subsided, there was a white superficial scar. The rash is more common on the trunk and extremities, less common on the palms and feet, and often occurs in batches, old and new. The appearance and location of the rash in five patients of our study were different from Degos-like disease. Further hisopathological identification may be performed if necessary.
In addition, two patients (P1, P2) had urinary system involvement in this group of cases, including ureteral stones, uretero-pelvic dilation and ureteral stenosis. With remission of the primary disease, ureteral stenosis disappeared in P1. This leads us to speculate that ureteral stenosis may be related to vasculopathy involving the urinary system. Morita et al. [23] reported a case of dermatomyositis who developed duodenal perforation as well as ureteral stenosis, with biopsy of stenotic ureter showing calcification with granulomatous tissue without any vasculitic lesion. Ruby Haviv et al. [24] reported a case of juvenile polymyositis (JPM) with right ureteral obstruction secondary to necrosis. The histopathology report of the resected ureter revealed moderate, acute, and chronic inflammatory infiltrates within the ureter wall, urothelial erosions, superficial granulation tissue, and degenerated smooth muscle fibres within the muscularis propria; some of which were infiltrated with lymphocytes and plasma cells, and multiple calcifications within the lamina propria. It also showed fragments of gross calcifications, similar calcifications in other parts of the ureter and obstructing calcifications within small blood vessels. Ruby Haviv et al. considered calcified ureteral necrosis to be a feature of visceral vasculopathy, related to both JDM and JPM. The mechanism is obscure, and the presence of calcifications within visceral tissues might suggest the pathogenesis of the typical calcinosis related to these diseases [24]. Considering that NXP-2 is a type prone to calcification, it was not clear whether ureteral calculi and ureteral stenosis in P1 and P2 were related to vasculopathy with calcification, which needs further studies of visceral calcinosis.
The underlying mechanisms of GI perforation in JDM are still obscure. Some researchers have reported glucocorticoids, non-steroidal anti inflammatory drugs and MTX to be risk factors for GI ulceration and perforation, especially at 1 month post-treatment or with an accumulated dose of steroids higher than 1 g [17]. In our study, Pred was reduced to a small dose before GI symptoms appeared in P1. After perforation was identified, pulse MP pulse and CYC were given, and the patient’s condition improved; thus, the perforation was not attributed to drug factors. Schneider et al. [6] assumed that ulceration in the proximal region and bulb of the duodenum was related to medication, while perforation in the descending part was related to vasculitis, causing intestinal ischemia and necrosis due to thrombogenesis and vascular occlusion. Recent researchers [16, 17] reported that perforated sites showed chronic vasculopathy rather than acute vasculitis. This chronic vasculopathy is characterized by narrowing or complete occlusion of multiple small and medium arteries, subintimal foam cells, fibromyxoid neointimal expansion, and significant luminal compromise with infiltration of macrophages through the muscle layers into the intima. Histopathology at the perforation site was recorded in three patients (P6, P12, P19) in the literature [6, 9, 13], and no vasculitis was noted. P12 exhibited mucosal ischemia, and P19 exhibited vasculopathy and CMV colitis. No manifestation of vasculitis was observed in the histopathology of the fistula. Histopathology of perforation site in P1 of our study showed inflammatory cells infiltrate and no vasculitic lesion was observed in the tissue. The other three patients were unable to undergo histopathology due to erosion of the perforation site. Therefore, whether chronic non-inflammatory vasculopathy causes ischemia and perforation must be considered. Bhaskaran et al. [13] reported a case of intestinal perforation in a child with JDM caused by CMV colitis. CMV-DNA was also detected in the blood of P5. No relevant pathological tests were performed. The other four patients did not undergo blood CMV-DNA tests. The role of CMV colitis in perforation requires further study.
The 120 patients in the JDM cohort were all tested by MSAs analysis, all five patients with GI perforation had strong positivity for anti-NXP2 antibody (3+), and no GI perforation was noted in other MSA patients, which led us question whether anti-NXP2 antibody is associated with GI perforation. After reviewing 16 cases in the literature, Besnard et al. [13] reported that most patients with severe GI manifestations were positive for anti-NXP2 antibody or anti-TIF-1γ antibody. Unfortunately, no specific antibody type was recorded in two patients with GI perforation in this study. The other patients described in the literature had not been tested for MSAs. In 2017, Tansley et al. [25] mentioned that 14 children who were positive for anti-NXP2 antibody had ulcers. Aouizerate et al. [26] reported that anti-NXP2 antibody had a positive association with GI involvement in JDM. The study evaluated the clinical, biological, and histological manifestations of 23 JDM patients and performed a multivariate analysis of 26 histopathological parameters. A case-control study can be performed to further uncover the relationship between anti-NXP2 antibody and GI perforation, which may further reveal the pathological mechanism of GI perforation. Based on our experience in this study, or even early in disease, clinicians should be highly alert to the possibility of GI perforation when abdominal pain occurs on anti-NXP2 antibody-positive patients with JDM.
The mortality rate among our patients was higher than that reported in the literature, which might be due to their severe condition and poor response to various therapeutic drugs, delayed surgery, surgical difficulties at the perforation site, economic reasons and the deficient number of cases. When a patient has intermittent abdominal pain and GI ulcers, the primary disease should be treated more actively to prevent GI perforation. Once GI perforation occurs, the primary disease is not well controlled, and the prognosis is poor. We need more research to choose appropriate treatment strategy for these diseases.
Conclusion
In this study, the clinical details of five cases of anti-NXP2 antibody-associated JDM complicated by GI perforation were summarized for the first time. Based on the these cases combined with a literature review, we suggest that once JDM patients present with abdominal pain, especially anti-NXP2 antibody-positive patients, GI perforation should be considered. For timely diagnosis, dynamic imaging is important. GI perforation may be a fatal complication of JDM, more research is needed to determine the pathogenesis and predictive factors of GI perforation in JDM.
Abbreviations
JDMJuvenile dermatomyositis
NXP2Nuclear matrix protein 2
GIGastrointestinal
MSAMyositis-specific antibody
CMASChild myositis assessment score
PredPrednisone
CYCCyclophosphamide
IVIGIntravenous immunoglobulin
MTXMethotrexate
MPMethylprednisolone
CsACyclosporine A
RTXRituximab
AZAAzathioprine
ThalThalidomide
PEPlasma exchanges
CMVCytomegalovirus
CTComputed tomography
HCQHydroxychloroquine
HbHaemoglobin
MRIMagnetic resonance imaging
JPMJuvenile polymyositis
CATCutaneous assessment tool
PPatient
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Acknowledgement
We would like to thank the Department of General Surgery, the Department of Intensive Medicine and the Department of Radiology of the Children’'s Hospital Affiliated to the Capital Institute of Pediatrics for their contributions to the treatment of patients in our study.
Authors’ contributions
YX wrote the first draft of the manuscript, contributed to patient management and to the literature review. XM made many contributions in the process of writing and revising the manuscript. ZZ supervised patient management. JL critically revised the manuscript and supervised patient management. JH, JZ, MK and JL contributed to patient management. XL revised the manuscript. All the authors read and approved the final version of the manuscript.
Funding
This work was supported by Beijing Municipal Administration of Hospitals Clinical Medicine Development of Special Funding Support (code: XMLX201813) and Capital Funds for Health Improvement and Research (code:2020–2-2102).
Availability of data and materials
The datasets during and/or analyzed during the current study available from the corresponding author on reasonable request.
Ethics approval and consent to participate
Parental informed consent for publication was obtained. This study was approved by the Ethics Committee of Capital Institute of Pediatrics.
Consent for publication
Written informed consent was obtained from the patient’s legal guardians for publication of this case report and any accompanying images.
Competing interests
The authors declare that they have no competing interests. | Recovered | ReactionOutcome | CC BY | 33407602 | 18,840,448 | 2021-01-06 |
Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Arthritis'. | Shrinking lung syndrome treated with rituximab in pediatric systemic lupus erythematosus: a case report and review of the literature.
BACKGROUND
Shrinking lung syndrome (SLS), a rare complication of systemic lupus erythematosus (SLE) characterized by dyspnea, low lung volumes, and a restrictive pattern on pulmonary function tests (PFTs), has only been reported in a few children. Given the rarity of SLS there is a paucity of literature regarding its optimal treatment. Outcomes are variable, with case reports documenting some improvement in most patients treated with corticosteroids, with or without additional immunosuppressive agents. However, most reported patients did not recover normal lung function. We report full recovery of a child with SLE and SLS following treatment with rituximab and review the current literature.
METHODS
An 11-year-old boy presented with a malar rash, myositis, arthritis, oral ulcers, leukopenia, anemia, positive lupus autoantibodies and Class II nephritis. He was diagnosed with SLE and treated with corticosteroids, hydroxychloroquine, azathioprine, and subsequently mycophenolate with symptom resolution. At age 14, his SLE flared coincident with a viral chest infection. He presented with a malar rash, polyarthritis, increased proteinuria and pleuritis which all improved with corticosteroids and ongoing treatment with mycophenolate. Six weeks later he presented with severe dyspnea, markedly decreased lung volumes, but otherwise normal chest X-ray (CXR) and high-resolution chest computed tomography (HRCT). He was found to have severely restricted PFTs (FEV1 27%, FVC 29%; TLC 43%). After additional investigations including echocardiography, pulmonary CT angiography, and diaphragmatic fluoroscopy, he was diagnosed with SLS and treated with rituximab and methylprednisolone. At 1 month his symptoms had improved, but he still had dyspnea with exertion and severely restricted PFTs. At 6 months his FVC and TLC had improved to 51 and 57% respectively, and were 83 and 94% respectively at 4 years. He had returned to all baseline activities, including competitive hockey.
CONCLUSIONS
Although extremely rare, it is important to recognize SLS as a possible cause of dyspnea and chest pain in a child with SLE. Optimal treatment strategies are unknown. This is the second reported case of a child treated with rituximab for SLS who recovered normal lung function. International lupus registries should carefully document the occurrence, treatment and outcome of patients with SLS to help determine the optimal treatment for this rare complication.
Background
Shrinking lung syndrome (SLS) is a rare complication of systemic lupus erythematosus (SLE) characterized by decreased lung volumes and a restrictive pattern on pulmonary function testing (PFTs). Patients typically present with progressive dyspnea and chest pain [1–3]. The diagnosis may be delayed, particularly in pediatric patients, because of failure to consider or recognize this disorder. The exact pathophysiology is unknown [1–3].
Given the rarity of SLS there is a paucity of literature regarding optimal treatment. Case reports and series have documented improvement in most patients treated with corticosteroids, with or without immunosuppressive agents. However, the majority of patients have an incomplete recovery [4, 5]. Recently, rituximab, a monoclonal antibody directed against the CD20 antigen found on the surface of B lymphocytes, has been used successfully in several adult patients and one child with SLE complicated by SLS [6, 7]. We report a child with SLE who developed SLS at age 14 and recovered fully following treatment with rituximab. We also review the literature on SLS in pediatric patients to increase awareness of this exceptionally rare complication, as well as review outcome of patients previously reported with SLS who were treated with rituximab.
Case presentation
At age 11 years, our patient was diagnosed with SLE after presenting with a malar rash, oral ulcers, polyarthritis, myositis, and anemia. His past history was remarkable only for mild asthma; family history was positive for maternal asthma and hypothyroidism. Work-up revealed leukopenia (WBC 2.5 10e9/L), hypocomplementemia (C3 0.23 g/L), positive anti-nuclear antibody, anti-dsDNA (633 IU/ml; normal less than10), anti-SSa/Ro, and anti-Smith antibodies, Class II lupus nephritis and a SLEDAI of 29. A baseline chest radiograph (CXR) was normal. He was treated with prednisone, hydroxychloroquine (HCQ), and azathioprine. A year later he had no symptoms of his SLE but was evaluated for an exercise-associated cough that was felt to be due to his asthma. A CXR was normal, PFTs showed moderate obstruction and symptoms resolved with a bronchodilator. Over the next few months, despite ongoing HCQ, azathioprine and low dose prednisone he had recurrence of malar rash and mild arthritis; a repeat renal biopsy showed Class III b lupus nephritis and azathioprine was replaced by mycophenolate mofetil (MMF) which was increased up to 700 mg/m2/dose BID, and subsequently decreased due to gastrointestinal side effects. This resulted in resolution of all symptoms but some ongoing nephritis (SLEDAI 12).
At age 14 he was admitted to his local hospital with fever, pleuritic chest pain, dyspnea, and cough. Bilateral pleural effusions were seen on CXR and he was given empiric antibiotics for possible pneumonia prior to transfer to our center, where he received a 3-day pulse of intravenous methylprednisolone (IVMP) for a suspected SLE flare (C3 0.70; anti dsDNA 95; SLEDAI 29). His chest symptoms resolved completely and respiratory syncytial virus (RSV) infection was subsequently confirmed by PCR and was thought to have triggered the flare. One month later, despite treatment with low dose prednisone and MMF (535 mg/m2/dose BID, although compliance was questionable), his SLE again flared. He presented with a malar rash, polyarthritis, as well as findings of pleuritis manifesting with chest pain, dyspnea, and a left pleural effusion. He was treated with pulse IVMP followed by increased MMF (625 mg/m2/dose BID) and daily oral prednisone (1 mg/kg/d).
Six weeks later his rash and arthritis had improved, but he reported increasing shortness of breath with marked exercise intolerance. On examination he was afebrile, his heart rate was 120, respiratory rate 40, and oxygen saturation 95% in room air. He appeared dyspneic with difficulty speaking in full sentences. Chest examination revealed shallow breathing and decreased air entry bilaterally. Physical examination was otherwise unremarkable. Work up for infection was negative. His SLEDAI had decreased to 14, C3 had normalized (0.97) and anti dsDNA had decreased to 39. CXR and high-resolution computed tomography (HRCT) showed severely reduced lung volumes with no pleural or interstitial disease; there was slight atelectasis but no other significant abnormalities (Figs. 1, 2). An echocardiogram was normal and a CT angiogram showed no evidence of pulmonary embolus. PFTs revealed a severe restrictive pattern with forced expiratory volume in 1 s (FEV1) of 27%, forced vital capacity (FVC) 29%, and total lung capacity (TLC) 43% (Fig. 3). Fluoroscopy documented significantly reduced diaphragmatic movement. He was diagnosed with SLS, and because of worsening dyspnea despite recently increased immunosuppression, he was treated with IVMP 1 g daily for 3 days followed by rituximab 1 g (2 doses, 2 weeks apart). He was also referred to physiotherapy for pulmonary rehabilitation.
Fig. 1 a Chest X-ray at presentation with SLS, showing decreased lung volumes and raised hemidiaphragms b Normal chest X-ray 3 years later
Fig. 2 High-resolution computed tomography (HRCT) of the chest at presentation with SLS, showing decreased lung volumes and slight atelectasis
Fig. 3 Pulmonary function tests (PFTs) over time in our patient with SLE and SLS; at diagnosis to 4 years following treatment with rituximab. FEV1, forced expiratory volume in 1 s; FVC, forced vital capacity; TLC, total lung capacity; RV, residual volume
One month later he reported some improvement in physical endurance, though he still had dyspnea with mild exertion and PFTs remained severely restrictive. At 6 months, however, he reported much improved exercise tolerance with ability to play some hockey. His FEV1 and FVC had improved to 42 and 51% respectively and TLC had increased to 57%. A planned second course of rituximab, (1 g, 2 doses, 2 weeks apart) was given at 6 months; preceding B cell counts were 8%. He was tapered off corticosteroids over the next 9 months and continued on HCQ (5 mg/kg/d) and MMF (600 mg/m2/dose BID). Serial CXRs showed gradual lung volume expansion. One year after his presentation he returned to playing competitive hockey, with no limitations and no respiratory symptoms. Four years later, he remained asymptomatic with no limitations in activity, no evidence of restrictive lung disease on PFTs (FVC 83%, TLC 94%), and a normal CXR. He remained on the same doses of HCQ and MMF with no clinical evidence of SLE disease activity, normal complement levels (C3 0.97), anti dsDNA 16, a SLEDAI of 2, and a follow renal biopsy showed no active nephritis.
Discussion
Shrinking lung syndrome is a rare complication of SLE with an incidence of approximately 1% in adult lupus patients [1, 5]. The incidence in pediatric SLE is unknown, but is likely even less common. As such, the diagnosis of SLS may not be considered or recognized in a child with SLE. Clinical features include progressive dyspnea, exercise intolerance, and pleuritic chest pain, all of which were described by our patient. Physical examination frequently reveals tachypnea with decreased air entry and the use of accessory respiratory muscles but is otherwise unremarkable. Findings on CXR often include significantly reduced lung volumes with elevated hemidiaphragms and may include pleural effusions, basal atelectasis, and pleural thickening. HRCT typically shows no parenchymal lung disease, though it may be more sensitive than CXR in demonstrating pleural effusions and atelectasis [4, 8]. PFTs show a restrictive pattern [4]. Reduced diaphragmatic excursion may be demonstrated on chest fluoroscopy, as was seen in our patient, or may be demonstrated using M-mode ultrasonography [8].
The pathogenesis of shrinking lung syndrome remains incompletely understood. When first described by Hoffbrand and Beck in 1965, the condition was thought to be due to surfactant deficiency causing microatelectasis [9]. Since then a number of mechanisms have been suggested, including phrenic nerve dysfunction, pleural inflammation and fibrosis, and diaphragmatic dysfunction due to myositis or neuropathy [3, 10]. Anti-SSa/Ro antibody positivity has been associated with both SLS and myositis, and has been suggested to support the theory that myositis contributes to diaphragmatic dysfunction in some patients [3, 11]. Of note, our patient was anti-SSa/Ro positive and had myositis as part of his SLE course. The frequent occurrence of pleuritic chest pain in up to 80% of patients with SLS has led to a more recently proposed mechanism of pleuritic pain leading to reflex inhibition of diaphragmatic activation and subsequent dysfunction in at least a subset of patients with SLS [1, 3]. Henderson et al. have proposed that pleural inflammation due to the underlying rheumatic disease may lead to activation of neural reflexes which inhibit deep inspiration and cause chronic lung hypoinflation. This is postulated to gradually reduce lung compliance and results in a positive feedback cycle [12]. Interestingly, our patient had developed pleuritic chest pain 2 months prior to his diagnosis of SLS, and had documented pleuritis associated with an RSV infection, and then associated with a flare of his SLE, which may have initiated the pathogenetic process leading to SLS.
There is no standard treatment for patients with SLS. Corticosteroids are the most frequently reported initial treatment of SLS, and can lead to full recovery in some patients [3, 5, 11, 13]. Immunosuppressive agents including cyclophosphamide, azathioprine, and methotrexate are often given along with corticosteroids or if corticosteroids alone are ineffective. There are also a few reports of theophylline and beta-agonists used effectively in SLS, and others advocate the use of analgesia to combat chest pain and pulmonary rehabilitation to improve lung expansion [1, 3, 5, 12, 13]. Although rare fatal cases have been described, the prognosis of SLS in adults is generally considered to be good, particularly in comparison with the progressive course and significant mortality associated with fibrotic interstitial lung disease in patients with SLE [1]. Some clinical improvement has been reported in most patients with SLS, however, recent literature makes it clear that despite treatment many patients do not achieve full recovery. Langenskiold et al., in a review of 35 cases with documented pre and post treatment PFTs, found that only 20% of patients with SLS regained normal lung function [4]. Duron et al. reported full recovery in only a minority of patients in their review of 155 patients with SLS, with 42.9% of patients showing chronic and persistent hemidiaphragm elevation [1]. A report of 20 cases from a large single center in 2018 showed a similar outcome, with 86.7% of patients showing continued restrictive defects on spirometry despite improved lung volumes [5]. The lack of full recovery in both adult and pediatric patients with SLS has led to 15 reports of rituximab use in adults and 2 reports in children with SLS complicating SLE [1, 3, 4, 6–8, 12, 14–16] (Table 1). Normal PFTs were reported in one child treated with rituximab [7], however the other child did not respond [12]. All 4 adult patients with well-documented post-treatment PFTs had normal or near normal findings [3, 4, 6]. Although the degree of objective improvement was not documented in the remaining 11 adult cases treated with rituximab, all were reported to have improved or stabilized. (Table 1). There has also been a recent report of a 19-year-old male with pediatric-onset SLE who developed SLS refractory to IVMP and cyclophosphamide and had some improvement with belimumab, a monoclonal antibody directed against BLyS receptors on B-cells, though long-term follow-up is still ongoing [11].
Table 1 Clinical features, treatment and outcome of patients with SLS associated with SLE who received treatment with rituximab
Reference Sex Age at SLE diagnosis Age at SLS diagnosis Clinical presentation Imaging findings at SLS diagnosis PFTs at SLS diagnosis Treatment Outcome
[1] F Unknown 61 Chest pain, history of pleurisy, dyspnea Elevated diaphragms, atelectasis, pleural thickening TLC 46%,
DLCO 25%, KCO 59%
CS + Beta-agonists + RTX (dose unknown) + Physiotherapy Improvement
[1] F Unknown 26 Chest pain, history of pleurisy, dyspnea Pleural thickening, reticulations FVC 41%,
TLC 68%,
DLCO 34%
CS + AZA + MMF + RTX (dose unknown) Improvement
[3] F 36 46 Dyspnea on exertion, orthopnea, pleuritic chest pain Elevated diaphragms, atelectasis, pleural thickening FVC 77%, TLC 68% CS + CYC + RTX (375 mg/m2 once weekly × 4 q6mo) Asymptomatic, normal PFTs
[4] F 28 28 (6 mo after diagnosis of SLE) Dyspnea, pleuritic chest pain, dry cough, orthopnea Elevated diaphragms FVC 61%, TLC 45% Beta-agonists + theophylline, RTX (1 g × 2, 2 weeks apart) + CYC Asymptomatic, normal PFTs
[6] F 38 38a Tachypnea, dyspnea Normal HRCT, elevated diaphragms FVC 64%, FEV1 73% CS + CYC without improvement; followed by RTX (1 g × 2, 2 weeks apart) Normal PFTs, normal CXR 6 months after treatment
[7] F 11 14 Dyspnea on exertion, chest pain Low lung volumes, small bilateral pleural effusions, small pericardial effusion, mild bibasilar atelectasis FVC 31%, TLC 32%, DLCO 96% CYC monthly × 1 year, then RTX (dose unknown) Clinical improvement,
PFTs 2 yrs. post: FVC 82%, TLC 80%
[14] F 22 27 Pleuritic chest pain, exertional dyspnea Elevated diaphragms, normal HRCT FVC 1.45 L (predicted value 4.20), TLC 2.35 (predicted value 5.76), DLCO 16.3 (predicted value 26.5) CS + RTX (375 mg/m2 × 2 doses 6 weeks apart) Initial clinical improvement, followed by re-presentation requiring second course of RTX. Improvement reported 2 yrs. later
[15] F 22 57 Dyspnea, dry cough, pleuritic chest pain Elevated diaphragms, bibasilar atelectasis FVC 43%, TLC 56%, DLCO 55% CS + beta-agonists + AZA + MMF, then 6 mo later RTX (1 g × 2 doses, 2 weeks apart, repeated q6mo) Clinical improvement. PFTs 5 years post: FVC 76%, TLC 79%, DLCO 53%
[16] F Unknown 28 Exercise intolerance, pleuritic chest pain Unknown FVC 0.99 L CS + MMF + RTX (2800 mg) Unlimited exercise tolerance, FVC 2.23 L
[12] F 12 14 Dyspnea, pleuritic chest pain, orthopnea Elevated right hemidiaphragm FVC 36%, TLC 39%, DLCO 102% CS + RTX (dose unknown) + CYC Active disease
[8] F 36 37 Dyspnea, pleuritic chest pain CXR: Bilateral diaphragmatic elevation with mild pleural effusion
HRCT: Mild pleural effusion
Restrictive pattern CS + MTX + beta-agonists + RTX (dose unknown) Restrictive defect improvement
[8] F 36 39 Dyspnea, pleuritic chest pain, fever CXR: Unilateral diaphragmatic elevation, left atelectasia
HRCT: Basal atelectasis
Restrictive pattern CS + MMF + beta-agonists + RTX (dose unknown) Restrictive defect stabilization. Developed ILD 4 yrs. later
[8] F 27 31 Dyspnea, pleuritic chest pain CXR: Unilateral diaphragmatic elevation, right atelectasia
HRCT: Basal atelectasis, mild pleural effusion
Restrictive pattern CS + theophylline + beta-agonists + RTX (dose unknown) Restrictive defect stabilization
[8] F 23 30 Dyspnea, pleuritic chest pain CXR: Unilateral diaphragmatic elevation
HRCT: Basal atelectasis
Restrictive pattern CS + MMF + beta-agonists + RTX (dose unknown) Restrictive defect improvement
[8] F 34 59 Dyspnea, pleuritic chest pain CXR: Bilateral diaphragmatic elevation, atelectasia
HRCT: Basal atelectasis
Restrictive pattern CS + MMF + RTX (dose unknown) + IVIG Restrictive defect stabilization
CS corticosteroids, RTX rituximab, CYC cyclophosphamide, AZA azathioprine, MMF mycophenolate mofetil, IVIG intravenous immunoglobulin, CXR chest X-ray, HRCT high-resolution computed tomography, PFTs pulmonary function tests, FEV1 forced expiratory volume in 1 s, FVC forced vital capacity, TLC total lung capacity, DLCO diffusing capacity for carbon monoxide, ILD interstitial lung disease. PFT results expressed in % predicted when available
a Diagnosis of SLS made at the time of diagnosis of SLE
Shrinking lung syndrome is extremely rare in pediatric lupus patients (defined as 16 years or less at diagnosis), with only 6 well-documented case reports identified in our literature review from 1984 to 2019 (Table 2). Age at onset of SLS ranged from 12 to 15 years, 5 were female, all presented with dyspnea, and 5 had associated chest pain. Interestingly, 3 of the 6 presented at the time of diagnosis of SLE, a much more frequent occurrence than that reported in adults with SLS. Of the 6 patients, only 2 reported a return to baseline respiratory function, both clinically and documented on PFTs [2, 7]. In addition to these 6 patients, our literature review identified 3 patients with pediatric onset SLE who developed SLS at age 19 or 20 [11, 19, 20]. Some improvement in lung function was documented in 2 of these patients, one treated with IVMP, cyclophosphamide and azathioprine, and 1 treated with belimumab. In addition, 7 SLE patients 16–18 years of age have been reported, most in case series of SLS, however very limited information was given on their disease course [1, 5, 12, 21, 22].
Table 2 Clinical features, treatment, and outcome of reported pediatric cases of SLS associated with SLE
Reference Sex Age at SLE diagnosis Age at SLS diagnosis Clinical presentation Imaging findings at SLS diagnosis PFTs at SLS diagnosis Treatment Outcome
[2] F 12 12a Prior diagnosis of mycoplasma pneumonia with recovery. Re-presented 6 months later with dyspnea CXR: Enlarged cardiac silhouette, low lung volumes, elevated diaphragms
HRCT: thoracic lymphadenopathy
FEV1 34%, FVC 27%, TLC 59% CS + CYC (q4weeks × 6 mo) Asymptomatic. Normal PFTs after 1 yr (FEV1 99%, FVC 97%, TLC 92%)
[7] F 11 14 Dyspnea on exertion, chest pain CXR: Low lung volumes, small pleural effusions, small pericardial effusion, mild bibasilar atelectasis FVC 31%, TLC 32%, DLCO 96% CYC monthly × 1 year, then RTX (dose unknown) Clinical improvement,
PFTs 2 yrs. post: FVC 82%, TLC 80%
[10] F 15 15a Pleuritic chest pain, dry cough, dyspnea on exertion Small lung fields, elevated bilateral hemidiaphragms, chest CT normal FEV1 26%, FVC 25%, TLC 31% Beta-agonist Clinical improvement. PFTs after 12d showed FEV1 increase of 58%, FVC increase of 50%, TLC increase of 47%
[17] M 11 14 Fatigue, dyspnea, pleuritic chest pain Enlarged cardiac silhouette, atelectasis, severely reduced diaphragmatic excursion on fluoroscopy FEV1 23%, FVC 20%, TLC 34% CS + AZA Follow-up 23 days later: FEV1 45%, FVC 45%, TLC 57%
[18] F 12 12a Pleuritic chest pain, dyspnea, fever, fatigue, anorexia CXR: Reduced lung volumes, elevated diaphragms, HRCT: pleural thickening Diaphragmatic fluoroscopy: minimal movement FVC 39%, TLC 60%, DLCO normal CS + HCQ 4 yrs. post: ongoing activity limitation, PFTs unchanged
[12] F 12 14 Dyspnea, pleuritic chest pain, orthopnea Elevated right hemidiaphragm FVC 36%, TLC 39%, DLCO 102% CS + RTX (dose unknown) + CYC Active disease
CS corticosteroids, RTX rituximab, CYC cyclophosphamide, AZA azathioprine, HCQ hydroxychloroquine, CXR chest X-ray, HRCT high-resolution computed tomography, PFTs pulmonary function tests, FEV1 forced expiratory volume in 1 s, FVC forced vital capacity, TLC total lung capacity, DLCO diffusing capacity for carbon monoxide. PFT results expressed in % predicted when available
a Diagnosis of SLS made at the time of diagnosis of SLE
Although extremely rare, it is important to recognize SLS as a possible cause of dyspnea and chest pain in a child with SLE, and be aware that in pediatric patients in particular, this complication may occur at the time of initial presentation of SLE. Our patient clearly stated that his goal for treatment was to return to competitive hockey. Recent literature on rituximab use in SLS, a review of pediatric SLS cases, and our case report suggest that additional therapy, including possible use of rituximab, should be considered in patients with SLS who have an incomplete response to initial immunosuppressive therapy. Careful documentation of the occurrence, treatment and outcome of patients with SLS utilizing large registries of adult and pediatric patients with SLE may help determine optimal treatment for this rare complication.
Abbreviations
SLSShrinking lung syndrome
SLESystemic lupus erythematosus
PFTPulmonary function test
FEV1Forced expiratory volume in 1 s
FVCForced vital capacity
TLCTotal lung capacity
RVResidual volume
RSVRespiratory syncytial virus
CXRChest x ray
dsDNADouble stranded DNA
ANAAntinuclear antibody
IVMPMethylprednisolone
PCRPolymerase chain reaction
HRCTHigh resolution computed tomography
Publisher’s Note
Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
Acknowledgements
We thank the patient and family for participating in this report.
Authors’ contributions
CD and BL reviewed the patient’s medical record pertaining to this case and were major contributors in writing the manuscript. All authors read and approved the final manuscript.
Funding
None.
Availability of data and materials
Data sharing is not applicable to this article as no datasets were generated or analyzed during the current study.
Ethics approval and consent to participate
Research Ethics Board approval (#1024379) was obtained from the IWK Health Centre. Written and informed consent was also obtained from the patient.
Consent for publication
Written and informed consent was obtained from the patient to publish this material.
Competing interests
The authors declare that they have no competing interests. | AZATHIOPRINE, HYDROXYCHLOROQUINE, MYCOPHENOLATE MOFETIL, PREDNISONE | DrugsGivenReaction | CC BY | 33407629 | 18,886,056 | 2021-01-06 |
Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Butterfly rash'. | Shrinking lung syndrome treated with rituximab in pediatric systemic lupus erythematosus: a case report and review of the literature.
BACKGROUND
Shrinking lung syndrome (SLS), a rare complication of systemic lupus erythematosus (SLE) characterized by dyspnea, low lung volumes, and a restrictive pattern on pulmonary function tests (PFTs), has only been reported in a few children. Given the rarity of SLS there is a paucity of literature regarding its optimal treatment. Outcomes are variable, with case reports documenting some improvement in most patients treated with corticosteroids, with or without additional immunosuppressive agents. However, most reported patients did not recover normal lung function. We report full recovery of a child with SLE and SLS following treatment with rituximab and review the current literature.
METHODS
An 11-year-old boy presented with a malar rash, myositis, arthritis, oral ulcers, leukopenia, anemia, positive lupus autoantibodies and Class II nephritis. He was diagnosed with SLE and treated with corticosteroids, hydroxychloroquine, azathioprine, and subsequently mycophenolate with symptom resolution. At age 14, his SLE flared coincident with a viral chest infection. He presented with a malar rash, polyarthritis, increased proteinuria and pleuritis which all improved with corticosteroids and ongoing treatment with mycophenolate. Six weeks later he presented with severe dyspnea, markedly decreased lung volumes, but otherwise normal chest X-ray (CXR) and high-resolution chest computed tomography (HRCT). He was found to have severely restricted PFTs (FEV1 27%, FVC 29%; TLC 43%). After additional investigations including echocardiography, pulmonary CT angiography, and diaphragmatic fluoroscopy, he was diagnosed with SLS and treated with rituximab and methylprednisolone. At 1 month his symptoms had improved, but he still had dyspnea with exertion and severely restricted PFTs. At 6 months his FVC and TLC had improved to 51 and 57% respectively, and were 83 and 94% respectively at 4 years. He had returned to all baseline activities, including competitive hockey.
CONCLUSIONS
Although extremely rare, it is important to recognize SLS as a possible cause of dyspnea and chest pain in a child with SLE. Optimal treatment strategies are unknown. This is the second reported case of a child treated with rituximab for SLS who recovered normal lung function. International lupus registries should carefully document the occurrence, treatment and outcome of patients with SLS to help determine the optimal treatment for this rare complication.
Background
Shrinking lung syndrome (SLS) is a rare complication of systemic lupus erythematosus (SLE) characterized by decreased lung volumes and a restrictive pattern on pulmonary function testing (PFTs). Patients typically present with progressive dyspnea and chest pain [1–3]. The diagnosis may be delayed, particularly in pediatric patients, because of failure to consider or recognize this disorder. The exact pathophysiology is unknown [1–3].
Given the rarity of SLS there is a paucity of literature regarding optimal treatment. Case reports and series have documented improvement in most patients treated with corticosteroids, with or without immunosuppressive agents. However, the majority of patients have an incomplete recovery [4, 5]. Recently, rituximab, a monoclonal antibody directed against the CD20 antigen found on the surface of B lymphocytes, has been used successfully in several adult patients and one child with SLE complicated by SLS [6, 7]. We report a child with SLE who developed SLS at age 14 and recovered fully following treatment with rituximab. We also review the literature on SLS in pediatric patients to increase awareness of this exceptionally rare complication, as well as review outcome of patients previously reported with SLS who were treated with rituximab.
Case presentation
At age 11 years, our patient was diagnosed with SLE after presenting with a malar rash, oral ulcers, polyarthritis, myositis, and anemia. His past history was remarkable only for mild asthma; family history was positive for maternal asthma and hypothyroidism. Work-up revealed leukopenia (WBC 2.5 10e9/L), hypocomplementemia (C3 0.23 g/L), positive anti-nuclear antibody, anti-dsDNA (633 IU/ml; normal less than10), anti-SSa/Ro, and anti-Smith antibodies, Class II lupus nephritis and a SLEDAI of 29. A baseline chest radiograph (CXR) was normal. He was treated with prednisone, hydroxychloroquine (HCQ), and azathioprine. A year later he had no symptoms of his SLE but was evaluated for an exercise-associated cough that was felt to be due to his asthma. A CXR was normal, PFTs showed moderate obstruction and symptoms resolved with a bronchodilator. Over the next few months, despite ongoing HCQ, azathioprine and low dose prednisone he had recurrence of malar rash and mild arthritis; a repeat renal biopsy showed Class III b lupus nephritis and azathioprine was replaced by mycophenolate mofetil (MMF) which was increased up to 700 mg/m2/dose BID, and subsequently decreased due to gastrointestinal side effects. This resulted in resolution of all symptoms but some ongoing nephritis (SLEDAI 12).
At age 14 he was admitted to his local hospital with fever, pleuritic chest pain, dyspnea, and cough. Bilateral pleural effusions were seen on CXR and he was given empiric antibiotics for possible pneumonia prior to transfer to our center, where he received a 3-day pulse of intravenous methylprednisolone (IVMP) for a suspected SLE flare (C3 0.70; anti dsDNA 95; SLEDAI 29). His chest symptoms resolved completely and respiratory syncytial virus (RSV) infection was subsequently confirmed by PCR and was thought to have triggered the flare. One month later, despite treatment with low dose prednisone and MMF (535 mg/m2/dose BID, although compliance was questionable), his SLE again flared. He presented with a malar rash, polyarthritis, as well as findings of pleuritis manifesting with chest pain, dyspnea, and a left pleural effusion. He was treated with pulse IVMP followed by increased MMF (625 mg/m2/dose BID) and daily oral prednisone (1 mg/kg/d).
Six weeks later his rash and arthritis had improved, but he reported increasing shortness of breath with marked exercise intolerance. On examination he was afebrile, his heart rate was 120, respiratory rate 40, and oxygen saturation 95% in room air. He appeared dyspneic with difficulty speaking in full sentences. Chest examination revealed shallow breathing and decreased air entry bilaterally. Physical examination was otherwise unremarkable. Work up for infection was negative. His SLEDAI had decreased to 14, C3 had normalized (0.97) and anti dsDNA had decreased to 39. CXR and high-resolution computed tomography (HRCT) showed severely reduced lung volumes with no pleural or interstitial disease; there was slight atelectasis but no other significant abnormalities (Figs. 1, 2). An echocardiogram was normal and a CT angiogram showed no evidence of pulmonary embolus. PFTs revealed a severe restrictive pattern with forced expiratory volume in 1 s (FEV1) of 27%, forced vital capacity (FVC) 29%, and total lung capacity (TLC) 43% (Fig. 3). Fluoroscopy documented significantly reduced diaphragmatic movement. He was diagnosed with SLS, and because of worsening dyspnea despite recently increased immunosuppression, he was treated with IVMP 1 g daily for 3 days followed by rituximab 1 g (2 doses, 2 weeks apart). He was also referred to physiotherapy for pulmonary rehabilitation.
Fig. 1 a Chest X-ray at presentation with SLS, showing decreased lung volumes and raised hemidiaphragms b Normal chest X-ray 3 years later
Fig. 2 High-resolution computed tomography (HRCT) of the chest at presentation with SLS, showing decreased lung volumes and slight atelectasis
Fig. 3 Pulmonary function tests (PFTs) over time in our patient with SLE and SLS; at diagnosis to 4 years following treatment with rituximab. FEV1, forced expiratory volume in 1 s; FVC, forced vital capacity; TLC, total lung capacity; RV, residual volume
One month later he reported some improvement in physical endurance, though he still had dyspnea with mild exertion and PFTs remained severely restrictive. At 6 months, however, he reported much improved exercise tolerance with ability to play some hockey. His FEV1 and FVC had improved to 42 and 51% respectively and TLC had increased to 57%. A planned second course of rituximab, (1 g, 2 doses, 2 weeks apart) was given at 6 months; preceding B cell counts were 8%. He was tapered off corticosteroids over the next 9 months and continued on HCQ (5 mg/kg/d) and MMF (600 mg/m2/dose BID). Serial CXRs showed gradual lung volume expansion. One year after his presentation he returned to playing competitive hockey, with no limitations and no respiratory symptoms. Four years later, he remained asymptomatic with no limitations in activity, no evidence of restrictive lung disease on PFTs (FVC 83%, TLC 94%), and a normal CXR. He remained on the same doses of HCQ and MMF with no clinical evidence of SLE disease activity, normal complement levels (C3 0.97), anti dsDNA 16, a SLEDAI of 2, and a follow renal biopsy showed no active nephritis.
Discussion
Shrinking lung syndrome is a rare complication of SLE with an incidence of approximately 1% in adult lupus patients [1, 5]. The incidence in pediatric SLE is unknown, but is likely even less common. As such, the diagnosis of SLS may not be considered or recognized in a child with SLE. Clinical features include progressive dyspnea, exercise intolerance, and pleuritic chest pain, all of which were described by our patient. Physical examination frequently reveals tachypnea with decreased air entry and the use of accessory respiratory muscles but is otherwise unremarkable. Findings on CXR often include significantly reduced lung volumes with elevated hemidiaphragms and may include pleural effusions, basal atelectasis, and pleural thickening. HRCT typically shows no parenchymal lung disease, though it may be more sensitive than CXR in demonstrating pleural effusions and atelectasis [4, 8]. PFTs show a restrictive pattern [4]. Reduced diaphragmatic excursion may be demonstrated on chest fluoroscopy, as was seen in our patient, or may be demonstrated using M-mode ultrasonography [8].
The pathogenesis of shrinking lung syndrome remains incompletely understood. When first described by Hoffbrand and Beck in 1965, the condition was thought to be due to surfactant deficiency causing microatelectasis [9]. Since then a number of mechanisms have been suggested, including phrenic nerve dysfunction, pleural inflammation and fibrosis, and diaphragmatic dysfunction due to myositis or neuropathy [3, 10]. Anti-SSa/Ro antibody positivity has been associated with both SLS and myositis, and has been suggested to support the theory that myositis contributes to diaphragmatic dysfunction in some patients [3, 11]. Of note, our patient was anti-SSa/Ro positive and had myositis as part of his SLE course. The frequent occurrence of pleuritic chest pain in up to 80% of patients with SLS has led to a more recently proposed mechanism of pleuritic pain leading to reflex inhibition of diaphragmatic activation and subsequent dysfunction in at least a subset of patients with SLS [1, 3]. Henderson et al. have proposed that pleural inflammation due to the underlying rheumatic disease may lead to activation of neural reflexes which inhibit deep inspiration and cause chronic lung hypoinflation. This is postulated to gradually reduce lung compliance and results in a positive feedback cycle [12]. Interestingly, our patient had developed pleuritic chest pain 2 months prior to his diagnosis of SLS, and had documented pleuritis associated with an RSV infection, and then associated with a flare of his SLE, which may have initiated the pathogenetic process leading to SLS.
There is no standard treatment for patients with SLS. Corticosteroids are the most frequently reported initial treatment of SLS, and can lead to full recovery in some patients [3, 5, 11, 13]. Immunosuppressive agents including cyclophosphamide, azathioprine, and methotrexate are often given along with corticosteroids or if corticosteroids alone are ineffective. There are also a few reports of theophylline and beta-agonists used effectively in SLS, and others advocate the use of analgesia to combat chest pain and pulmonary rehabilitation to improve lung expansion [1, 3, 5, 12, 13]. Although rare fatal cases have been described, the prognosis of SLS in adults is generally considered to be good, particularly in comparison with the progressive course and significant mortality associated with fibrotic interstitial lung disease in patients with SLE [1]. Some clinical improvement has been reported in most patients with SLS, however, recent literature makes it clear that despite treatment many patients do not achieve full recovery. Langenskiold et al., in a review of 35 cases with documented pre and post treatment PFTs, found that only 20% of patients with SLS regained normal lung function [4]. Duron et al. reported full recovery in only a minority of patients in their review of 155 patients with SLS, with 42.9% of patients showing chronic and persistent hemidiaphragm elevation [1]. A report of 20 cases from a large single center in 2018 showed a similar outcome, with 86.7% of patients showing continued restrictive defects on spirometry despite improved lung volumes [5]. The lack of full recovery in both adult and pediatric patients with SLS has led to 15 reports of rituximab use in adults and 2 reports in children with SLS complicating SLE [1, 3, 4, 6–8, 12, 14–16] (Table 1). Normal PFTs were reported in one child treated with rituximab [7], however the other child did not respond [12]. All 4 adult patients with well-documented post-treatment PFTs had normal or near normal findings [3, 4, 6]. Although the degree of objective improvement was not documented in the remaining 11 adult cases treated with rituximab, all were reported to have improved or stabilized. (Table 1). There has also been a recent report of a 19-year-old male with pediatric-onset SLE who developed SLS refractory to IVMP and cyclophosphamide and had some improvement with belimumab, a monoclonal antibody directed against BLyS receptors on B-cells, though long-term follow-up is still ongoing [11].
Table 1 Clinical features, treatment and outcome of patients with SLS associated with SLE who received treatment with rituximab
Reference Sex Age at SLE diagnosis Age at SLS diagnosis Clinical presentation Imaging findings at SLS diagnosis PFTs at SLS diagnosis Treatment Outcome
[1] F Unknown 61 Chest pain, history of pleurisy, dyspnea Elevated diaphragms, atelectasis, pleural thickening TLC 46%,
DLCO 25%, KCO 59%
CS + Beta-agonists + RTX (dose unknown) + Physiotherapy Improvement
[1] F Unknown 26 Chest pain, history of pleurisy, dyspnea Pleural thickening, reticulations FVC 41%,
TLC 68%,
DLCO 34%
CS + AZA + MMF + RTX (dose unknown) Improvement
[3] F 36 46 Dyspnea on exertion, orthopnea, pleuritic chest pain Elevated diaphragms, atelectasis, pleural thickening FVC 77%, TLC 68% CS + CYC + RTX (375 mg/m2 once weekly × 4 q6mo) Asymptomatic, normal PFTs
[4] F 28 28 (6 mo after diagnosis of SLE) Dyspnea, pleuritic chest pain, dry cough, orthopnea Elevated diaphragms FVC 61%, TLC 45% Beta-agonists + theophylline, RTX (1 g × 2, 2 weeks apart) + CYC Asymptomatic, normal PFTs
[6] F 38 38a Tachypnea, dyspnea Normal HRCT, elevated diaphragms FVC 64%, FEV1 73% CS + CYC without improvement; followed by RTX (1 g × 2, 2 weeks apart) Normal PFTs, normal CXR 6 months after treatment
[7] F 11 14 Dyspnea on exertion, chest pain Low lung volumes, small bilateral pleural effusions, small pericardial effusion, mild bibasilar atelectasis FVC 31%, TLC 32%, DLCO 96% CYC monthly × 1 year, then RTX (dose unknown) Clinical improvement,
PFTs 2 yrs. post: FVC 82%, TLC 80%
[14] F 22 27 Pleuritic chest pain, exertional dyspnea Elevated diaphragms, normal HRCT FVC 1.45 L (predicted value 4.20), TLC 2.35 (predicted value 5.76), DLCO 16.3 (predicted value 26.5) CS + RTX (375 mg/m2 × 2 doses 6 weeks apart) Initial clinical improvement, followed by re-presentation requiring second course of RTX. Improvement reported 2 yrs. later
[15] F 22 57 Dyspnea, dry cough, pleuritic chest pain Elevated diaphragms, bibasilar atelectasis FVC 43%, TLC 56%, DLCO 55% CS + beta-agonists + AZA + MMF, then 6 mo later RTX (1 g × 2 doses, 2 weeks apart, repeated q6mo) Clinical improvement. PFTs 5 years post: FVC 76%, TLC 79%, DLCO 53%
[16] F Unknown 28 Exercise intolerance, pleuritic chest pain Unknown FVC 0.99 L CS + MMF + RTX (2800 mg) Unlimited exercise tolerance, FVC 2.23 L
[12] F 12 14 Dyspnea, pleuritic chest pain, orthopnea Elevated right hemidiaphragm FVC 36%, TLC 39%, DLCO 102% CS + RTX (dose unknown) + CYC Active disease
[8] F 36 37 Dyspnea, pleuritic chest pain CXR: Bilateral diaphragmatic elevation with mild pleural effusion
HRCT: Mild pleural effusion
Restrictive pattern CS + MTX + beta-agonists + RTX (dose unknown) Restrictive defect improvement
[8] F 36 39 Dyspnea, pleuritic chest pain, fever CXR: Unilateral diaphragmatic elevation, left atelectasia
HRCT: Basal atelectasis
Restrictive pattern CS + MMF + beta-agonists + RTX (dose unknown) Restrictive defect stabilization. Developed ILD 4 yrs. later
[8] F 27 31 Dyspnea, pleuritic chest pain CXR: Unilateral diaphragmatic elevation, right atelectasia
HRCT: Basal atelectasis, mild pleural effusion
Restrictive pattern CS + theophylline + beta-agonists + RTX (dose unknown) Restrictive defect stabilization
[8] F 23 30 Dyspnea, pleuritic chest pain CXR: Unilateral diaphragmatic elevation
HRCT: Basal atelectasis
Restrictive pattern CS + MMF + beta-agonists + RTX (dose unknown) Restrictive defect improvement
[8] F 34 59 Dyspnea, pleuritic chest pain CXR: Bilateral diaphragmatic elevation, atelectasia
HRCT: Basal atelectasis
Restrictive pattern CS + MMF + RTX (dose unknown) + IVIG Restrictive defect stabilization
CS corticosteroids, RTX rituximab, CYC cyclophosphamide, AZA azathioprine, MMF mycophenolate mofetil, IVIG intravenous immunoglobulin, CXR chest X-ray, HRCT high-resolution computed tomography, PFTs pulmonary function tests, FEV1 forced expiratory volume in 1 s, FVC forced vital capacity, TLC total lung capacity, DLCO diffusing capacity for carbon monoxide, ILD interstitial lung disease. PFT results expressed in % predicted when available
a Diagnosis of SLS made at the time of diagnosis of SLE
Shrinking lung syndrome is extremely rare in pediatric lupus patients (defined as 16 years or less at diagnosis), with only 6 well-documented case reports identified in our literature review from 1984 to 2019 (Table 2). Age at onset of SLS ranged from 12 to 15 years, 5 were female, all presented with dyspnea, and 5 had associated chest pain. Interestingly, 3 of the 6 presented at the time of diagnosis of SLE, a much more frequent occurrence than that reported in adults with SLS. Of the 6 patients, only 2 reported a return to baseline respiratory function, both clinically and documented on PFTs [2, 7]. In addition to these 6 patients, our literature review identified 3 patients with pediatric onset SLE who developed SLS at age 19 or 20 [11, 19, 20]. Some improvement in lung function was documented in 2 of these patients, one treated with IVMP, cyclophosphamide and azathioprine, and 1 treated with belimumab. In addition, 7 SLE patients 16–18 years of age have been reported, most in case series of SLS, however very limited information was given on their disease course [1, 5, 12, 21, 22].
Table 2 Clinical features, treatment, and outcome of reported pediatric cases of SLS associated with SLE
Reference Sex Age at SLE diagnosis Age at SLS diagnosis Clinical presentation Imaging findings at SLS diagnosis PFTs at SLS diagnosis Treatment Outcome
[2] F 12 12a Prior diagnosis of mycoplasma pneumonia with recovery. Re-presented 6 months later with dyspnea CXR: Enlarged cardiac silhouette, low lung volumes, elevated diaphragms
HRCT: thoracic lymphadenopathy
FEV1 34%, FVC 27%, TLC 59% CS + CYC (q4weeks × 6 mo) Asymptomatic. Normal PFTs after 1 yr (FEV1 99%, FVC 97%, TLC 92%)
[7] F 11 14 Dyspnea on exertion, chest pain CXR: Low lung volumes, small pleural effusions, small pericardial effusion, mild bibasilar atelectasis FVC 31%, TLC 32%, DLCO 96% CYC monthly × 1 year, then RTX (dose unknown) Clinical improvement,
PFTs 2 yrs. post: FVC 82%, TLC 80%
[10] F 15 15a Pleuritic chest pain, dry cough, dyspnea on exertion Small lung fields, elevated bilateral hemidiaphragms, chest CT normal FEV1 26%, FVC 25%, TLC 31% Beta-agonist Clinical improvement. PFTs after 12d showed FEV1 increase of 58%, FVC increase of 50%, TLC increase of 47%
[17] M 11 14 Fatigue, dyspnea, pleuritic chest pain Enlarged cardiac silhouette, atelectasis, severely reduced diaphragmatic excursion on fluoroscopy FEV1 23%, FVC 20%, TLC 34% CS + AZA Follow-up 23 days later: FEV1 45%, FVC 45%, TLC 57%
[18] F 12 12a Pleuritic chest pain, dyspnea, fever, fatigue, anorexia CXR: Reduced lung volumes, elevated diaphragms, HRCT: pleural thickening Diaphragmatic fluoroscopy: minimal movement FVC 39%, TLC 60%, DLCO normal CS + HCQ 4 yrs. post: ongoing activity limitation, PFTs unchanged
[12] F 12 14 Dyspnea, pleuritic chest pain, orthopnea Elevated right hemidiaphragm FVC 36%, TLC 39%, DLCO 102% CS + RTX (dose unknown) + CYC Active disease
CS corticosteroids, RTX rituximab, CYC cyclophosphamide, AZA azathioprine, HCQ hydroxychloroquine, CXR chest X-ray, HRCT high-resolution computed tomography, PFTs pulmonary function tests, FEV1 forced expiratory volume in 1 s, FVC forced vital capacity, TLC total lung capacity, DLCO diffusing capacity for carbon monoxide. PFT results expressed in % predicted when available
a Diagnosis of SLS made at the time of diagnosis of SLE
Although extremely rare, it is important to recognize SLS as a possible cause of dyspnea and chest pain in a child with SLE, and be aware that in pediatric patients in particular, this complication may occur at the time of initial presentation of SLE. Our patient clearly stated that his goal for treatment was to return to competitive hockey. Recent literature on rituximab use in SLS, a review of pediatric SLS cases, and our case report suggest that additional therapy, including possible use of rituximab, should be considered in patients with SLS who have an incomplete response to initial immunosuppressive therapy. Careful documentation of the occurrence, treatment and outcome of patients with SLS utilizing large registries of adult and pediatric patients with SLE may help determine optimal treatment for this rare complication.
Abbreviations
SLSShrinking lung syndrome
SLESystemic lupus erythematosus
PFTPulmonary function test
FEV1Forced expiratory volume in 1 s
FVCForced vital capacity
TLCTotal lung capacity
RVResidual volume
RSVRespiratory syncytial virus
CXRChest x ray
dsDNADouble stranded DNA
ANAAntinuclear antibody
IVMPMethylprednisolone
PCRPolymerase chain reaction
HRCTHigh resolution computed tomography
Publisher’s Note
Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
Acknowledgements
We thank the patient and family for participating in this report.
Authors’ contributions
CD and BL reviewed the patient’s medical record pertaining to this case and were major contributors in writing the manuscript. All authors read and approved the final manuscript.
Funding
None.
Availability of data and materials
Data sharing is not applicable to this article as no datasets were generated or analyzed during the current study.
Ethics approval and consent to participate
Research Ethics Board approval (#1024379) was obtained from the IWK Health Centre. Written and informed consent was also obtained from the patient.
Consent for publication
Written and informed consent was obtained from the patient to publish this material.
Competing interests
The authors declare that they have no competing interests. | AZATHIOPRINE, HYDROXYCHLOROQUINE, MYCOPHENOLATE MOFETIL, PREDNISONE | DrugsGivenReaction | CC BY | 33407629 | 18,886,056 | 2021-01-06 |
Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Disease recurrence'. | Shrinking lung syndrome treated with rituximab in pediatric systemic lupus erythematosus: a case report and review of the literature.
BACKGROUND
Shrinking lung syndrome (SLS), a rare complication of systemic lupus erythematosus (SLE) characterized by dyspnea, low lung volumes, and a restrictive pattern on pulmonary function tests (PFTs), has only been reported in a few children. Given the rarity of SLS there is a paucity of literature regarding its optimal treatment. Outcomes are variable, with case reports documenting some improvement in most patients treated with corticosteroids, with or without additional immunosuppressive agents. However, most reported patients did not recover normal lung function. We report full recovery of a child with SLE and SLS following treatment with rituximab and review the current literature.
METHODS
An 11-year-old boy presented with a malar rash, myositis, arthritis, oral ulcers, leukopenia, anemia, positive lupus autoantibodies and Class II nephritis. He was diagnosed with SLE and treated with corticosteroids, hydroxychloroquine, azathioprine, and subsequently mycophenolate with symptom resolution. At age 14, his SLE flared coincident with a viral chest infection. He presented with a malar rash, polyarthritis, increased proteinuria and pleuritis which all improved with corticosteroids and ongoing treatment with mycophenolate. Six weeks later he presented with severe dyspnea, markedly decreased lung volumes, but otherwise normal chest X-ray (CXR) and high-resolution chest computed tomography (HRCT). He was found to have severely restricted PFTs (FEV1 27%, FVC 29%; TLC 43%). After additional investigations including echocardiography, pulmonary CT angiography, and diaphragmatic fluoroscopy, he was diagnosed with SLS and treated with rituximab and methylprednisolone. At 1 month his symptoms had improved, but he still had dyspnea with exertion and severely restricted PFTs. At 6 months his FVC and TLC had improved to 51 and 57% respectively, and were 83 and 94% respectively at 4 years. He had returned to all baseline activities, including competitive hockey.
CONCLUSIONS
Although extremely rare, it is important to recognize SLS as a possible cause of dyspnea and chest pain in a child with SLE. Optimal treatment strategies are unknown. This is the second reported case of a child treated with rituximab for SLS who recovered normal lung function. International lupus registries should carefully document the occurrence, treatment and outcome of patients with SLS to help determine the optimal treatment for this rare complication.
Background
Shrinking lung syndrome (SLS) is a rare complication of systemic lupus erythematosus (SLE) characterized by decreased lung volumes and a restrictive pattern on pulmonary function testing (PFTs). Patients typically present with progressive dyspnea and chest pain [1–3]. The diagnosis may be delayed, particularly in pediatric patients, because of failure to consider or recognize this disorder. The exact pathophysiology is unknown [1–3].
Given the rarity of SLS there is a paucity of literature regarding optimal treatment. Case reports and series have documented improvement in most patients treated with corticosteroids, with or without immunosuppressive agents. However, the majority of patients have an incomplete recovery [4, 5]. Recently, rituximab, a monoclonal antibody directed against the CD20 antigen found on the surface of B lymphocytes, has been used successfully in several adult patients and one child with SLE complicated by SLS [6, 7]. We report a child with SLE who developed SLS at age 14 and recovered fully following treatment with rituximab. We also review the literature on SLS in pediatric patients to increase awareness of this exceptionally rare complication, as well as review outcome of patients previously reported with SLS who were treated with rituximab.
Case presentation
At age 11 years, our patient was diagnosed with SLE after presenting with a malar rash, oral ulcers, polyarthritis, myositis, and anemia. His past history was remarkable only for mild asthma; family history was positive for maternal asthma and hypothyroidism. Work-up revealed leukopenia (WBC 2.5 10e9/L), hypocomplementemia (C3 0.23 g/L), positive anti-nuclear antibody, anti-dsDNA (633 IU/ml; normal less than10), anti-SSa/Ro, and anti-Smith antibodies, Class II lupus nephritis and a SLEDAI of 29. A baseline chest radiograph (CXR) was normal. He was treated with prednisone, hydroxychloroquine (HCQ), and azathioprine. A year later he had no symptoms of his SLE but was evaluated for an exercise-associated cough that was felt to be due to his asthma. A CXR was normal, PFTs showed moderate obstruction and symptoms resolved with a bronchodilator. Over the next few months, despite ongoing HCQ, azathioprine and low dose prednisone he had recurrence of malar rash and mild arthritis; a repeat renal biopsy showed Class III b lupus nephritis and azathioprine was replaced by mycophenolate mofetil (MMF) which was increased up to 700 mg/m2/dose BID, and subsequently decreased due to gastrointestinal side effects. This resulted in resolution of all symptoms but some ongoing nephritis (SLEDAI 12).
At age 14 he was admitted to his local hospital with fever, pleuritic chest pain, dyspnea, and cough. Bilateral pleural effusions were seen on CXR and he was given empiric antibiotics for possible pneumonia prior to transfer to our center, where he received a 3-day pulse of intravenous methylprednisolone (IVMP) for a suspected SLE flare (C3 0.70; anti dsDNA 95; SLEDAI 29). His chest symptoms resolved completely and respiratory syncytial virus (RSV) infection was subsequently confirmed by PCR and was thought to have triggered the flare. One month later, despite treatment with low dose prednisone and MMF (535 mg/m2/dose BID, although compliance was questionable), his SLE again flared. He presented with a malar rash, polyarthritis, as well as findings of pleuritis manifesting with chest pain, dyspnea, and a left pleural effusion. He was treated with pulse IVMP followed by increased MMF (625 mg/m2/dose BID) and daily oral prednisone (1 mg/kg/d).
Six weeks later his rash and arthritis had improved, but he reported increasing shortness of breath with marked exercise intolerance. On examination he was afebrile, his heart rate was 120, respiratory rate 40, and oxygen saturation 95% in room air. He appeared dyspneic with difficulty speaking in full sentences. Chest examination revealed shallow breathing and decreased air entry bilaterally. Physical examination was otherwise unremarkable. Work up for infection was negative. His SLEDAI had decreased to 14, C3 had normalized (0.97) and anti dsDNA had decreased to 39. CXR and high-resolution computed tomography (HRCT) showed severely reduced lung volumes with no pleural or interstitial disease; there was slight atelectasis but no other significant abnormalities (Figs. 1, 2). An echocardiogram was normal and a CT angiogram showed no evidence of pulmonary embolus. PFTs revealed a severe restrictive pattern with forced expiratory volume in 1 s (FEV1) of 27%, forced vital capacity (FVC) 29%, and total lung capacity (TLC) 43% (Fig. 3). Fluoroscopy documented significantly reduced diaphragmatic movement. He was diagnosed with SLS, and because of worsening dyspnea despite recently increased immunosuppression, he was treated with IVMP 1 g daily for 3 days followed by rituximab 1 g (2 doses, 2 weeks apart). He was also referred to physiotherapy for pulmonary rehabilitation.
Fig. 1 a Chest X-ray at presentation with SLS, showing decreased lung volumes and raised hemidiaphragms b Normal chest X-ray 3 years later
Fig. 2 High-resolution computed tomography (HRCT) of the chest at presentation with SLS, showing decreased lung volumes and slight atelectasis
Fig. 3 Pulmonary function tests (PFTs) over time in our patient with SLE and SLS; at diagnosis to 4 years following treatment with rituximab. FEV1, forced expiratory volume in 1 s; FVC, forced vital capacity; TLC, total lung capacity; RV, residual volume
One month later he reported some improvement in physical endurance, though he still had dyspnea with mild exertion and PFTs remained severely restrictive. At 6 months, however, he reported much improved exercise tolerance with ability to play some hockey. His FEV1 and FVC had improved to 42 and 51% respectively and TLC had increased to 57%. A planned second course of rituximab, (1 g, 2 doses, 2 weeks apart) was given at 6 months; preceding B cell counts were 8%. He was tapered off corticosteroids over the next 9 months and continued on HCQ (5 mg/kg/d) and MMF (600 mg/m2/dose BID). Serial CXRs showed gradual lung volume expansion. One year after his presentation he returned to playing competitive hockey, with no limitations and no respiratory symptoms. Four years later, he remained asymptomatic with no limitations in activity, no evidence of restrictive lung disease on PFTs (FVC 83%, TLC 94%), and a normal CXR. He remained on the same doses of HCQ and MMF with no clinical evidence of SLE disease activity, normal complement levels (C3 0.97), anti dsDNA 16, a SLEDAI of 2, and a follow renal biopsy showed no active nephritis.
Discussion
Shrinking lung syndrome is a rare complication of SLE with an incidence of approximately 1% in adult lupus patients [1, 5]. The incidence in pediatric SLE is unknown, but is likely even less common. As such, the diagnosis of SLS may not be considered or recognized in a child with SLE. Clinical features include progressive dyspnea, exercise intolerance, and pleuritic chest pain, all of which were described by our patient. Physical examination frequently reveals tachypnea with decreased air entry and the use of accessory respiratory muscles but is otherwise unremarkable. Findings on CXR often include significantly reduced lung volumes with elevated hemidiaphragms and may include pleural effusions, basal atelectasis, and pleural thickening. HRCT typically shows no parenchymal lung disease, though it may be more sensitive than CXR in demonstrating pleural effusions and atelectasis [4, 8]. PFTs show a restrictive pattern [4]. Reduced diaphragmatic excursion may be demonstrated on chest fluoroscopy, as was seen in our patient, or may be demonstrated using M-mode ultrasonography [8].
The pathogenesis of shrinking lung syndrome remains incompletely understood. When first described by Hoffbrand and Beck in 1965, the condition was thought to be due to surfactant deficiency causing microatelectasis [9]. Since then a number of mechanisms have been suggested, including phrenic nerve dysfunction, pleural inflammation and fibrosis, and diaphragmatic dysfunction due to myositis or neuropathy [3, 10]. Anti-SSa/Ro antibody positivity has been associated with both SLS and myositis, and has been suggested to support the theory that myositis contributes to diaphragmatic dysfunction in some patients [3, 11]. Of note, our patient was anti-SSa/Ro positive and had myositis as part of his SLE course. The frequent occurrence of pleuritic chest pain in up to 80% of patients with SLS has led to a more recently proposed mechanism of pleuritic pain leading to reflex inhibition of diaphragmatic activation and subsequent dysfunction in at least a subset of patients with SLS [1, 3]. Henderson et al. have proposed that pleural inflammation due to the underlying rheumatic disease may lead to activation of neural reflexes which inhibit deep inspiration and cause chronic lung hypoinflation. This is postulated to gradually reduce lung compliance and results in a positive feedback cycle [12]. Interestingly, our patient had developed pleuritic chest pain 2 months prior to his diagnosis of SLS, and had documented pleuritis associated with an RSV infection, and then associated with a flare of his SLE, which may have initiated the pathogenetic process leading to SLS.
There is no standard treatment for patients with SLS. Corticosteroids are the most frequently reported initial treatment of SLS, and can lead to full recovery in some patients [3, 5, 11, 13]. Immunosuppressive agents including cyclophosphamide, azathioprine, and methotrexate are often given along with corticosteroids or if corticosteroids alone are ineffective. There are also a few reports of theophylline and beta-agonists used effectively in SLS, and others advocate the use of analgesia to combat chest pain and pulmonary rehabilitation to improve lung expansion [1, 3, 5, 12, 13]. Although rare fatal cases have been described, the prognosis of SLS in adults is generally considered to be good, particularly in comparison with the progressive course and significant mortality associated with fibrotic interstitial lung disease in patients with SLE [1]. Some clinical improvement has been reported in most patients with SLS, however, recent literature makes it clear that despite treatment many patients do not achieve full recovery. Langenskiold et al., in a review of 35 cases with documented pre and post treatment PFTs, found that only 20% of patients with SLS regained normal lung function [4]. Duron et al. reported full recovery in only a minority of patients in their review of 155 patients with SLS, with 42.9% of patients showing chronic and persistent hemidiaphragm elevation [1]. A report of 20 cases from a large single center in 2018 showed a similar outcome, with 86.7% of patients showing continued restrictive defects on spirometry despite improved lung volumes [5]. The lack of full recovery in both adult and pediatric patients with SLS has led to 15 reports of rituximab use in adults and 2 reports in children with SLS complicating SLE [1, 3, 4, 6–8, 12, 14–16] (Table 1). Normal PFTs were reported in one child treated with rituximab [7], however the other child did not respond [12]. All 4 adult patients with well-documented post-treatment PFTs had normal or near normal findings [3, 4, 6]. Although the degree of objective improvement was not documented in the remaining 11 adult cases treated with rituximab, all were reported to have improved or stabilized. (Table 1). There has also been a recent report of a 19-year-old male with pediatric-onset SLE who developed SLS refractory to IVMP and cyclophosphamide and had some improvement with belimumab, a monoclonal antibody directed against BLyS receptors on B-cells, though long-term follow-up is still ongoing [11].
Table 1 Clinical features, treatment and outcome of patients with SLS associated with SLE who received treatment with rituximab
Reference Sex Age at SLE diagnosis Age at SLS diagnosis Clinical presentation Imaging findings at SLS diagnosis PFTs at SLS diagnosis Treatment Outcome
[1] F Unknown 61 Chest pain, history of pleurisy, dyspnea Elevated diaphragms, atelectasis, pleural thickening TLC 46%,
DLCO 25%, KCO 59%
CS + Beta-agonists + RTX (dose unknown) + Physiotherapy Improvement
[1] F Unknown 26 Chest pain, history of pleurisy, dyspnea Pleural thickening, reticulations FVC 41%,
TLC 68%,
DLCO 34%
CS + AZA + MMF + RTX (dose unknown) Improvement
[3] F 36 46 Dyspnea on exertion, orthopnea, pleuritic chest pain Elevated diaphragms, atelectasis, pleural thickening FVC 77%, TLC 68% CS + CYC + RTX (375 mg/m2 once weekly × 4 q6mo) Asymptomatic, normal PFTs
[4] F 28 28 (6 mo after diagnosis of SLE) Dyspnea, pleuritic chest pain, dry cough, orthopnea Elevated diaphragms FVC 61%, TLC 45% Beta-agonists + theophylline, RTX (1 g × 2, 2 weeks apart) + CYC Asymptomatic, normal PFTs
[6] F 38 38a Tachypnea, dyspnea Normal HRCT, elevated diaphragms FVC 64%, FEV1 73% CS + CYC without improvement; followed by RTX (1 g × 2, 2 weeks apart) Normal PFTs, normal CXR 6 months after treatment
[7] F 11 14 Dyspnea on exertion, chest pain Low lung volumes, small bilateral pleural effusions, small pericardial effusion, mild bibasilar atelectasis FVC 31%, TLC 32%, DLCO 96% CYC monthly × 1 year, then RTX (dose unknown) Clinical improvement,
PFTs 2 yrs. post: FVC 82%, TLC 80%
[14] F 22 27 Pleuritic chest pain, exertional dyspnea Elevated diaphragms, normal HRCT FVC 1.45 L (predicted value 4.20), TLC 2.35 (predicted value 5.76), DLCO 16.3 (predicted value 26.5) CS + RTX (375 mg/m2 × 2 doses 6 weeks apart) Initial clinical improvement, followed by re-presentation requiring second course of RTX. Improvement reported 2 yrs. later
[15] F 22 57 Dyspnea, dry cough, pleuritic chest pain Elevated diaphragms, bibasilar atelectasis FVC 43%, TLC 56%, DLCO 55% CS + beta-agonists + AZA + MMF, then 6 mo later RTX (1 g × 2 doses, 2 weeks apart, repeated q6mo) Clinical improvement. PFTs 5 years post: FVC 76%, TLC 79%, DLCO 53%
[16] F Unknown 28 Exercise intolerance, pleuritic chest pain Unknown FVC 0.99 L CS + MMF + RTX (2800 mg) Unlimited exercise tolerance, FVC 2.23 L
[12] F 12 14 Dyspnea, pleuritic chest pain, orthopnea Elevated right hemidiaphragm FVC 36%, TLC 39%, DLCO 102% CS + RTX (dose unknown) + CYC Active disease
[8] F 36 37 Dyspnea, pleuritic chest pain CXR: Bilateral diaphragmatic elevation with mild pleural effusion
HRCT: Mild pleural effusion
Restrictive pattern CS + MTX + beta-agonists + RTX (dose unknown) Restrictive defect improvement
[8] F 36 39 Dyspnea, pleuritic chest pain, fever CXR: Unilateral diaphragmatic elevation, left atelectasia
HRCT: Basal atelectasis
Restrictive pattern CS + MMF + beta-agonists + RTX (dose unknown) Restrictive defect stabilization. Developed ILD 4 yrs. later
[8] F 27 31 Dyspnea, pleuritic chest pain CXR: Unilateral diaphragmatic elevation, right atelectasia
HRCT: Basal atelectasis, mild pleural effusion
Restrictive pattern CS + theophylline + beta-agonists + RTX (dose unknown) Restrictive defect stabilization
[8] F 23 30 Dyspnea, pleuritic chest pain CXR: Unilateral diaphragmatic elevation
HRCT: Basal atelectasis
Restrictive pattern CS + MMF + beta-agonists + RTX (dose unknown) Restrictive defect improvement
[8] F 34 59 Dyspnea, pleuritic chest pain CXR: Bilateral diaphragmatic elevation, atelectasia
HRCT: Basal atelectasis
Restrictive pattern CS + MMF + RTX (dose unknown) + IVIG Restrictive defect stabilization
CS corticosteroids, RTX rituximab, CYC cyclophosphamide, AZA azathioprine, MMF mycophenolate mofetil, IVIG intravenous immunoglobulin, CXR chest X-ray, HRCT high-resolution computed tomography, PFTs pulmonary function tests, FEV1 forced expiratory volume in 1 s, FVC forced vital capacity, TLC total lung capacity, DLCO diffusing capacity for carbon monoxide, ILD interstitial lung disease. PFT results expressed in % predicted when available
a Diagnosis of SLS made at the time of diagnosis of SLE
Shrinking lung syndrome is extremely rare in pediatric lupus patients (defined as 16 years or less at diagnosis), with only 6 well-documented case reports identified in our literature review from 1984 to 2019 (Table 2). Age at onset of SLS ranged from 12 to 15 years, 5 were female, all presented with dyspnea, and 5 had associated chest pain. Interestingly, 3 of the 6 presented at the time of diagnosis of SLE, a much more frequent occurrence than that reported in adults with SLS. Of the 6 patients, only 2 reported a return to baseline respiratory function, both clinically and documented on PFTs [2, 7]. In addition to these 6 patients, our literature review identified 3 patients with pediatric onset SLE who developed SLS at age 19 or 20 [11, 19, 20]. Some improvement in lung function was documented in 2 of these patients, one treated with IVMP, cyclophosphamide and azathioprine, and 1 treated with belimumab. In addition, 7 SLE patients 16–18 years of age have been reported, most in case series of SLS, however very limited information was given on their disease course [1, 5, 12, 21, 22].
Table 2 Clinical features, treatment, and outcome of reported pediatric cases of SLS associated with SLE
Reference Sex Age at SLE diagnosis Age at SLS diagnosis Clinical presentation Imaging findings at SLS diagnosis PFTs at SLS diagnosis Treatment Outcome
[2] F 12 12a Prior diagnosis of mycoplasma pneumonia with recovery. Re-presented 6 months later with dyspnea CXR: Enlarged cardiac silhouette, low lung volumes, elevated diaphragms
HRCT: thoracic lymphadenopathy
FEV1 34%, FVC 27%, TLC 59% CS + CYC (q4weeks × 6 mo) Asymptomatic. Normal PFTs after 1 yr (FEV1 99%, FVC 97%, TLC 92%)
[7] F 11 14 Dyspnea on exertion, chest pain CXR: Low lung volumes, small pleural effusions, small pericardial effusion, mild bibasilar atelectasis FVC 31%, TLC 32%, DLCO 96% CYC monthly × 1 year, then RTX (dose unknown) Clinical improvement,
PFTs 2 yrs. post: FVC 82%, TLC 80%
[10] F 15 15a Pleuritic chest pain, dry cough, dyspnea on exertion Small lung fields, elevated bilateral hemidiaphragms, chest CT normal FEV1 26%, FVC 25%, TLC 31% Beta-agonist Clinical improvement. PFTs after 12d showed FEV1 increase of 58%, FVC increase of 50%, TLC increase of 47%
[17] M 11 14 Fatigue, dyspnea, pleuritic chest pain Enlarged cardiac silhouette, atelectasis, severely reduced diaphragmatic excursion on fluoroscopy FEV1 23%, FVC 20%, TLC 34% CS + AZA Follow-up 23 days later: FEV1 45%, FVC 45%, TLC 57%
[18] F 12 12a Pleuritic chest pain, dyspnea, fever, fatigue, anorexia CXR: Reduced lung volumes, elevated diaphragms, HRCT: pleural thickening Diaphragmatic fluoroscopy: minimal movement FVC 39%, TLC 60%, DLCO normal CS + HCQ 4 yrs. post: ongoing activity limitation, PFTs unchanged
[12] F 12 14 Dyspnea, pleuritic chest pain, orthopnea Elevated right hemidiaphragm FVC 36%, TLC 39%, DLCO 102% CS + RTX (dose unknown) + CYC Active disease
CS corticosteroids, RTX rituximab, CYC cyclophosphamide, AZA azathioprine, HCQ hydroxychloroquine, CXR chest X-ray, HRCT high-resolution computed tomography, PFTs pulmonary function tests, FEV1 forced expiratory volume in 1 s, FVC forced vital capacity, TLC total lung capacity, DLCO diffusing capacity for carbon monoxide. PFT results expressed in % predicted when available
a Diagnosis of SLS made at the time of diagnosis of SLE
Although extremely rare, it is important to recognize SLS as a possible cause of dyspnea and chest pain in a child with SLE, and be aware that in pediatric patients in particular, this complication may occur at the time of initial presentation of SLE. Our patient clearly stated that his goal for treatment was to return to competitive hockey. Recent literature on rituximab use in SLS, a review of pediatric SLS cases, and our case report suggest that additional therapy, including possible use of rituximab, should be considered in patients with SLS who have an incomplete response to initial immunosuppressive therapy. Careful documentation of the occurrence, treatment and outcome of patients with SLS utilizing large registries of adult and pediatric patients with SLE may help determine optimal treatment for this rare complication.
Abbreviations
SLSShrinking lung syndrome
SLESystemic lupus erythematosus
PFTPulmonary function test
FEV1Forced expiratory volume in 1 s
FVCForced vital capacity
TLCTotal lung capacity
RVResidual volume
RSVRespiratory syncytial virus
CXRChest x ray
dsDNADouble stranded DNA
ANAAntinuclear antibody
IVMPMethylprednisolone
PCRPolymerase chain reaction
HRCTHigh resolution computed tomography
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Acknowledgements
We thank the patient and family for participating in this report.
Authors’ contributions
CD and BL reviewed the patient’s medical record pertaining to this case and were major contributors in writing the manuscript. All authors read and approved the final manuscript.
Funding
None.
Availability of data and materials
Data sharing is not applicable to this article as no datasets were generated or analyzed during the current study.
Ethics approval and consent to participate
Research Ethics Board approval (#1024379) was obtained from the IWK Health Centre. Written and informed consent was also obtained from the patient.
Consent for publication
Written and informed consent was obtained from the patient to publish this material.
Competing interests
The authors declare that they have no competing interests. | AZATHIOPRINE, HYDROXYCHLOROQUINE, MYCOPHENOLATE MOFETIL, PREDNISONE | DrugsGivenReaction | CC BY | 33407629 | 18,886,056 | 2021-01-06 |
Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Gastrointestinal disorder'. | Shrinking lung syndrome treated with rituximab in pediatric systemic lupus erythematosus: a case report and review of the literature.
BACKGROUND
Shrinking lung syndrome (SLS), a rare complication of systemic lupus erythematosus (SLE) characterized by dyspnea, low lung volumes, and a restrictive pattern on pulmonary function tests (PFTs), has only been reported in a few children. Given the rarity of SLS there is a paucity of literature regarding its optimal treatment. Outcomes are variable, with case reports documenting some improvement in most patients treated with corticosteroids, with or without additional immunosuppressive agents. However, most reported patients did not recover normal lung function. We report full recovery of a child with SLE and SLS following treatment with rituximab and review the current literature.
METHODS
An 11-year-old boy presented with a malar rash, myositis, arthritis, oral ulcers, leukopenia, anemia, positive lupus autoantibodies and Class II nephritis. He was diagnosed with SLE and treated with corticosteroids, hydroxychloroquine, azathioprine, and subsequently mycophenolate with symptom resolution. At age 14, his SLE flared coincident with a viral chest infection. He presented with a malar rash, polyarthritis, increased proteinuria and pleuritis which all improved with corticosteroids and ongoing treatment with mycophenolate. Six weeks later he presented with severe dyspnea, markedly decreased lung volumes, but otherwise normal chest X-ray (CXR) and high-resolution chest computed tomography (HRCT). He was found to have severely restricted PFTs (FEV1 27%, FVC 29%; TLC 43%). After additional investigations including echocardiography, pulmonary CT angiography, and diaphragmatic fluoroscopy, he was diagnosed with SLS and treated with rituximab and methylprednisolone. At 1 month his symptoms had improved, but he still had dyspnea with exertion and severely restricted PFTs. At 6 months his FVC and TLC had improved to 51 and 57% respectively, and were 83 and 94% respectively at 4 years. He had returned to all baseline activities, including competitive hockey.
CONCLUSIONS
Although extremely rare, it is important to recognize SLS as a possible cause of dyspnea and chest pain in a child with SLE. Optimal treatment strategies are unknown. This is the second reported case of a child treated with rituximab for SLS who recovered normal lung function. International lupus registries should carefully document the occurrence, treatment and outcome of patients with SLS to help determine the optimal treatment for this rare complication.
Background
Shrinking lung syndrome (SLS) is a rare complication of systemic lupus erythematosus (SLE) characterized by decreased lung volumes and a restrictive pattern on pulmonary function testing (PFTs). Patients typically present with progressive dyspnea and chest pain [1–3]. The diagnosis may be delayed, particularly in pediatric patients, because of failure to consider or recognize this disorder. The exact pathophysiology is unknown [1–3].
Given the rarity of SLS there is a paucity of literature regarding optimal treatment. Case reports and series have documented improvement in most patients treated with corticosteroids, with or without immunosuppressive agents. However, the majority of patients have an incomplete recovery [4, 5]. Recently, rituximab, a monoclonal antibody directed against the CD20 antigen found on the surface of B lymphocytes, has been used successfully in several adult patients and one child with SLE complicated by SLS [6, 7]. We report a child with SLE who developed SLS at age 14 and recovered fully following treatment with rituximab. We also review the literature on SLS in pediatric patients to increase awareness of this exceptionally rare complication, as well as review outcome of patients previously reported with SLS who were treated with rituximab.
Case presentation
At age 11 years, our patient was diagnosed with SLE after presenting with a malar rash, oral ulcers, polyarthritis, myositis, and anemia. His past history was remarkable only for mild asthma; family history was positive for maternal asthma and hypothyroidism. Work-up revealed leukopenia (WBC 2.5 10e9/L), hypocomplementemia (C3 0.23 g/L), positive anti-nuclear antibody, anti-dsDNA (633 IU/ml; normal less than10), anti-SSa/Ro, and anti-Smith antibodies, Class II lupus nephritis and a SLEDAI of 29. A baseline chest radiograph (CXR) was normal. He was treated with prednisone, hydroxychloroquine (HCQ), and azathioprine. A year later he had no symptoms of his SLE but was evaluated for an exercise-associated cough that was felt to be due to his asthma. A CXR was normal, PFTs showed moderate obstruction and symptoms resolved with a bronchodilator. Over the next few months, despite ongoing HCQ, azathioprine and low dose prednisone he had recurrence of malar rash and mild arthritis; a repeat renal biopsy showed Class III b lupus nephritis and azathioprine was replaced by mycophenolate mofetil (MMF) which was increased up to 700 mg/m2/dose BID, and subsequently decreased due to gastrointestinal side effects. This resulted in resolution of all symptoms but some ongoing nephritis (SLEDAI 12).
At age 14 he was admitted to his local hospital with fever, pleuritic chest pain, dyspnea, and cough. Bilateral pleural effusions were seen on CXR and he was given empiric antibiotics for possible pneumonia prior to transfer to our center, where he received a 3-day pulse of intravenous methylprednisolone (IVMP) for a suspected SLE flare (C3 0.70; anti dsDNA 95; SLEDAI 29). His chest symptoms resolved completely and respiratory syncytial virus (RSV) infection was subsequently confirmed by PCR and was thought to have triggered the flare. One month later, despite treatment with low dose prednisone and MMF (535 mg/m2/dose BID, although compliance was questionable), his SLE again flared. He presented with a malar rash, polyarthritis, as well as findings of pleuritis manifesting with chest pain, dyspnea, and a left pleural effusion. He was treated with pulse IVMP followed by increased MMF (625 mg/m2/dose BID) and daily oral prednisone (1 mg/kg/d).
Six weeks later his rash and arthritis had improved, but he reported increasing shortness of breath with marked exercise intolerance. On examination he was afebrile, his heart rate was 120, respiratory rate 40, and oxygen saturation 95% in room air. He appeared dyspneic with difficulty speaking in full sentences. Chest examination revealed shallow breathing and decreased air entry bilaterally. Physical examination was otherwise unremarkable. Work up for infection was negative. His SLEDAI had decreased to 14, C3 had normalized (0.97) and anti dsDNA had decreased to 39. CXR and high-resolution computed tomography (HRCT) showed severely reduced lung volumes with no pleural or interstitial disease; there was slight atelectasis but no other significant abnormalities (Figs. 1, 2). An echocardiogram was normal and a CT angiogram showed no evidence of pulmonary embolus. PFTs revealed a severe restrictive pattern with forced expiratory volume in 1 s (FEV1) of 27%, forced vital capacity (FVC) 29%, and total lung capacity (TLC) 43% (Fig. 3). Fluoroscopy documented significantly reduced diaphragmatic movement. He was diagnosed with SLS, and because of worsening dyspnea despite recently increased immunosuppression, he was treated with IVMP 1 g daily for 3 days followed by rituximab 1 g (2 doses, 2 weeks apart). He was also referred to physiotherapy for pulmonary rehabilitation.
Fig. 1 a Chest X-ray at presentation with SLS, showing decreased lung volumes and raised hemidiaphragms b Normal chest X-ray 3 years later
Fig. 2 High-resolution computed tomography (HRCT) of the chest at presentation with SLS, showing decreased lung volumes and slight atelectasis
Fig. 3 Pulmonary function tests (PFTs) over time in our patient with SLE and SLS; at diagnosis to 4 years following treatment with rituximab. FEV1, forced expiratory volume in 1 s; FVC, forced vital capacity; TLC, total lung capacity; RV, residual volume
One month later he reported some improvement in physical endurance, though he still had dyspnea with mild exertion and PFTs remained severely restrictive. At 6 months, however, he reported much improved exercise tolerance with ability to play some hockey. His FEV1 and FVC had improved to 42 and 51% respectively and TLC had increased to 57%. A planned second course of rituximab, (1 g, 2 doses, 2 weeks apart) was given at 6 months; preceding B cell counts were 8%. He was tapered off corticosteroids over the next 9 months and continued on HCQ (5 mg/kg/d) and MMF (600 mg/m2/dose BID). Serial CXRs showed gradual lung volume expansion. One year after his presentation he returned to playing competitive hockey, with no limitations and no respiratory symptoms. Four years later, he remained asymptomatic with no limitations in activity, no evidence of restrictive lung disease on PFTs (FVC 83%, TLC 94%), and a normal CXR. He remained on the same doses of HCQ and MMF with no clinical evidence of SLE disease activity, normal complement levels (C3 0.97), anti dsDNA 16, a SLEDAI of 2, and a follow renal biopsy showed no active nephritis.
Discussion
Shrinking lung syndrome is a rare complication of SLE with an incidence of approximately 1% in adult lupus patients [1, 5]. The incidence in pediatric SLE is unknown, but is likely even less common. As such, the diagnosis of SLS may not be considered or recognized in a child with SLE. Clinical features include progressive dyspnea, exercise intolerance, and pleuritic chest pain, all of which were described by our patient. Physical examination frequently reveals tachypnea with decreased air entry and the use of accessory respiratory muscles but is otherwise unremarkable. Findings on CXR often include significantly reduced lung volumes with elevated hemidiaphragms and may include pleural effusions, basal atelectasis, and pleural thickening. HRCT typically shows no parenchymal lung disease, though it may be more sensitive than CXR in demonstrating pleural effusions and atelectasis [4, 8]. PFTs show a restrictive pattern [4]. Reduced diaphragmatic excursion may be demonstrated on chest fluoroscopy, as was seen in our patient, or may be demonstrated using M-mode ultrasonography [8].
The pathogenesis of shrinking lung syndrome remains incompletely understood. When first described by Hoffbrand and Beck in 1965, the condition was thought to be due to surfactant deficiency causing microatelectasis [9]. Since then a number of mechanisms have been suggested, including phrenic nerve dysfunction, pleural inflammation and fibrosis, and diaphragmatic dysfunction due to myositis or neuropathy [3, 10]. Anti-SSa/Ro antibody positivity has been associated with both SLS and myositis, and has been suggested to support the theory that myositis contributes to diaphragmatic dysfunction in some patients [3, 11]. Of note, our patient was anti-SSa/Ro positive and had myositis as part of his SLE course. The frequent occurrence of pleuritic chest pain in up to 80% of patients with SLS has led to a more recently proposed mechanism of pleuritic pain leading to reflex inhibition of diaphragmatic activation and subsequent dysfunction in at least a subset of patients with SLS [1, 3]. Henderson et al. have proposed that pleural inflammation due to the underlying rheumatic disease may lead to activation of neural reflexes which inhibit deep inspiration and cause chronic lung hypoinflation. This is postulated to gradually reduce lung compliance and results in a positive feedback cycle [12]. Interestingly, our patient had developed pleuritic chest pain 2 months prior to his diagnosis of SLS, and had documented pleuritis associated with an RSV infection, and then associated with a flare of his SLE, which may have initiated the pathogenetic process leading to SLS.
There is no standard treatment for patients with SLS. Corticosteroids are the most frequently reported initial treatment of SLS, and can lead to full recovery in some patients [3, 5, 11, 13]. Immunosuppressive agents including cyclophosphamide, azathioprine, and methotrexate are often given along with corticosteroids or if corticosteroids alone are ineffective. There are also a few reports of theophylline and beta-agonists used effectively in SLS, and others advocate the use of analgesia to combat chest pain and pulmonary rehabilitation to improve lung expansion [1, 3, 5, 12, 13]. Although rare fatal cases have been described, the prognosis of SLS in adults is generally considered to be good, particularly in comparison with the progressive course and significant mortality associated with fibrotic interstitial lung disease in patients with SLE [1]. Some clinical improvement has been reported in most patients with SLS, however, recent literature makes it clear that despite treatment many patients do not achieve full recovery. Langenskiold et al., in a review of 35 cases with documented pre and post treatment PFTs, found that only 20% of patients with SLS regained normal lung function [4]. Duron et al. reported full recovery in only a minority of patients in their review of 155 patients with SLS, with 42.9% of patients showing chronic and persistent hemidiaphragm elevation [1]. A report of 20 cases from a large single center in 2018 showed a similar outcome, with 86.7% of patients showing continued restrictive defects on spirometry despite improved lung volumes [5]. The lack of full recovery in both adult and pediatric patients with SLS has led to 15 reports of rituximab use in adults and 2 reports in children with SLS complicating SLE [1, 3, 4, 6–8, 12, 14–16] (Table 1). Normal PFTs were reported in one child treated with rituximab [7], however the other child did not respond [12]. All 4 adult patients with well-documented post-treatment PFTs had normal or near normal findings [3, 4, 6]. Although the degree of objective improvement was not documented in the remaining 11 adult cases treated with rituximab, all were reported to have improved or stabilized. (Table 1). There has also been a recent report of a 19-year-old male with pediatric-onset SLE who developed SLS refractory to IVMP and cyclophosphamide and had some improvement with belimumab, a monoclonal antibody directed against BLyS receptors on B-cells, though long-term follow-up is still ongoing [11].
Table 1 Clinical features, treatment and outcome of patients with SLS associated with SLE who received treatment with rituximab
Reference Sex Age at SLE diagnosis Age at SLS diagnosis Clinical presentation Imaging findings at SLS diagnosis PFTs at SLS diagnosis Treatment Outcome
[1] F Unknown 61 Chest pain, history of pleurisy, dyspnea Elevated diaphragms, atelectasis, pleural thickening TLC 46%,
DLCO 25%, KCO 59%
CS + Beta-agonists + RTX (dose unknown) + Physiotherapy Improvement
[1] F Unknown 26 Chest pain, history of pleurisy, dyspnea Pleural thickening, reticulations FVC 41%,
TLC 68%,
DLCO 34%
CS + AZA + MMF + RTX (dose unknown) Improvement
[3] F 36 46 Dyspnea on exertion, orthopnea, pleuritic chest pain Elevated diaphragms, atelectasis, pleural thickening FVC 77%, TLC 68% CS + CYC + RTX (375 mg/m2 once weekly × 4 q6mo) Asymptomatic, normal PFTs
[4] F 28 28 (6 mo after diagnosis of SLE) Dyspnea, pleuritic chest pain, dry cough, orthopnea Elevated diaphragms FVC 61%, TLC 45% Beta-agonists + theophylline, RTX (1 g × 2, 2 weeks apart) + CYC Asymptomatic, normal PFTs
[6] F 38 38a Tachypnea, dyspnea Normal HRCT, elevated diaphragms FVC 64%, FEV1 73% CS + CYC without improvement; followed by RTX (1 g × 2, 2 weeks apart) Normal PFTs, normal CXR 6 months after treatment
[7] F 11 14 Dyspnea on exertion, chest pain Low lung volumes, small bilateral pleural effusions, small pericardial effusion, mild bibasilar atelectasis FVC 31%, TLC 32%, DLCO 96% CYC monthly × 1 year, then RTX (dose unknown) Clinical improvement,
PFTs 2 yrs. post: FVC 82%, TLC 80%
[14] F 22 27 Pleuritic chest pain, exertional dyspnea Elevated diaphragms, normal HRCT FVC 1.45 L (predicted value 4.20), TLC 2.35 (predicted value 5.76), DLCO 16.3 (predicted value 26.5) CS + RTX (375 mg/m2 × 2 doses 6 weeks apart) Initial clinical improvement, followed by re-presentation requiring second course of RTX. Improvement reported 2 yrs. later
[15] F 22 57 Dyspnea, dry cough, pleuritic chest pain Elevated diaphragms, bibasilar atelectasis FVC 43%, TLC 56%, DLCO 55% CS + beta-agonists + AZA + MMF, then 6 mo later RTX (1 g × 2 doses, 2 weeks apart, repeated q6mo) Clinical improvement. PFTs 5 years post: FVC 76%, TLC 79%, DLCO 53%
[16] F Unknown 28 Exercise intolerance, pleuritic chest pain Unknown FVC 0.99 L CS + MMF + RTX (2800 mg) Unlimited exercise tolerance, FVC 2.23 L
[12] F 12 14 Dyspnea, pleuritic chest pain, orthopnea Elevated right hemidiaphragm FVC 36%, TLC 39%, DLCO 102% CS + RTX (dose unknown) + CYC Active disease
[8] F 36 37 Dyspnea, pleuritic chest pain CXR: Bilateral diaphragmatic elevation with mild pleural effusion
HRCT: Mild pleural effusion
Restrictive pattern CS + MTX + beta-agonists + RTX (dose unknown) Restrictive defect improvement
[8] F 36 39 Dyspnea, pleuritic chest pain, fever CXR: Unilateral diaphragmatic elevation, left atelectasia
HRCT: Basal atelectasis
Restrictive pattern CS + MMF + beta-agonists + RTX (dose unknown) Restrictive defect stabilization. Developed ILD 4 yrs. later
[8] F 27 31 Dyspnea, pleuritic chest pain CXR: Unilateral diaphragmatic elevation, right atelectasia
HRCT: Basal atelectasis, mild pleural effusion
Restrictive pattern CS + theophylline + beta-agonists + RTX (dose unknown) Restrictive defect stabilization
[8] F 23 30 Dyspnea, pleuritic chest pain CXR: Unilateral diaphragmatic elevation
HRCT: Basal atelectasis
Restrictive pattern CS + MMF + beta-agonists + RTX (dose unknown) Restrictive defect improvement
[8] F 34 59 Dyspnea, pleuritic chest pain CXR: Bilateral diaphragmatic elevation, atelectasia
HRCT: Basal atelectasis
Restrictive pattern CS + MMF + RTX (dose unknown) + IVIG Restrictive defect stabilization
CS corticosteroids, RTX rituximab, CYC cyclophosphamide, AZA azathioprine, MMF mycophenolate mofetil, IVIG intravenous immunoglobulin, CXR chest X-ray, HRCT high-resolution computed tomography, PFTs pulmonary function tests, FEV1 forced expiratory volume in 1 s, FVC forced vital capacity, TLC total lung capacity, DLCO diffusing capacity for carbon monoxide, ILD interstitial lung disease. PFT results expressed in % predicted when available
a Diagnosis of SLS made at the time of diagnosis of SLE
Shrinking lung syndrome is extremely rare in pediatric lupus patients (defined as 16 years or less at diagnosis), with only 6 well-documented case reports identified in our literature review from 1984 to 2019 (Table 2). Age at onset of SLS ranged from 12 to 15 years, 5 were female, all presented with dyspnea, and 5 had associated chest pain. Interestingly, 3 of the 6 presented at the time of diagnosis of SLE, a much more frequent occurrence than that reported in adults with SLS. Of the 6 patients, only 2 reported a return to baseline respiratory function, both clinically and documented on PFTs [2, 7]. In addition to these 6 patients, our literature review identified 3 patients with pediatric onset SLE who developed SLS at age 19 or 20 [11, 19, 20]. Some improvement in lung function was documented in 2 of these patients, one treated with IVMP, cyclophosphamide and azathioprine, and 1 treated with belimumab. In addition, 7 SLE patients 16–18 years of age have been reported, most in case series of SLS, however very limited information was given on their disease course [1, 5, 12, 21, 22].
Table 2 Clinical features, treatment, and outcome of reported pediatric cases of SLS associated with SLE
Reference Sex Age at SLE diagnosis Age at SLS diagnosis Clinical presentation Imaging findings at SLS diagnosis PFTs at SLS diagnosis Treatment Outcome
[2] F 12 12a Prior diagnosis of mycoplasma pneumonia with recovery. Re-presented 6 months later with dyspnea CXR: Enlarged cardiac silhouette, low lung volumes, elevated diaphragms
HRCT: thoracic lymphadenopathy
FEV1 34%, FVC 27%, TLC 59% CS + CYC (q4weeks × 6 mo) Asymptomatic. Normal PFTs after 1 yr (FEV1 99%, FVC 97%, TLC 92%)
[7] F 11 14 Dyspnea on exertion, chest pain CXR: Low lung volumes, small pleural effusions, small pericardial effusion, mild bibasilar atelectasis FVC 31%, TLC 32%, DLCO 96% CYC monthly × 1 year, then RTX (dose unknown) Clinical improvement,
PFTs 2 yrs. post: FVC 82%, TLC 80%
[10] F 15 15a Pleuritic chest pain, dry cough, dyspnea on exertion Small lung fields, elevated bilateral hemidiaphragms, chest CT normal FEV1 26%, FVC 25%, TLC 31% Beta-agonist Clinical improvement. PFTs after 12d showed FEV1 increase of 58%, FVC increase of 50%, TLC increase of 47%
[17] M 11 14 Fatigue, dyspnea, pleuritic chest pain Enlarged cardiac silhouette, atelectasis, severely reduced diaphragmatic excursion on fluoroscopy FEV1 23%, FVC 20%, TLC 34% CS + AZA Follow-up 23 days later: FEV1 45%, FVC 45%, TLC 57%
[18] F 12 12a Pleuritic chest pain, dyspnea, fever, fatigue, anorexia CXR: Reduced lung volumes, elevated diaphragms, HRCT: pleural thickening Diaphragmatic fluoroscopy: minimal movement FVC 39%, TLC 60%, DLCO normal CS + HCQ 4 yrs. post: ongoing activity limitation, PFTs unchanged
[12] F 12 14 Dyspnea, pleuritic chest pain, orthopnea Elevated right hemidiaphragm FVC 36%, TLC 39%, DLCO 102% CS + RTX (dose unknown) + CYC Active disease
CS corticosteroids, RTX rituximab, CYC cyclophosphamide, AZA azathioprine, HCQ hydroxychloroquine, CXR chest X-ray, HRCT high-resolution computed tomography, PFTs pulmonary function tests, FEV1 forced expiratory volume in 1 s, FVC forced vital capacity, TLC total lung capacity, DLCO diffusing capacity for carbon monoxide. PFT results expressed in % predicted when available
a Diagnosis of SLS made at the time of diagnosis of SLE
Although extremely rare, it is important to recognize SLS as a possible cause of dyspnea and chest pain in a child with SLE, and be aware that in pediatric patients in particular, this complication may occur at the time of initial presentation of SLE. Our patient clearly stated that his goal for treatment was to return to competitive hockey. Recent literature on rituximab use in SLS, a review of pediatric SLS cases, and our case report suggest that additional therapy, including possible use of rituximab, should be considered in patients with SLS who have an incomplete response to initial immunosuppressive therapy. Careful documentation of the occurrence, treatment and outcome of patients with SLS utilizing large registries of adult and pediatric patients with SLE may help determine optimal treatment for this rare complication.
Abbreviations
SLSShrinking lung syndrome
SLESystemic lupus erythematosus
PFTPulmonary function test
FEV1Forced expiratory volume in 1 s
FVCForced vital capacity
TLCTotal lung capacity
RVResidual volume
RSVRespiratory syncytial virus
CXRChest x ray
dsDNADouble stranded DNA
ANAAntinuclear antibody
IVMPMethylprednisolone
PCRPolymerase chain reaction
HRCTHigh resolution computed tomography
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Acknowledgements
We thank the patient and family for participating in this report.
Authors’ contributions
CD and BL reviewed the patient’s medical record pertaining to this case and were major contributors in writing the manuscript. All authors read and approved the final manuscript.
Funding
None.
Availability of data and materials
Data sharing is not applicable to this article as no datasets were generated or analyzed during the current study.
Ethics approval and consent to participate
Research Ethics Board approval (#1024379) was obtained from the IWK Health Centre. Written and informed consent was also obtained from the patient.
Consent for publication
Written and informed consent was obtained from the patient to publish this material.
Competing interests
The authors declare that they have no competing interests. | AZATHIOPRINE, HYDROXYCHLOROQUINE, MYCOPHENOLATE MOFETIL, PREDNISONE | DrugsGivenReaction | CC BY | 33407629 | 18,886,056 | 2021-01-06 |
Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Lupus nephritis'. | Shrinking lung syndrome treated with rituximab in pediatric systemic lupus erythematosus: a case report and review of the literature.
BACKGROUND
Shrinking lung syndrome (SLS), a rare complication of systemic lupus erythematosus (SLE) characterized by dyspnea, low lung volumes, and a restrictive pattern on pulmonary function tests (PFTs), has only been reported in a few children. Given the rarity of SLS there is a paucity of literature regarding its optimal treatment. Outcomes are variable, with case reports documenting some improvement in most patients treated with corticosteroids, with or without additional immunosuppressive agents. However, most reported patients did not recover normal lung function. We report full recovery of a child with SLE and SLS following treatment with rituximab and review the current literature.
METHODS
An 11-year-old boy presented with a malar rash, myositis, arthritis, oral ulcers, leukopenia, anemia, positive lupus autoantibodies and Class II nephritis. He was diagnosed with SLE and treated with corticosteroids, hydroxychloroquine, azathioprine, and subsequently mycophenolate with symptom resolution. At age 14, his SLE flared coincident with a viral chest infection. He presented with a malar rash, polyarthritis, increased proteinuria and pleuritis which all improved with corticosteroids and ongoing treatment with mycophenolate. Six weeks later he presented with severe dyspnea, markedly decreased lung volumes, but otherwise normal chest X-ray (CXR) and high-resolution chest computed tomography (HRCT). He was found to have severely restricted PFTs (FEV1 27%, FVC 29%; TLC 43%). After additional investigations including echocardiography, pulmonary CT angiography, and diaphragmatic fluoroscopy, he was diagnosed with SLS and treated with rituximab and methylprednisolone. At 1 month his symptoms had improved, but he still had dyspnea with exertion and severely restricted PFTs. At 6 months his FVC and TLC had improved to 51 and 57% respectively, and were 83 and 94% respectively at 4 years. He had returned to all baseline activities, including competitive hockey.
CONCLUSIONS
Although extremely rare, it is important to recognize SLS as a possible cause of dyspnea and chest pain in a child with SLE. Optimal treatment strategies are unknown. This is the second reported case of a child treated with rituximab for SLS who recovered normal lung function. International lupus registries should carefully document the occurrence, treatment and outcome of patients with SLS to help determine the optimal treatment for this rare complication.
Background
Shrinking lung syndrome (SLS) is a rare complication of systemic lupus erythematosus (SLE) characterized by decreased lung volumes and a restrictive pattern on pulmonary function testing (PFTs). Patients typically present with progressive dyspnea and chest pain [1–3]. The diagnosis may be delayed, particularly in pediatric patients, because of failure to consider or recognize this disorder. The exact pathophysiology is unknown [1–3].
Given the rarity of SLS there is a paucity of literature regarding optimal treatment. Case reports and series have documented improvement in most patients treated with corticosteroids, with or without immunosuppressive agents. However, the majority of patients have an incomplete recovery [4, 5]. Recently, rituximab, a monoclonal antibody directed against the CD20 antigen found on the surface of B lymphocytes, has been used successfully in several adult patients and one child with SLE complicated by SLS [6, 7]. We report a child with SLE who developed SLS at age 14 and recovered fully following treatment with rituximab. We also review the literature on SLS in pediatric patients to increase awareness of this exceptionally rare complication, as well as review outcome of patients previously reported with SLS who were treated with rituximab.
Case presentation
At age 11 years, our patient was diagnosed with SLE after presenting with a malar rash, oral ulcers, polyarthritis, myositis, and anemia. His past history was remarkable only for mild asthma; family history was positive for maternal asthma and hypothyroidism. Work-up revealed leukopenia (WBC 2.5 10e9/L), hypocomplementemia (C3 0.23 g/L), positive anti-nuclear antibody, anti-dsDNA (633 IU/ml; normal less than10), anti-SSa/Ro, and anti-Smith antibodies, Class II lupus nephritis and a SLEDAI of 29. A baseline chest radiograph (CXR) was normal. He was treated with prednisone, hydroxychloroquine (HCQ), and azathioprine. A year later he had no symptoms of his SLE but was evaluated for an exercise-associated cough that was felt to be due to his asthma. A CXR was normal, PFTs showed moderate obstruction and symptoms resolved with a bronchodilator. Over the next few months, despite ongoing HCQ, azathioprine and low dose prednisone he had recurrence of malar rash and mild arthritis; a repeat renal biopsy showed Class III b lupus nephritis and azathioprine was replaced by mycophenolate mofetil (MMF) which was increased up to 700 mg/m2/dose BID, and subsequently decreased due to gastrointestinal side effects. This resulted in resolution of all symptoms but some ongoing nephritis (SLEDAI 12).
At age 14 he was admitted to his local hospital with fever, pleuritic chest pain, dyspnea, and cough. Bilateral pleural effusions were seen on CXR and he was given empiric antibiotics for possible pneumonia prior to transfer to our center, where he received a 3-day pulse of intravenous methylprednisolone (IVMP) for a suspected SLE flare (C3 0.70; anti dsDNA 95; SLEDAI 29). His chest symptoms resolved completely and respiratory syncytial virus (RSV) infection was subsequently confirmed by PCR and was thought to have triggered the flare. One month later, despite treatment with low dose prednisone and MMF (535 mg/m2/dose BID, although compliance was questionable), his SLE again flared. He presented with a malar rash, polyarthritis, as well as findings of pleuritis manifesting with chest pain, dyspnea, and a left pleural effusion. He was treated with pulse IVMP followed by increased MMF (625 mg/m2/dose BID) and daily oral prednisone (1 mg/kg/d).
Six weeks later his rash and arthritis had improved, but he reported increasing shortness of breath with marked exercise intolerance. On examination he was afebrile, his heart rate was 120, respiratory rate 40, and oxygen saturation 95% in room air. He appeared dyspneic with difficulty speaking in full sentences. Chest examination revealed shallow breathing and decreased air entry bilaterally. Physical examination was otherwise unremarkable. Work up for infection was negative. His SLEDAI had decreased to 14, C3 had normalized (0.97) and anti dsDNA had decreased to 39. CXR and high-resolution computed tomography (HRCT) showed severely reduced lung volumes with no pleural or interstitial disease; there was slight atelectasis but no other significant abnormalities (Figs. 1, 2). An echocardiogram was normal and a CT angiogram showed no evidence of pulmonary embolus. PFTs revealed a severe restrictive pattern with forced expiratory volume in 1 s (FEV1) of 27%, forced vital capacity (FVC) 29%, and total lung capacity (TLC) 43% (Fig. 3). Fluoroscopy documented significantly reduced diaphragmatic movement. He was diagnosed with SLS, and because of worsening dyspnea despite recently increased immunosuppression, he was treated with IVMP 1 g daily for 3 days followed by rituximab 1 g (2 doses, 2 weeks apart). He was also referred to physiotherapy for pulmonary rehabilitation.
Fig. 1 a Chest X-ray at presentation with SLS, showing decreased lung volumes and raised hemidiaphragms b Normal chest X-ray 3 years later
Fig. 2 High-resolution computed tomography (HRCT) of the chest at presentation with SLS, showing decreased lung volumes and slight atelectasis
Fig. 3 Pulmonary function tests (PFTs) over time in our patient with SLE and SLS; at diagnosis to 4 years following treatment with rituximab. FEV1, forced expiratory volume in 1 s; FVC, forced vital capacity; TLC, total lung capacity; RV, residual volume
One month later he reported some improvement in physical endurance, though he still had dyspnea with mild exertion and PFTs remained severely restrictive. At 6 months, however, he reported much improved exercise tolerance with ability to play some hockey. His FEV1 and FVC had improved to 42 and 51% respectively and TLC had increased to 57%. A planned second course of rituximab, (1 g, 2 doses, 2 weeks apart) was given at 6 months; preceding B cell counts were 8%. He was tapered off corticosteroids over the next 9 months and continued on HCQ (5 mg/kg/d) and MMF (600 mg/m2/dose BID). Serial CXRs showed gradual lung volume expansion. One year after his presentation he returned to playing competitive hockey, with no limitations and no respiratory symptoms. Four years later, he remained asymptomatic with no limitations in activity, no evidence of restrictive lung disease on PFTs (FVC 83%, TLC 94%), and a normal CXR. He remained on the same doses of HCQ and MMF with no clinical evidence of SLE disease activity, normal complement levels (C3 0.97), anti dsDNA 16, a SLEDAI of 2, and a follow renal biopsy showed no active nephritis.
Discussion
Shrinking lung syndrome is a rare complication of SLE with an incidence of approximately 1% in adult lupus patients [1, 5]. The incidence in pediatric SLE is unknown, but is likely even less common. As such, the diagnosis of SLS may not be considered or recognized in a child with SLE. Clinical features include progressive dyspnea, exercise intolerance, and pleuritic chest pain, all of which were described by our patient. Physical examination frequently reveals tachypnea with decreased air entry and the use of accessory respiratory muscles but is otherwise unremarkable. Findings on CXR often include significantly reduced lung volumes with elevated hemidiaphragms and may include pleural effusions, basal atelectasis, and pleural thickening. HRCT typically shows no parenchymal lung disease, though it may be more sensitive than CXR in demonstrating pleural effusions and atelectasis [4, 8]. PFTs show a restrictive pattern [4]. Reduced diaphragmatic excursion may be demonstrated on chest fluoroscopy, as was seen in our patient, or may be demonstrated using M-mode ultrasonography [8].
The pathogenesis of shrinking lung syndrome remains incompletely understood. When first described by Hoffbrand and Beck in 1965, the condition was thought to be due to surfactant deficiency causing microatelectasis [9]. Since then a number of mechanisms have been suggested, including phrenic nerve dysfunction, pleural inflammation and fibrosis, and diaphragmatic dysfunction due to myositis or neuropathy [3, 10]. Anti-SSa/Ro antibody positivity has been associated with both SLS and myositis, and has been suggested to support the theory that myositis contributes to diaphragmatic dysfunction in some patients [3, 11]. Of note, our patient was anti-SSa/Ro positive and had myositis as part of his SLE course. The frequent occurrence of pleuritic chest pain in up to 80% of patients with SLS has led to a more recently proposed mechanism of pleuritic pain leading to reflex inhibition of diaphragmatic activation and subsequent dysfunction in at least a subset of patients with SLS [1, 3]. Henderson et al. have proposed that pleural inflammation due to the underlying rheumatic disease may lead to activation of neural reflexes which inhibit deep inspiration and cause chronic lung hypoinflation. This is postulated to gradually reduce lung compliance and results in a positive feedback cycle [12]. Interestingly, our patient had developed pleuritic chest pain 2 months prior to his diagnosis of SLS, and had documented pleuritis associated with an RSV infection, and then associated with a flare of his SLE, which may have initiated the pathogenetic process leading to SLS.
There is no standard treatment for patients with SLS. Corticosteroids are the most frequently reported initial treatment of SLS, and can lead to full recovery in some patients [3, 5, 11, 13]. Immunosuppressive agents including cyclophosphamide, azathioprine, and methotrexate are often given along with corticosteroids or if corticosteroids alone are ineffective. There are also a few reports of theophylline and beta-agonists used effectively in SLS, and others advocate the use of analgesia to combat chest pain and pulmonary rehabilitation to improve lung expansion [1, 3, 5, 12, 13]. Although rare fatal cases have been described, the prognosis of SLS in adults is generally considered to be good, particularly in comparison with the progressive course and significant mortality associated with fibrotic interstitial lung disease in patients with SLE [1]. Some clinical improvement has been reported in most patients with SLS, however, recent literature makes it clear that despite treatment many patients do not achieve full recovery. Langenskiold et al., in a review of 35 cases with documented pre and post treatment PFTs, found that only 20% of patients with SLS regained normal lung function [4]. Duron et al. reported full recovery in only a minority of patients in their review of 155 patients with SLS, with 42.9% of patients showing chronic and persistent hemidiaphragm elevation [1]. A report of 20 cases from a large single center in 2018 showed a similar outcome, with 86.7% of patients showing continued restrictive defects on spirometry despite improved lung volumes [5]. The lack of full recovery in both adult and pediatric patients with SLS has led to 15 reports of rituximab use in adults and 2 reports in children with SLS complicating SLE [1, 3, 4, 6–8, 12, 14–16] (Table 1). Normal PFTs were reported in one child treated with rituximab [7], however the other child did not respond [12]. All 4 adult patients with well-documented post-treatment PFTs had normal or near normal findings [3, 4, 6]. Although the degree of objective improvement was not documented in the remaining 11 adult cases treated with rituximab, all were reported to have improved or stabilized. (Table 1). There has also been a recent report of a 19-year-old male with pediatric-onset SLE who developed SLS refractory to IVMP and cyclophosphamide and had some improvement with belimumab, a monoclonal antibody directed against BLyS receptors on B-cells, though long-term follow-up is still ongoing [11].
Table 1 Clinical features, treatment and outcome of patients with SLS associated with SLE who received treatment with rituximab
Reference Sex Age at SLE diagnosis Age at SLS diagnosis Clinical presentation Imaging findings at SLS diagnosis PFTs at SLS diagnosis Treatment Outcome
[1] F Unknown 61 Chest pain, history of pleurisy, dyspnea Elevated diaphragms, atelectasis, pleural thickening TLC 46%,
DLCO 25%, KCO 59%
CS + Beta-agonists + RTX (dose unknown) + Physiotherapy Improvement
[1] F Unknown 26 Chest pain, history of pleurisy, dyspnea Pleural thickening, reticulations FVC 41%,
TLC 68%,
DLCO 34%
CS + AZA + MMF + RTX (dose unknown) Improvement
[3] F 36 46 Dyspnea on exertion, orthopnea, pleuritic chest pain Elevated diaphragms, atelectasis, pleural thickening FVC 77%, TLC 68% CS + CYC + RTX (375 mg/m2 once weekly × 4 q6mo) Asymptomatic, normal PFTs
[4] F 28 28 (6 mo after diagnosis of SLE) Dyspnea, pleuritic chest pain, dry cough, orthopnea Elevated diaphragms FVC 61%, TLC 45% Beta-agonists + theophylline, RTX (1 g × 2, 2 weeks apart) + CYC Asymptomatic, normal PFTs
[6] F 38 38a Tachypnea, dyspnea Normal HRCT, elevated diaphragms FVC 64%, FEV1 73% CS + CYC without improvement; followed by RTX (1 g × 2, 2 weeks apart) Normal PFTs, normal CXR 6 months after treatment
[7] F 11 14 Dyspnea on exertion, chest pain Low lung volumes, small bilateral pleural effusions, small pericardial effusion, mild bibasilar atelectasis FVC 31%, TLC 32%, DLCO 96% CYC monthly × 1 year, then RTX (dose unknown) Clinical improvement,
PFTs 2 yrs. post: FVC 82%, TLC 80%
[14] F 22 27 Pleuritic chest pain, exertional dyspnea Elevated diaphragms, normal HRCT FVC 1.45 L (predicted value 4.20), TLC 2.35 (predicted value 5.76), DLCO 16.3 (predicted value 26.5) CS + RTX (375 mg/m2 × 2 doses 6 weeks apart) Initial clinical improvement, followed by re-presentation requiring second course of RTX. Improvement reported 2 yrs. later
[15] F 22 57 Dyspnea, dry cough, pleuritic chest pain Elevated diaphragms, bibasilar atelectasis FVC 43%, TLC 56%, DLCO 55% CS + beta-agonists + AZA + MMF, then 6 mo later RTX (1 g × 2 doses, 2 weeks apart, repeated q6mo) Clinical improvement. PFTs 5 years post: FVC 76%, TLC 79%, DLCO 53%
[16] F Unknown 28 Exercise intolerance, pleuritic chest pain Unknown FVC 0.99 L CS + MMF + RTX (2800 mg) Unlimited exercise tolerance, FVC 2.23 L
[12] F 12 14 Dyspnea, pleuritic chest pain, orthopnea Elevated right hemidiaphragm FVC 36%, TLC 39%, DLCO 102% CS + RTX (dose unknown) + CYC Active disease
[8] F 36 37 Dyspnea, pleuritic chest pain CXR: Bilateral diaphragmatic elevation with mild pleural effusion
HRCT: Mild pleural effusion
Restrictive pattern CS + MTX + beta-agonists + RTX (dose unknown) Restrictive defect improvement
[8] F 36 39 Dyspnea, pleuritic chest pain, fever CXR: Unilateral diaphragmatic elevation, left atelectasia
HRCT: Basal atelectasis
Restrictive pattern CS + MMF + beta-agonists + RTX (dose unknown) Restrictive defect stabilization. Developed ILD 4 yrs. later
[8] F 27 31 Dyspnea, pleuritic chest pain CXR: Unilateral diaphragmatic elevation, right atelectasia
HRCT: Basal atelectasis, mild pleural effusion
Restrictive pattern CS + theophylline + beta-agonists + RTX (dose unknown) Restrictive defect stabilization
[8] F 23 30 Dyspnea, pleuritic chest pain CXR: Unilateral diaphragmatic elevation
HRCT: Basal atelectasis
Restrictive pattern CS + MMF + beta-agonists + RTX (dose unknown) Restrictive defect improvement
[8] F 34 59 Dyspnea, pleuritic chest pain CXR: Bilateral diaphragmatic elevation, atelectasia
HRCT: Basal atelectasis
Restrictive pattern CS + MMF + RTX (dose unknown) + IVIG Restrictive defect stabilization
CS corticosteroids, RTX rituximab, CYC cyclophosphamide, AZA azathioprine, MMF mycophenolate mofetil, IVIG intravenous immunoglobulin, CXR chest X-ray, HRCT high-resolution computed tomography, PFTs pulmonary function tests, FEV1 forced expiratory volume in 1 s, FVC forced vital capacity, TLC total lung capacity, DLCO diffusing capacity for carbon monoxide, ILD interstitial lung disease. PFT results expressed in % predicted when available
a Diagnosis of SLS made at the time of diagnosis of SLE
Shrinking lung syndrome is extremely rare in pediatric lupus patients (defined as 16 years or less at diagnosis), with only 6 well-documented case reports identified in our literature review from 1984 to 2019 (Table 2). Age at onset of SLS ranged from 12 to 15 years, 5 were female, all presented with dyspnea, and 5 had associated chest pain. Interestingly, 3 of the 6 presented at the time of diagnosis of SLE, a much more frequent occurrence than that reported in adults with SLS. Of the 6 patients, only 2 reported a return to baseline respiratory function, both clinically and documented on PFTs [2, 7]. In addition to these 6 patients, our literature review identified 3 patients with pediatric onset SLE who developed SLS at age 19 or 20 [11, 19, 20]. Some improvement in lung function was documented in 2 of these patients, one treated with IVMP, cyclophosphamide and azathioprine, and 1 treated with belimumab. In addition, 7 SLE patients 16–18 years of age have been reported, most in case series of SLS, however very limited information was given on their disease course [1, 5, 12, 21, 22].
Table 2 Clinical features, treatment, and outcome of reported pediatric cases of SLS associated with SLE
Reference Sex Age at SLE diagnosis Age at SLS diagnosis Clinical presentation Imaging findings at SLS diagnosis PFTs at SLS diagnosis Treatment Outcome
[2] F 12 12a Prior diagnosis of mycoplasma pneumonia with recovery. Re-presented 6 months later with dyspnea CXR: Enlarged cardiac silhouette, low lung volumes, elevated diaphragms
HRCT: thoracic lymphadenopathy
FEV1 34%, FVC 27%, TLC 59% CS + CYC (q4weeks × 6 mo) Asymptomatic. Normal PFTs after 1 yr (FEV1 99%, FVC 97%, TLC 92%)
[7] F 11 14 Dyspnea on exertion, chest pain CXR: Low lung volumes, small pleural effusions, small pericardial effusion, mild bibasilar atelectasis FVC 31%, TLC 32%, DLCO 96% CYC monthly × 1 year, then RTX (dose unknown) Clinical improvement,
PFTs 2 yrs. post: FVC 82%, TLC 80%
[10] F 15 15a Pleuritic chest pain, dry cough, dyspnea on exertion Small lung fields, elevated bilateral hemidiaphragms, chest CT normal FEV1 26%, FVC 25%, TLC 31% Beta-agonist Clinical improvement. PFTs after 12d showed FEV1 increase of 58%, FVC increase of 50%, TLC increase of 47%
[17] M 11 14 Fatigue, dyspnea, pleuritic chest pain Enlarged cardiac silhouette, atelectasis, severely reduced diaphragmatic excursion on fluoroscopy FEV1 23%, FVC 20%, TLC 34% CS + AZA Follow-up 23 days later: FEV1 45%, FVC 45%, TLC 57%
[18] F 12 12a Pleuritic chest pain, dyspnea, fever, fatigue, anorexia CXR: Reduced lung volumes, elevated diaphragms, HRCT: pleural thickening Diaphragmatic fluoroscopy: minimal movement FVC 39%, TLC 60%, DLCO normal CS + HCQ 4 yrs. post: ongoing activity limitation, PFTs unchanged
[12] F 12 14 Dyspnea, pleuritic chest pain, orthopnea Elevated right hemidiaphragm FVC 36%, TLC 39%, DLCO 102% CS + RTX (dose unknown) + CYC Active disease
CS corticosteroids, RTX rituximab, CYC cyclophosphamide, AZA azathioprine, HCQ hydroxychloroquine, CXR chest X-ray, HRCT high-resolution computed tomography, PFTs pulmonary function tests, FEV1 forced expiratory volume in 1 s, FVC forced vital capacity, TLC total lung capacity, DLCO diffusing capacity for carbon monoxide. PFT results expressed in % predicted when available
a Diagnosis of SLS made at the time of diagnosis of SLE
Although extremely rare, it is important to recognize SLS as a possible cause of dyspnea and chest pain in a child with SLE, and be aware that in pediatric patients in particular, this complication may occur at the time of initial presentation of SLE. Our patient clearly stated that his goal for treatment was to return to competitive hockey. Recent literature on rituximab use in SLS, a review of pediatric SLS cases, and our case report suggest that additional therapy, including possible use of rituximab, should be considered in patients with SLS who have an incomplete response to initial immunosuppressive therapy. Careful documentation of the occurrence, treatment and outcome of patients with SLS utilizing large registries of adult and pediatric patients with SLE may help determine optimal treatment for this rare complication.
Abbreviations
SLSShrinking lung syndrome
SLESystemic lupus erythematosus
PFTPulmonary function test
FEV1Forced expiratory volume in 1 s
FVCForced vital capacity
TLCTotal lung capacity
RVResidual volume
RSVRespiratory syncytial virus
CXRChest x ray
dsDNADouble stranded DNA
ANAAntinuclear antibody
IVMPMethylprednisolone
PCRPolymerase chain reaction
HRCTHigh resolution computed tomography
Publisher’s Note
Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
Acknowledgements
We thank the patient and family for participating in this report.
Authors’ contributions
CD and BL reviewed the patient’s medical record pertaining to this case and were major contributors in writing the manuscript. All authors read and approved the final manuscript.
Funding
None.
Availability of data and materials
Data sharing is not applicable to this article as no datasets were generated or analyzed during the current study.
Ethics approval and consent to participate
Research Ethics Board approval (#1024379) was obtained from the IWK Health Centre. Written and informed consent was also obtained from the patient.
Consent for publication
Written and informed consent was obtained from the patient to publish this material.
Competing interests
The authors declare that they have no competing interests. | AZATHIOPRINE, HYDROXYCHLOROQUINE, MYCOPHENOLATE MOFETIL, PREDNISONE | DrugsGivenReaction | CC BY | 33407629 | 18,886,056 | 2021-01-06 |
Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Pneumonia'. | Shrinking lung syndrome treated with rituximab in pediatric systemic lupus erythematosus: a case report and review of the literature.
BACKGROUND
Shrinking lung syndrome (SLS), a rare complication of systemic lupus erythematosus (SLE) characterized by dyspnea, low lung volumes, and a restrictive pattern on pulmonary function tests (PFTs), has only been reported in a few children. Given the rarity of SLS there is a paucity of literature regarding its optimal treatment. Outcomes are variable, with case reports documenting some improvement in most patients treated with corticosteroids, with or without additional immunosuppressive agents. However, most reported patients did not recover normal lung function. We report full recovery of a child with SLE and SLS following treatment with rituximab and review the current literature.
METHODS
An 11-year-old boy presented with a malar rash, myositis, arthritis, oral ulcers, leukopenia, anemia, positive lupus autoantibodies and Class II nephritis. He was diagnosed with SLE and treated with corticosteroids, hydroxychloroquine, azathioprine, and subsequently mycophenolate with symptom resolution. At age 14, his SLE flared coincident with a viral chest infection. He presented with a malar rash, polyarthritis, increased proteinuria and pleuritis which all improved with corticosteroids and ongoing treatment with mycophenolate. Six weeks later he presented with severe dyspnea, markedly decreased lung volumes, but otherwise normal chest X-ray (CXR) and high-resolution chest computed tomography (HRCT). He was found to have severely restricted PFTs (FEV1 27%, FVC 29%; TLC 43%). After additional investigations including echocardiography, pulmonary CT angiography, and diaphragmatic fluoroscopy, he was diagnosed with SLS and treated with rituximab and methylprednisolone. At 1 month his symptoms had improved, but he still had dyspnea with exertion and severely restricted PFTs. At 6 months his FVC and TLC had improved to 51 and 57% respectively, and were 83 and 94% respectively at 4 years. He had returned to all baseline activities, including competitive hockey.
CONCLUSIONS
Although extremely rare, it is important to recognize SLS as a possible cause of dyspnea and chest pain in a child with SLE. Optimal treatment strategies are unknown. This is the second reported case of a child treated with rituximab for SLS who recovered normal lung function. International lupus registries should carefully document the occurrence, treatment and outcome of patients with SLS to help determine the optimal treatment for this rare complication.
Background
Shrinking lung syndrome (SLS) is a rare complication of systemic lupus erythematosus (SLE) characterized by decreased lung volumes and a restrictive pattern on pulmonary function testing (PFTs). Patients typically present with progressive dyspnea and chest pain [1–3]. The diagnosis may be delayed, particularly in pediatric patients, because of failure to consider or recognize this disorder. The exact pathophysiology is unknown [1–3].
Given the rarity of SLS there is a paucity of literature regarding optimal treatment. Case reports and series have documented improvement in most patients treated with corticosteroids, with or without immunosuppressive agents. However, the majority of patients have an incomplete recovery [4, 5]. Recently, rituximab, a monoclonal antibody directed against the CD20 antigen found on the surface of B lymphocytes, has been used successfully in several adult patients and one child with SLE complicated by SLS [6, 7]. We report a child with SLE who developed SLS at age 14 and recovered fully following treatment with rituximab. We also review the literature on SLS in pediatric patients to increase awareness of this exceptionally rare complication, as well as review outcome of patients previously reported with SLS who were treated with rituximab.
Case presentation
At age 11 years, our patient was diagnosed with SLE after presenting with a malar rash, oral ulcers, polyarthritis, myositis, and anemia. His past history was remarkable only for mild asthma; family history was positive for maternal asthma and hypothyroidism. Work-up revealed leukopenia (WBC 2.5 10e9/L), hypocomplementemia (C3 0.23 g/L), positive anti-nuclear antibody, anti-dsDNA (633 IU/ml; normal less than10), anti-SSa/Ro, and anti-Smith antibodies, Class II lupus nephritis and a SLEDAI of 29. A baseline chest radiograph (CXR) was normal. He was treated with prednisone, hydroxychloroquine (HCQ), and azathioprine. A year later he had no symptoms of his SLE but was evaluated for an exercise-associated cough that was felt to be due to his asthma. A CXR was normal, PFTs showed moderate obstruction and symptoms resolved with a bronchodilator. Over the next few months, despite ongoing HCQ, azathioprine and low dose prednisone he had recurrence of malar rash and mild arthritis; a repeat renal biopsy showed Class III b lupus nephritis and azathioprine was replaced by mycophenolate mofetil (MMF) which was increased up to 700 mg/m2/dose BID, and subsequently decreased due to gastrointestinal side effects. This resulted in resolution of all symptoms but some ongoing nephritis (SLEDAI 12).
At age 14 he was admitted to his local hospital with fever, pleuritic chest pain, dyspnea, and cough. Bilateral pleural effusions were seen on CXR and he was given empiric antibiotics for possible pneumonia prior to transfer to our center, where he received a 3-day pulse of intravenous methylprednisolone (IVMP) for a suspected SLE flare (C3 0.70; anti dsDNA 95; SLEDAI 29). His chest symptoms resolved completely and respiratory syncytial virus (RSV) infection was subsequently confirmed by PCR and was thought to have triggered the flare. One month later, despite treatment with low dose prednisone and MMF (535 mg/m2/dose BID, although compliance was questionable), his SLE again flared. He presented with a malar rash, polyarthritis, as well as findings of pleuritis manifesting with chest pain, dyspnea, and a left pleural effusion. He was treated with pulse IVMP followed by increased MMF (625 mg/m2/dose BID) and daily oral prednisone (1 mg/kg/d).
Six weeks later his rash and arthritis had improved, but he reported increasing shortness of breath with marked exercise intolerance. On examination he was afebrile, his heart rate was 120, respiratory rate 40, and oxygen saturation 95% in room air. He appeared dyspneic with difficulty speaking in full sentences. Chest examination revealed shallow breathing and decreased air entry bilaterally. Physical examination was otherwise unremarkable. Work up for infection was negative. His SLEDAI had decreased to 14, C3 had normalized (0.97) and anti dsDNA had decreased to 39. CXR and high-resolution computed tomography (HRCT) showed severely reduced lung volumes with no pleural or interstitial disease; there was slight atelectasis but no other significant abnormalities (Figs. 1, 2). An echocardiogram was normal and a CT angiogram showed no evidence of pulmonary embolus. PFTs revealed a severe restrictive pattern with forced expiratory volume in 1 s (FEV1) of 27%, forced vital capacity (FVC) 29%, and total lung capacity (TLC) 43% (Fig. 3). Fluoroscopy documented significantly reduced diaphragmatic movement. He was diagnosed with SLS, and because of worsening dyspnea despite recently increased immunosuppression, he was treated with IVMP 1 g daily for 3 days followed by rituximab 1 g (2 doses, 2 weeks apart). He was also referred to physiotherapy for pulmonary rehabilitation.
Fig. 1 a Chest X-ray at presentation with SLS, showing decreased lung volumes and raised hemidiaphragms b Normal chest X-ray 3 years later
Fig. 2 High-resolution computed tomography (HRCT) of the chest at presentation with SLS, showing decreased lung volumes and slight atelectasis
Fig. 3 Pulmonary function tests (PFTs) over time in our patient with SLE and SLS; at diagnosis to 4 years following treatment with rituximab. FEV1, forced expiratory volume in 1 s; FVC, forced vital capacity; TLC, total lung capacity; RV, residual volume
One month later he reported some improvement in physical endurance, though he still had dyspnea with mild exertion and PFTs remained severely restrictive. At 6 months, however, he reported much improved exercise tolerance with ability to play some hockey. His FEV1 and FVC had improved to 42 and 51% respectively and TLC had increased to 57%. A planned second course of rituximab, (1 g, 2 doses, 2 weeks apart) was given at 6 months; preceding B cell counts were 8%. He was tapered off corticosteroids over the next 9 months and continued on HCQ (5 mg/kg/d) and MMF (600 mg/m2/dose BID). Serial CXRs showed gradual lung volume expansion. One year after his presentation he returned to playing competitive hockey, with no limitations and no respiratory symptoms. Four years later, he remained asymptomatic with no limitations in activity, no evidence of restrictive lung disease on PFTs (FVC 83%, TLC 94%), and a normal CXR. He remained on the same doses of HCQ and MMF with no clinical evidence of SLE disease activity, normal complement levels (C3 0.97), anti dsDNA 16, a SLEDAI of 2, and a follow renal biopsy showed no active nephritis.
Discussion
Shrinking lung syndrome is a rare complication of SLE with an incidence of approximately 1% in adult lupus patients [1, 5]. The incidence in pediatric SLE is unknown, but is likely even less common. As such, the diagnosis of SLS may not be considered or recognized in a child with SLE. Clinical features include progressive dyspnea, exercise intolerance, and pleuritic chest pain, all of which were described by our patient. Physical examination frequently reveals tachypnea with decreased air entry and the use of accessory respiratory muscles but is otherwise unremarkable. Findings on CXR often include significantly reduced lung volumes with elevated hemidiaphragms and may include pleural effusions, basal atelectasis, and pleural thickening. HRCT typically shows no parenchymal lung disease, though it may be more sensitive than CXR in demonstrating pleural effusions and atelectasis [4, 8]. PFTs show a restrictive pattern [4]. Reduced diaphragmatic excursion may be demonstrated on chest fluoroscopy, as was seen in our patient, or may be demonstrated using M-mode ultrasonography [8].
The pathogenesis of shrinking lung syndrome remains incompletely understood. When first described by Hoffbrand and Beck in 1965, the condition was thought to be due to surfactant deficiency causing microatelectasis [9]. Since then a number of mechanisms have been suggested, including phrenic nerve dysfunction, pleural inflammation and fibrosis, and diaphragmatic dysfunction due to myositis or neuropathy [3, 10]. Anti-SSa/Ro antibody positivity has been associated with both SLS and myositis, and has been suggested to support the theory that myositis contributes to diaphragmatic dysfunction in some patients [3, 11]. Of note, our patient was anti-SSa/Ro positive and had myositis as part of his SLE course. The frequent occurrence of pleuritic chest pain in up to 80% of patients with SLS has led to a more recently proposed mechanism of pleuritic pain leading to reflex inhibition of diaphragmatic activation and subsequent dysfunction in at least a subset of patients with SLS [1, 3]. Henderson et al. have proposed that pleural inflammation due to the underlying rheumatic disease may lead to activation of neural reflexes which inhibit deep inspiration and cause chronic lung hypoinflation. This is postulated to gradually reduce lung compliance and results in a positive feedback cycle [12]. Interestingly, our patient had developed pleuritic chest pain 2 months prior to his diagnosis of SLS, and had documented pleuritis associated with an RSV infection, and then associated with a flare of his SLE, which may have initiated the pathogenetic process leading to SLS.
There is no standard treatment for patients with SLS. Corticosteroids are the most frequently reported initial treatment of SLS, and can lead to full recovery in some patients [3, 5, 11, 13]. Immunosuppressive agents including cyclophosphamide, azathioprine, and methotrexate are often given along with corticosteroids or if corticosteroids alone are ineffective. There are also a few reports of theophylline and beta-agonists used effectively in SLS, and others advocate the use of analgesia to combat chest pain and pulmonary rehabilitation to improve lung expansion [1, 3, 5, 12, 13]. Although rare fatal cases have been described, the prognosis of SLS in adults is generally considered to be good, particularly in comparison with the progressive course and significant mortality associated with fibrotic interstitial lung disease in patients with SLE [1]. Some clinical improvement has been reported in most patients with SLS, however, recent literature makes it clear that despite treatment many patients do not achieve full recovery. Langenskiold et al., in a review of 35 cases with documented pre and post treatment PFTs, found that only 20% of patients with SLS regained normal lung function [4]. Duron et al. reported full recovery in only a minority of patients in their review of 155 patients with SLS, with 42.9% of patients showing chronic and persistent hemidiaphragm elevation [1]. A report of 20 cases from a large single center in 2018 showed a similar outcome, with 86.7% of patients showing continued restrictive defects on spirometry despite improved lung volumes [5]. The lack of full recovery in both adult and pediatric patients with SLS has led to 15 reports of rituximab use in adults and 2 reports in children with SLS complicating SLE [1, 3, 4, 6–8, 12, 14–16] (Table 1). Normal PFTs were reported in one child treated with rituximab [7], however the other child did not respond [12]. All 4 adult patients with well-documented post-treatment PFTs had normal or near normal findings [3, 4, 6]. Although the degree of objective improvement was not documented in the remaining 11 adult cases treated with rituximab, all were reported to have improved or stabilized. (Table 1). There has also been a recent report of a 19-year-old male with pediatric-onset SLE who developed SLS refractory to IVMP and cyclophosphamide and had some improvement with belimumab, a monoclonal antibody directed against BLyS receptors on B-cells, though long-term follow-up is still ongoing [11].
Table 1 Clinical features, treatment and outcome of patients with SLS associated with SLE who received treatment with rituximab
Reference Sex Age at SLE diagnosis Age at SLS diagnosis Clinical presentation Imaging findings at SLS diagnosis PFTs at SLS diagnosis Treatment Outcome
[1] F Unknown 61 Chest pain, history of pleurisy, dyspnea Elevated diaphragms, atelectasis, pleural thickening TLC 46%,
DLCO 25%, KCO 59%
CS + Beta-agonists + RTX (dose unknown) + Physiotherapy Improvement
[1] F Unknown 26 Chest pain, history of pleurisy, dyspnea Pleural thickening, reticulations FVC 41%,
TLC 68%,
DLCO 34%
CS + AZA + MMF + RTX (dose unknown) Improvement
[3] F 36 46 Dyspnea on exertion, orthopnea, pleuritic chest pain Elevated diaphragms, atelectasis, pleural thickening FVC 77%, TLC 68% CS + CYC + RTX (375 mg/m2 once weekly × 4 q6mo) Asymptomatic, normal PFTs
[4] F 28 28 (6 mo after diagnosis of SLE) Dyspnea, pleuritic chest pain, dry cough, orthopnea Elevated diaphragms FVC 61%, TLC 45% Beta-agonists + theophylline, RTX (1 g × 2, 2 weeks apart) + CYC Asymptomatic, normal PFTs
[6] F 38 38a Tachypnea, dyspnea Normal HRCT, elevated diaphragms FVC 64%, FEV1 73% CS + CYC without improvement; followed by RTX (1 g × 2, 2 weeks apart) Normal PFTs, normal CXR 6 months after treatment
[7] F 11 14 Dyspnea on exertion, chest pain Low lung volumes, small bilateral pleural effusions, small pericardial effusion, mild bibasilar atelectasis FVC 31%, TLC 32%, DLCO 96% CYC monthly × 1 year, then RTX (dose unknown) Clinical improvement,
PFTs 2 yrs. post: FVC 82%, TLC 80%
[14] F 22 27 Pleuritic chest pain, exertional dyspnea Elevated diaphragms, normal HRCT FVC 1.45 L (predicted value 4.20), TLC 2.35 (predicted value 5.76), DLCO 16.3 (predicted value 26.5) CS + RTX (375 mg/m2 × 2 doses 6 weeks apart) Initial clinical improvement, followed by re-presentation requiring second course of RTX. Improvement reported 2 yrs. later
[15] F 22 57 Dyspnea, dry cough, pleuritic chest pain Elevated diaphragms, bibasilar atelectasis FVC 43%, TLC 56%, DLCO 55% CS + beta-agonists + AZA + MMF, then 6 mo later RTX (1 g × 2 doses, 2 weeks apart, repeated q6mo) Clinical improvement. PFTs 5 years post: FVC 76%, TLC 79%, DLCO 53%
[16] F Unknown 28 Exercise intolerance, pleuritic chest pain Unknown FVC 0.99 L CS + MMF + RTX (2800 mg) Unlimited exercise tolerance, FVC 2.23 L
[12] F 12 14 Dyspnea, pleuritic chest pain, orthopnea Elevated right hemidiaphragm FVC 36%, TLC 39%, DLCO 102% CS + RTX (dose unknown) + CYC Active disease
[8] F 36 37 Dyspnea, pleuritic chest pain CXR: Bilateral diaphragmatic elevation with mild pleural effusion
HRCT: Mild pleural effusion
Restrictive pattern CS + MTX + beta-agonists + RTX (dose unknown) Restrictive defect improvement
[8] F 36 39 Dyspnea, pleuritic chest pain, fever CXR: Unilateral diaphragmatic elevation, left atelectasia
HRCT: Basal atelectasis
Restrictive pattern CS + MMF + beta-agonists + RTX (dose unknown) Restrictive defect stabilization. Developed ILD 4 yrs. later
[8] F 27 31 Dyspnea, pleuritic chest pain CXR: Unilateral diaphragmatic elevation, right atelectasia
HRCT: Basal atelectasis, mild pleural effusion
Restrictive pattern CS + theophylline + beta-agonists + RTX (dose unknown) Restrictive defect stabilization
[8] F 23 30 Dyspnea, pleuritic chest pain CXR: Unilateral diaphragmatic elevation
HRCT: Basal atelectasis
Restrictive pattern CS + MMF + beta-agonists + RTX (dose unknown) Restrictive defect improvement
[8] F 34 59 Dyspnea, pleuritic chest pain CXR: Bilateral diaphragmatic elevation, atelectasia
HRCT: Basal atelectasis
Restrictive pattern CS + MMF + RTX (dose unknown) + IVIG Restrictive defect stabilization
CS corticosteroids, RTX rituximab, CYC cyclophosphamide, AZA azathioprine, MMF mycophenolate mofetil, IVIG intravenous immunoglobulin, CXR chest X-ray, HRCT high-resolution computed tomography, PFTs pulmonary function tests, FEV1 forced expiratory volume in 1 s, FVC forced vital capacity, TLC total lung capacity, DLCO diffusing capacity for carbon monoxide, ILD interstitial lung disease. PFT results expressed in % predicted when available
a Diagnosis of SLS made at the time of diagnosis of SLE
Shrinking lung syndrome is extremely rare in pediatric lupus patients (defined as 16 years or less at diagnosis), with only 6 well-documented case reports identified in our literature review from 1984 to 2019 (Table 2). Age at onset of SLS ranged from 12 to 15 years, 5 were female, all presented with dyspnea, and 5 had associated chest pain. Interestingly, 3 of the 6 presented at the time of diagnosis of SLE, a much more frequent occurrence than that reported in adults with SLS. Of the 6 patients, only 2 reported a return to baseline respiratory function, both clinically and documented on PFTs [2, 7]. In addition to these 6 patients, our literature review identified 3 patients with pediatric onset SLE who developed SLS at age 19 or 20 [11, 19, 20]. Some improvement in lung function was documented in 2 of these patients, one treated with IVMP, cyclophosphamide and azathioprine, and 1 treated with belimumab. In addition, 7 SLE patients 16–18 years of age have been reported, most in case series of SLS, however very limited information was given on their disease course [1, 5, 12, 21, 22].
Table 2 Clinical features, treatment, and outcome of reported pediatric cases of SLS associated with SLE
Reference Sex Age at SLE diagnosis Age at SLS diagnosis Clinical presentation Imaging findings at SLS diagnosis PFTs at SLS diagnosis Treatment Outcome
[2] F 12 12a Prior diagnosis of mycoplasma pneumonia with recovery. Re-presented 6 months later with dyspnea CXR: Enlarged cardiac silhouette, low lung volumes, elevated diaphragms
HRCT: thoracic lymphadenopathy
FEV1 34%, FVC 27%, TLC 59% CS + CYC (q4weeks × 6 mo) Asymptomatic. Normal PFTs after 1 yr (FEV1 99%, FVC 97%, TLC 92%)
[7] F 11 14 Dyspnea on exertion, chest pain CXR: Low lung volumes, small pleural effusions, small pericardial effusion, mild bibasilar atelectasis FVC 31%, TLC 32%, DLCO 96% CYC monthly × 1 year, then RTX (dose unknown) Clinical improvement,
PFTs 2 yrs. post: FVC 82%, TLC 80%
[10] F 15 15a Pleuritic chest pain, dry cough, dyspnea on exertion Small lung fields, elevated bilateral hemidiaphragms, chest CT normal FEV1 26%, FVC 25%, TLC 31% Beta-agonist Clinical improvement. PFTs after 12d showed FEV1 increase of 58%, FVC increase of 50%, TLC increase of 47%
[17] M 11 14 Fatigue, dyspnea, pleuritic chest pain Enlarged cardiac silhouette, atelectasis, severely reduced diaphragmatic excursion on fluoroscopy FEV1 23%, FVC 20%, TLC 34% CS + AZA Follow-up 23 days later: FEV1 45%, FVC 45%, TLC 57%
[18] F 12 12a Pleuritic chest pain, dyspnea, fever, fatigue, anorexia CXR: Reduced lung volumes, elevated diaphragms, HRCT: pleural thickening Diaphragmatic fluoroscopy: minimal movement FVC 39%, TLC 60%, DLCO normal CS + HCQ 4 yrs. post: ongoing activity limitation, PFTs unchanged
[12] F 12 14 Dyspnea, pleuritic chest pain, orthopnea Elevated right hemidiaphragm FVC 36%, TLC 39%, DLCO 102% CS + RTX (dose unknown) + CYC Active disease
CS corticosteroids, RTX rituximab, CYC cyclophosphamide, AZA azathioprine, HCQ hydroxychloroquine, CXR chest X-ray, HRCT high-resolution computed tomography, PFTs pulmonary function tests, FEV1 forced expiratory volume in 1 s, FVC forced vital capacity, TLC total lung capacity, DLCO diffusing capacity for carbon monoxide. PFT results expressed in % predicted when available
a Diagnosis of SLS made at the time of diagnosis of SLE
Although extremely rare, it is important to recognize SLS as a possible cause of dyspnea and chest pain in a child with SLE, and be aware that in pediatric patients in particular, this complication may occur at the time of initial presentation of SLE. Our patient clearly stated that his goal for treatment was to return to competitive hockey. Recent literature on rituximab use in SLS, a review of pediatric SLS cases, and our case report suggest that additional therapy, including possible use of rituximab, should be considered in patients with SLS who have an incomplete response to initial immunosuppressive therapy. Careful documentation of the occurrence, treatment and outcome of patients with SLS utilizing large registries of adult and pediatric patients with SLE may help determine optimal treatment for this rare complication.
Abbreviations
SLSShrinking lung syndrome
SLESystemic lupus erythematosus
PFTPulmonary function test
FEV1Forced expiratory volume in 1 s
FVCForced vital capacity
TLCTotal lung capacity
RVResidual volume
RSVRespiratory syncytial virus
CXRChest x ray
dsDNADouble stranded DNA
ANAAntinuclear antibody
IVMPMethylprednisolone
PCRPolymerase chain reaction
HRCTHigh resolution computed tomography
Publisher’s Note
Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
Acknowledgements
We thank the patient and family for participating in this report.
Authors’ contributions
CD and BL reviewed the patient’s medical record pertaining to this case and were major contributors in writing the manuscript. All authors read and approved the final manuscript.
Funding
None.
Availability of data and materials
Data sharing is not applicable to this article as no datasets were generated or analyzed during the current study.
Ethics approval and consent to participate
Research Ethics Board approval (#1024379) was obtained from the IWK Health Centre. Written and informed consent was also obtained from the patient.
Consent for publication
Written and informed consent was obtained from the patient to publish this material.
Competing interests
The authors declare that they have no competing interests. | AZATHIOPRINE, HYDROXYCHLOROQUINE, MYCOPHENOLATE MOFETIL, PREDNISONE | DrugsGivenReaction | CC BY | 33407629 | 18,886,056 | 2021-01-06 |
Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Respiratory syncytial virus infection'. | Shrinking lung syndrome treated with rituximab in pediatric systemic lupus erythematosus: a case report and review of the literature.
BACKGROUND
Shrinking lung syndrome (SLS), a rare complication of systemic lupus erythematosus (SLE) characterized by dyspnea, low lung volumes, and a restrictive pattern on pulmonary function tests (PFTs), has only been reported in a few children. Given the rarity of SLS there is a paucity of literature regarding its optimal treatment. Outcomes are variable, with case reports documenting some improvement in most patients treated with corticosteroids, with or without additional immunosuppressive agents. However, most reported patients did not recover normal lung function. We report full recovery of a child with SLE and SLS following treatment with rituximab and review the current literature.
METHODS
An 11-year-old boy presented with a malar rash, myositis, arthritis, oral ulcers, leukopenia, anemia, positive lupus autoantibodies and Class II nephritis. He was diagnosed with SLE and treated with corticosteroids, hydroxychloroquine, azathioprine, and subsequently mycophenolate with symptom resolution. At age 14, his SLE flared coincident with a viral chest infection. He presented with a malar rash, polyarthritis, increased proteinuria and pleuritis which all improved with corticosteroids and ongoing treatment with mycophenolate. Six weeks later he presented with severe dyspnea, markedly decreased lung volumes, but otherwise normal chest X-ray (CXR) and high-resolution chest computed tomography (HRCT). He was found to have severely restricted PFTs (FEV1 27%, FVC 29%; TLC 43%). After additional investigations including echocardiography, pulmonary CT angiography, and diaphragmatic fluoroscopy, he was diagnosed with SLS and treated with rituximab and methylprednisolone. At 1 month his symptoms had improved, but he still had dyspnea with exertion and severely restricted PFTs. At 6 months his FVC and TLC had improved to 51 and 57% respectively, and were 83 and 94% respectively at 4 years. He had returned to all baseline activities, including competitive hockey.
CONCLUSIONS
Although extremely rare, it is important to recognize SLS as a possible cause of dyspnea and chest pain in a child with SLE. Optimal treatment strategies are unknown. This is the second reported case of a child treated with rituximab for SLS who recovered normal lung function. International lupus registries should carefully document the occurrence, treatment and outcome of patients with SLS to help determine the optimal treatment for this rare complication.
Background
Shrinking lung syndrome (SLS) is a rare complication of systemic lupus erythematosus (SLE) characterized by decreased lung volumes and a restrictive pattern on pulmonary function testing (PFTs). Patients typically present with progressive dyspnea and chest pain [1–3]. The diagnosis may be delayed, particularly in pediatric patients, because of failure to consider or recognize this disorder. The exact pathophysiology is unknown [1–3].
Given the rarity of SLS there is a paucity of literature regarding optimal treatment. Case reports and series have documented improvement in most patients treated with corticosteroids, with or without immunosuppressive agents. However, the majority of patients have an incomplete recovery [4, 5]. Recently, rituximab, a monoclonal antibody directed against the CD20 antigen found on the surface of B lymphocytes, has been used successfully in several adult patients and one child with SLE complicated by SLS [6, 7]. We report a child with SLE who developed SLS at age 14 and recovered fully following treatment with rituximab. We also review the literature on SLS in pediatric patients to increase awareness of this exceptionally rare complication, as well as review outcome of patients previously reported with SLS who were treated with rituximab.
Case presentation
At age 11 years, our patient was diagnosed with SLE after presenting with a malar rash, oral ulcers, polyarthritis, myositis, and anemia. His past history was remarkable only for mild asthma; family history was positive for maternal asthma and hypothyroidism. Work-up revealed leukopenia (WBC 2.5 10e9/L), hypocomplementemia (C3 0.23 g/L), positive anti-nuclear antibody, anti-dsDNA (633 IU/ml; normal less than10), anti-SSa/Ro, and anti-Smith antibodies, Class II lupus nephritis and a SLEDAI of 29. A baseline chest radiograph (CXR) was normal. He was treated with prednisone, hydroxychloroquine (HCQ), and azathioprine. A year later he had no symptoms of his SLE but was evaluated for an exercise-associated cough that was felt to be due to his asthma. A CXR was normal, PFTs showed moderate obstruction and symptoms resolved with a bronchodilator. Over the next few months, despite ongoing HCQ, azathioprine and low dose prednisone he had recurrence of malar rash and mild arthritis; a repeat renal biopsy showed Class III b lupus nephritis and azathioprine was replaced by mycophenolate mofetil (MMF) which was increased up to 700 mg/m2/dose BID, and subsequently decreased due to gastrointestinal side effects. This resulted in resolution of all symptoms but some ongoing nephritis (SLEDAI 12).
At age 14 he was admitted to his local hospital with fever, pleuritic chest pain, dyspnea, and cough. Bilateral pleural effusions were seen on CXR and he was given empiric antibiotics for possible pneumonia prior to transfer to our center, where he received a 3-day pulse of intravenous methylprednisolone (IVMP) for a suspected SLE flare (C3 0.70; anti dsDNA 95; SLEDAI 29). His chest symptoms resolved completely and respiratory syncytial virus (RSV) infection was subsequently confirmed by PCR and was thought to have triggered the flare. One month later, despite treatment with low dose prednisone and MMF (535 mg/m2/dose BID, although compliance was questionable), his SLE again flared. He presented with a malar rash, polyarthritis, as well as findings of pleuritis manifesting with chest pain, dyspnea, and a left pleural effusion. He was treated with pulse IVMP followed by increased MMF (625 mg/m2/dose BID) and daily oral prednisone (1 mg/kg/d).
Six weeks later his rash and arthritis had improved, but he reported increasing shortness of breath with marked exercise intolerance. On examination he was afebrile, his heart rate was 120, respiratory rate 40, and oxygen saturation 95% in room air. He appeared dyspneic with difficulty speaking in full sentences. Chest examination revealed shallow breathing and decreased air entry bilaterally. Physical examination was otherwise unremarkable. Work up for infection was negative. His SLEDAI had decreased to 14, C3 had normalized (0.97) and anti dsDNA had decreased to 39. CXR and high-resolution computed tomography (HRCT) showed severely reduced lung volumes with no pleural or interstitial disease; there was slight atelectasis but no other significant abnormalities (Figs. 1, 2). An echocardiogram was normal and a CT angiogram showed no evidence of pulmonary embolus. PFTs revealed a severe restrictive pattern with forced expiratory volume in 1 s (FEV1) of 27%, forced vital capacity (FVC) 29%, and total lung capacity (TLC) 43% (Fig. 3). Fluoroscopy documented significantly reduced diaphragmatic movement. He was diagnosed with SLS, and because of worsening dyspnea despite recently increased immunosuppression, he was treated with IVMP 1 g daily for 3 days followed by rituximab 1 g (2 doses, 2 weeks apart). He was also referred to physiotherapy for pulmonary rehabilitation.
Fig. 1 a Chest X-ray at presentation with SLS, showing decreased lung volumes and raised hemidiaphragms b Normal chest X-ray 3 years later
Fig. 2 High-resolution computed tomography (HRCT) of the chest at presentation with SLS, showing decreased lung volumes and slight atelectasis
Fig. 3 Pulmonary function tests (PFTs) over time in our patient with SLE and SLS; at diagnosis to 4 years following treatment with rituximab. FEV1, forced expiratory volume in 1 s; FVC, forced vital capacity; TLC, total lung capacity; RV, residual volume
One month later he reported some improvement in physical endurance, though he still had dyspnea with mild exertion and PFTs remained severely restrictive. At 6 months, however, he reported much improved exercise tolerance with ability to play some hockey. His FEV1 and FVC had improved to 42 and 51% respectively and TLC had increased to 57%. A planned second course of rituximab, (1 g, 2 doses, 2 weeks apart) was given at 6 months; preceding B cell counts were 8%. He was tapered off corticosteroids over the next 9 months and continued on HCQ (5 mg/kg/d) and MMF (600 mg/m2/dose BID). Serial CXRs showed gradual lung volume expansion. One year after his presentation he returned to playing competitive hockey, with no limitations and no respiratory symptoms. Four years later, he remained asymptomatic with no limitations in activity, no evidence of restrictive lung disease on PFTs (FVC 83%, TLC 94%), and a normal CXR. He remained on the same doses of HCQ and MMF with no clinical evidence of SLE disease activity, normal complement levels (C3 0.97), anti dsDNA 16, a SLEDAI of 2, and a follow renal biopsy showed no active nephritis.
Discussion
Shrinking lung syndrome is a rare complication of SLE with an incidence of approximately 1% in adult lupus patients [1, 5]. The incidence in pediatric SLE is unknown, but is likely even less common. As such, the diagnosis of SLS may not be considered or recognized in a child with SLE. Clinical features include progressive dyspnea, exercise intolerance, and pleuritic chest pain, all of which were described by our patient. Physical examination frequently reveals tachypnea with decreased air entry and the use of accessory respiratory muscles but is otherwise unremarkable. Findings on CXR often include significantly reduced lung volumes with elevated hemidiaphragms and may include pleural effusions, basal atelectasis, and pleural thickening. HRCT typically shows no parenchymal lung disease, though it may be more sensitive than CXR in demonstrating pleural effusions and atelectasis [4, 8]. PFTs show a restrictive pattern [4]. Reduced diaphragmatic excursion may be demonstrated on chest fluoroscopy, as was seen in our patient, or may be demonstrated using M-mode ultrasonography [8].
The pathogenesis of shrinking lung syndrome remains incompletely understood. When first described by Hoffbrand and Beck in 1965, the condition was thought to be due to surfactant deficiency causing microatelectasis [9]. Since then a number of mechanisms have been suggested, including phrenic nerve dysfunction, pleural inflammation and fibrosis, and diaphragmatic dysfunction due to myositis or neuropathy [3, 10]. Anti-SSa/Ro antibody positivity has been associated with both SLS and myositis, and has been suggested to support the theory that myositis contributes to diaphragmatic dysfunction in some patients [3, 11]. Of note, our patient was anti-SSa/Ro positive and had myositis as part of his SLE course. The frequent occurrence of pleuritic chest pain in up to 80% of patients with SLS has led to a more recently proposed mechanism of pleuritic pain leading to reflex inhibition of diaphragmatic activation and subsequent dysfunction in at least a subset of patients with SLS [1, 3]. Henderson et al. have proposed that pleural inflammation due to the underlying rheumatic disease may lead to activation of neural reflexes which inhibit deep inspiration and cause chronic lung hypoinflation. This is postulated to gradually reduce lung compliance and results in a positive feedback cycle [12]. Interestingly, our patient had developed pleuritic chest pain 2 months prior to his diagnosis of SLS, and had documented pleuritis associated with an RSV infection, and then associated with a flare of his SLE, which may have initiated the pathogenetic process leading to SLS.
There is no standard treatment for patients with SLS. Corticosteroids are the most frequently reported initial treatment of SLS, and can lead to full recovery in some patients [3, 5, 11, 13]. Immunosuppressive agents including cyclophosphamide, azathioprine, and methotrexate are often given along with corticosteroids or if corticosteroids alone are ineffective. There are also a few reports of theophylline and beta-agonists used effectively in SLS, and others advocate the use of analgesia to combat chest pain and pulmonary rehabilitation to improve lung expansion [1, 3, 5, 12, 13]. Although rare fatal cases have been described, the prognosis of SLS in adults is generally considered to be good, particularly in comparison with the progressive course and significant mortality associated with fibrotic interstitial lung disease in patients with SLE [1]. Some clinical improvement has been reported in most patients with SLS, however, recent literature makes it clear that despite treatment many patients do not achieve full recovery. Langenskiold et al., in a review of 35 cases with documented pre and post treatment PFTs, found that only 20% of patients with SLS regained normal lung function [4]. Duron et al. reported full recovery in only a minority of patients in their review of 155 patients with SLS, with 42.9% of patients showing chronic and persistent hemidiaphragm elevation [1]. A report of 20 cases from a large single center in 2018 showed a similar outcome, with 86.7% of patients showing continued restrictive defects on spirometry despite improved lung volumes [5]. The lack of full recovery in both adult and pediatric patients with SLS has led to 15 reports of rituximab use in adults and 2 reports in children with SLS complicating SLE [1, 3, 4, 6–8, 12, 14–16] (Table 1). Normal PFTs were reported in one child treated with rituximab [7], however the other child did not respond [12]. All 4 adult patients with well-documented post-treatment PFTs had normal or near normal findings [3, 4, 6]. Although the degree of objective improvement was not documented in the remaining 11 adult cases treated with rituximab, all were reported to have improved or stabilized. (Table 1). There has also been a recent report of a 19-year-old male with pediatric-onset SLE who developed SLS refractory to IVMP and cyclophosphamide and had some improvement with belimumab, a monoclonal antibody directed against BLyS receptors on B-cells, though long-term follow-up is still ongoing [11].
Table 1 Clinical features, treatment and outcome of patients with SLS associated with SLE who received treatment with rituximab
Reference Sex Age at SLE diagnosis Age at SLS diagnosis Clinical presentation Imaging findings at SLS diagnosis PFTs at SLS diagnosis Treatment Outcome
[1] F Unknown 61 Chest pain, history of pleurisy, dyspnea Elevated diaphragms, atelectasis, pleural thickening TLC 46%,
DLCO 25%, KCO 59%
CS + Beta-agonists + RTX (dose unknown) + Physiotherapy Improvement
[1] F Unknown 26 Chest pain, history of pleurisy, dyspnea Pleural thickening, reticulations FVC 41%,
TLC 68%,
DLCO 34%
CS + AZA + MMF + RTX (dose unknown) Improvement
[3] F 36 46 Dyspnea on exertion, orthopnea, pleuritic chest pain Elevated diaphragms, atelectasis, pleural thickening FVC 77%, TLC 68% CS + CYC + RTX (375 mg/m2 once weekly × 4 q6mo) Asymptomatic, normal PFTs
[4] F 28 28 (6 mo after diagnosis of SLE) Dyspnea, pleuritic chest pain, dry cough, orthopnea Elevated diaphragms FVC 61%, TLC 45% Beta-agonists + theophylline, RTX (1 g × 2, 2 weeks apart) + CYC Asymptomatic, normal PFTs
[6] F 38 38a Tachypnea, dyspnea Normal HRCT, elevated diaphragms FVC 64%, FEV1 73% CS + CYC without improvement; followed by RTX (1 g × 2, 2 weeks apart) Normal PFTs, normal CXR 6 months after treatment
[7] F 11 14 Dyspnea on exertion, chest pain Low lung volumes, small bilateral pleural effusions, small pericardial effusion, mild bibasilar atelectasis FVC 31%, TLC 32%, DLCO 96% CYC monthly × 1 year, then RTX (dose unknown) Clinical improvement,
PFTs 2 yrs. post: FVC 82%, TLC 80%
[14] F 22 27 Pleuritic chest pain, exertional dyspnea Elevated diaphragms, normal HRCT FVC 1.45 L (predicted value 4.20), TLC 2.35 (predicted value 5.76), DLCO 16.3 (predicted value 26.5) CS + RTX (375 mg/m2 × 2 doses 6 weeks apart) Initial clinical improvement, followed by re-presentation requiring second course of RTX. Improvement reported 2 yrs. later
[15] F 22 57 Dyspnea, dry cough, pleuritic chest pain Elevated diaphragms, bibasilar atelectasis FVC 43%, TLC 56%, DLCO 55% CS + beta-agonists + AZA + MMF, then 6 mo later RTX (1 g × 2 doses, 2 weeks apart, repeated q6mo) Clinical improvement. PFTs 5 years post: FVC 76%, TLC 79%, DLCO 53%
[16] F Unknown 28 Exercise intolerance, pleuritic chest pain Unknown FVC 0.99 L CS + MMF + RTX (2800 mg) Unlimited exercise tolerance, FVC 2.23 L
[12] F 12 14 Dyspnea, pleuritic chest pain, orthopnea Elevated right hemidiaphragm FVC 36%, TLC 39%, DLCO 102% CS + RTX (dose unknown) + CYC Active disease
[8] F 36 37 Dyspnea, pleuritic chest pain CXR: Bilateral diaphragmatic elevation with mild pleural effusion
HRCT: Mild pleural effusion
Restrictive pattern CS + MTX + beta-agonists + RTX (dose unknown) Restrictive defect improvement
[8] F 36 39 Dyspnea, pleuritic chest pain, fever CXR: Unilateral diaphragmatic elevation, left atelectasia
HRCT: Basal atelectasis
Restrictive pattern CS + MMF + beta-agonists + RTX (dose unknown) Restrictive defect stabilization. Developed ILD 4 yrs. later
[8] F 27 31 Dyspnea, pleuritic chest pain CXR: Unilateral diaphragmatic elevation, right atelectasia
HRCT: Basal atelectasis, mild pleural effusion
Restrictive pattern CS + theophylline + beta-agonists + RTX (dose unknown) Restrictive defect stabilization
[8] F 23 30 Dyspnea, pleuritic chest pain CXR: Unilateral diaphragmatic elevation
HRCT: Basal atelectasis
Restrictive pattern CS + MMF + beta-agonists + RTX (dose unknown) Restrictive defect improvement
[8] F 34 59 Dyspnea, pleuritic chest pain CXR: Bilateral diaphragmatic elevation, atelectasia
HRCT: Basal atelectasis
Restrictive pattern CS + MMF + RTX (dose unknown) + IVIG Restrictive defect stabilization
CS corticosteroids, RTX rituximab, CYC cyclophosphamide, AZA azathioprine, MMF mycophenolate mofetil, IVIG intravenous immunoglobulin, CXR chest X-ray, HRCT high-resolution computed tomography, PFTs pulmonary function tests, FEV1 forced expiratory volume in 1 s, FVC forced vital capacity, TLC total lung capacity, DLCO diffusing capacity for carbon monoxide, ILD interstitial lung disease. PFT results expressed in % predicted when available
a Diagnosis of SLS made at the time of diagnosis of SLE
Shrinking lung syndrome is extremely rare in pediatric lupus patients (defined as 16 years or less at diagnosis), with only 6 well-documented case reports identified in our literature review from 1984 to 2019 (Table 2). Age at onset of SLS ranged from 12 to 15 years, 5 were female, all presented with dyspnea, and 5 had associated chest pain. Interestingly, 3 of the 6 presented at the time of diagnosis of SLE, a much more frequent occurrence than that reported in adults with SLS. Of the 6 patients, only 2 reported a return to baseline respiratory function, both clinically and documented on PFTs [2, 7]. In addition to these 6 patients, our literature review identified 3 patients with pediatric onset SLE who developed SLS at age 19 or 20 [11, 19, 20]. Some improvement in lung function was documented in 2 of these patients, one treated with IVMP, cyclophosphamide and azathioprine, and 1 treated with belimumab. In addition, 7 SLE patients 16–18 years of age have been reported, most in case series of SLS, however very limited information was given on their disease course [1, 5, 12, 21, 22].
Table 2 Clinical features, treatment, and outcome of reported pediatric cases of SLS associated with SLE
Reference Sex Age at SLE diagnosis Age at SLS diagnosis Clinical presentation Imaging findings at SLS diagnosis PFTs at SLS diagnosis Treatment Outcome
[2] F 12 12a Prior diagnosis of mycoplasma pneumonia with recovery. Re-presented 6 months later with dyspnea CXR: Enlarged cardiac silhouette, low lung volumes, elevated diaphragms
HRCT: thoracic lymphadenopathy
FEV1 34%, FVC 27%, TLC 59% CS + CYC (q4weeks × 6 mo) Asymptomatic. Normal PFTs after 1 yr (FEV1 99%, FVC 97%, TLC 92%)
[7] F 11 14 Dyspnea on exertion, chest pain CXR: Low lung volumes, small pleural effusions, small pericardial effusion, mild bibasilar atelectasis FVC 31%, TLC 32%, DLCO 96% CYC monthly × 1 year, then RTX (dose unknown) Clinical improvement,
PFTs 2 yrs. post: FVC 82%, TLC 80%
[10] F 15 15a Pleuritic chest pain, dry cough, dyspnea on exertion Small lung fields, elevated bilateral hemidiaphragms, chest CT normal FEV1 26%, FVC 25%, TLC 31% Beta-agonist Clinical improvement. PFTs after 12d showed FEV1 increase of 58%, FVC increase of 50%, TLC increase of 47%
[17] M 11 14 Fatigue, dyspnea, pleuritic chest pain Enlarged cardiac silhouette, atelectasis, severely reduced diaphragmatic excursion on fluoroscopy FEV1 23%, FVC 20%, TLC 34% CS + AZA Follow-up 23 days later: FEV1 45%, FVC 45%, TLC 57%
[18] F 12 12a Pleuritic chest pain, dyspnea, fever, fatigue, anorexia CXR: Reduced lung volumes, elevated diaphragms, HRCT: pleural thickening Diaphragmatic fluoroscopy: minimal movement FVC 39%, TLC 60%, DLCO normal CS + HCQ 4 yrs. post: ongoing activity limitation, PFTs unchanged
[12] F 12 14 Dyspnea, pleuritic chest pain, orthopnea Elevated right hemidiaphragm FVC 36%, TLC 39%, DLCO 102% CS + RTX (dose unknown) + CYC Active disease
CS corticosteroids, RTX rituximab, CYC cyclophosphamide, AZA azathioprine, HCQ hydroxychloroquine, CXR chest X-ray, HRCT high-resolution computed tomography, PFTs pulmonary function tests, FEV1 forced expiratory volume in 1 s, FVC forced vital capacity, TLC total lung capacity, DLCO diffusing capacity for carbon monoxide. PFT results expressed in % predicted when available
a Diagnosis of SLS made at the time of diagnosis of SLE
Although extremely rare, it is important to recognize SLS as a possible cause of dyspnea and chest pain in a child with SLE, and be aware that in pediatric patients in particular, this complication may occur at the time of initial presentation of SLE. Our patient clearly stated that his goal for treatment was to return to competitive hockey. Recent literature on rituximab use in SLS, a review of pediatric SLS cases, and our case report suggest that additional therapy, including possible use of rituximab, should be considered in patients with SLS who have an incomplete response to initial immunosuppressive therapy. Careful documentation of the occurrence, treatment and outcome of patients with SLS utilizing large registries of adult and pediatric patients with SLE may help determine optimal treatment for this rare complication.
Abbreviations
SLSShrinking lung syndrome
SLESystemic lupus erythematosus
PFTPulmonary function test
FEV1Forced expiratory volume in 1 s
FVCForced vital capacity
TLCTotal lung capacity
RVResidual volume
RSVRespiratory syncytial virus
CXRChest x ray
dsDNADouble stranded DNA
ANAAntinuclear antibody
IVMPMethylprednisolone
PCRPolymerase chain reaction
HRCTHigh resolution computed tomography
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Acknowledgements
We thank the patient and family for participating in this report.
Authors’ contributions
CD and BL reviewed the patient’s medical record pertaining to this case and were major contributors in writing the manuscript. All authors read and approved the final manuscript.
Funding
None.
Availability of data and materials
Data sharing is not applicable to this article as no datasets were generated or analyzed during the current study.
Ethics approval and consent to participate
Research Ethics Board approval (#1024379) was obtained from the IWK Health Centre. Written and informed consent was also obtained from the patient.
Consent for publication
Written and informed consent was obtained from the patient to publish this material.
Competing interests
The authors declare that they have no competing interests. | AZATHIOPRINE, HYDROXYCHLOROQUINE, MYCOPHENOLATE MOFETIL, PREDNISONE | DrugsGivenReaction | CC BY | 33407629 | 18,886,056 | 2021-01-06 |
Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Treatment noncompliance'. | Shrinking lung syndrome treated with rituximab in pediatric systemic lupus erythematosus: a case report and review of the literature.
BACKGROUND
Shrinking lung syndrome (SLS), a rare complication of systemic lupus erythematosus (SLE) characterized by dyspnea, low lung volumes, and a restrictive pattern on pulmonary function tests (PFTs), has only been reported in a few children. Given the rarity of SLS there is a paucity of literature regarding its optimal treatment. Outcomes are variable, with case reports documenting some improvement in most patients treated with corticosteroids, with or without additional immunosuppressive agents. However, most reported patients did not recover normal lung function. We report full recovery of a child with SLE and SLS following treatment with rituximab and review the current literature.
METHODS
An 11-year-old boy presented with a malar rash, myositis, arthritis, oral ulcers, leukopenia, anemia, positive lupus autoantibodies and Class II nephritis. He was diagnosed with SLE and treated with corticosteroids, hydroxychloroquine, azathioprine, and subsequently mycophenolate with symptom resolution. At age 14, his SLE flared coincident with a viral chest infection. He presented with a malar rash, polyarthritis, increased proteinuria and pleuritis which all improved with corticosteroids and ongoing treatment with mycophenolate. Six weeks later he presented with severe dyspnea, markedly decreased lung volumes, but otherwise normal chest X-ray (CXR) and high-resolution chest computed tomography (HRCT). He was found to have severely restricted PFTs (FEV1 27%, FVC 29%; TLC 43%). After additional investigations including echocardiography, pulmonary CT angiography, and diaphragmatic fluoroscopy, he was diagnosed with SLS and treated with rituximab and methylprednisolone. At 1 month his symptoms had improved, but he still had dyspnea with exertion and severely restricted PFTs. At 6 months his FVC and TLC had improved to 51 and 57% respectively, and were 83 and 94% respectively at 4 years. He had returned to all baseline activities, including competitive hockey.
CONCLUSIONS
Although extremely rare, it is important to recognize SLS as a possible cause of dyspnea and chest pain in a child with SLE. Optimal treatment strategies are unknown. This is the second reported case of a child treated with rituximab for SLS who recovered normal lung function. International lupus registries should carefully document the occurrence, treatment and outcome of patients with SLS to help determine the optimal treatment for this rare complication.
Background
Shrinking lung syndrome (SLS) is a rare complication of systemic lupus erythematosus (SLE) characterized by decreased lung volumes and a restrictive pattern on pulmonary function testing (PFTs). Patients typically present with progressive dyspnea and chest pain [1–3]. The diagnosis may be delayed, particularly in pediatric patients, because of failure to consider or recognize this disorder. The exact pathophysiology is unknown [1–3].
Given the rarity of SLS there is a paucity of literature regarding optimal treatment. Case reports and series have documented improvement in most patients treated with corticosteroids, with or without immunosuppressive agents. However, the majority of patients have an incomplete recovery [4, 5]. Recently, rituximab, a monoclonal antibody directed against the CD20 antigen found on the surface of B lymphocytes, has been used successfully in several adult patients and one child with SLE complicated by SLS [6, 7]. We report a child with SLE who developed SLS at age 14 and recovered fully following treatment with rituximab. We also review the literature on SLS in pediatric patients to increase awareness of this exceptionally rare complication, as well as review outcome of patients previously reported with SLS who were treated with rituximab.
Case presentation
At age 11 years, our patient was diagnosed with SLE after presenting with a malar rash, oral ulcers, polyarthritis, myositis, and anemia. His past history was remarkable only for mild asthma; family history was positive for maternal asthma and hypothyroidism. Work-up revealed leukopenia (WBC 2.5 10e9/L), hypocomplementemia (C3 0.23 g/L), positive anti-nuclear antibody, anti-dsDNA (633 IU/ml; normal less than10), anti-SSa/Ro, and anti-Smith antibodies, Class II lupus nephritis and a SLEDAI of 29. A baseline chest radiograph (CXR) was normal. He was treated with prednisone, hydroxychloroquine (HCQ), and azathioprine. A year later he had no symptoms of his SLE but was evaluated for an exercise-associated cough that was felt to be due to his asthma. A CXR was normal, PFTs showed moderate obstruction and symptoms resolved with a bronchodilator. Over the next few months, despite ongoing HCQ, azathioprine and low dose prednisone he had recurrence of malar rash and mild arthritis; a repeat renal biopsy showed Class III b lupus nephritis and azathioprine was replaced by mycophenolate mofetil (MMF) which was increased up to 700 mg/m2/dose BID, and subsequently decreased due to gastrointestinal side effects. This resulted in resolution of all symptoms but some ongoing nephritis (SLEDAI 12).
At age 14 he was admitted to his local hospital with fever, pleuritic chest pain, dyspnea, and cough. Bilateral pleural effusions were seen on CXR and he was given empiric antibiotics for possible pneumonia prior to transfer to our center, where he received a 3-day pulse of intravenous methylprednisolone (IVMP) for a suspected SLE flare (C3 0.70; anti dsDNA 95; SLEDAI 29). His chest symptoms resolved completely and respiratory syncytial virus (RSV) infection was subsequently confirmed by PCR and was thought to have triggered the flare. One month later, despite treatment with low dose prednisone and MMF (535 mg/m2/dose BID, although compliance was questionable), his SLE again flared. He presented with a malar rash, polyarthritis, as well as findings of pleuritis manifesting with chest pain, dyspnea, and a left pleural effusion. He was treated with pulse IVMP followed by increased MMF (625 mg/m2/dose BID) and daily oral prednisone (1 mg/kg/d).
Six weeks later his rash and arthritis had improved, but he reported increasing shortness of breath with marked exercise intolerance. On examination he was afebrile, his heart rate was 120, respiratory rate 40, and oxygen saturation 95% in room air. He appeared dyspneic with difficulty speaking in full sentences. Chest examination revealed shallow breathing and decreased air entry bilaterally. Physical examination was otherwise unremarkable. Work up for infection was negative. His SLEDAI had decreased to 14, C3 had normalized (0.97) and anti dsDNA had decreased to 39. CXR and high-resolution computed tomography (HRCT) showed severely reduced lung volumes with no pleural or interstitial disease; there was slight atelectasis but no other significant abnormalities (Figs. 1, 2). An echocardiogram was normal and a CT angiogram showed no evidence of pulmonary embolus. PFTs revealed a severe restrictive pattern with forced expiratory volume in 1 s (FEV1) of 27%, forced vital capacity (FVC) 29%, and total lung capacity (TLC) 43% (Fig. 3). Fluoroscopy documented significantly reduced diaphragmatic movement. He was diagnosed with SLS, and because of worsening dyspnea despite recently increased immunosuppression, he was treated with IVMP 1 g daily for 3 days followed by rituximab 1 g (2 doses, 2 weeks apart). He was also referred to physiotherapy for pulmonary rehabilitation.
Fig. 1 a Chest X-ray at presentation with SLS, showing decreased lung volumes and raised hemidiaphragms b Normal chest X-ray 3 years later
Fig. 2 High-resolution computed tomography (HRCT) of the chest at presentation with SLS, showing decreased lung volumes and slight atelectasis
Fig. 3 Pulmonary function tests (PFTs) over time in our patient with SLE and SLS; at diagnosis to 4 years following treatment with rituximab. FEV1, forced expiratory volume in 1 s; FVC, forced vital capacity; TLC, total lung capacity; RV, residual volume
One month later he reported some improvement in physical endurance, though he still had dyspnea with mild exertion and PFTs remained severely restrictive. At 6 months, however, he reported much improved exercise tolerance with ability to play some hockey. His FEV1 and FVC had improved to 42 and 51% respectively and TLC had increased to 57%. A planned second course of rituximab, (1 g, 2 doses, 2 weeks apart) was given at 6 months; preceding B cell counts were 8%. He was tapered off corticosteroids over the next 9 months and continued on HCQ (5 mg/kg/d) and MMF (600 mg/m2/dose BID). Serial CXRs showed gradual lung volume expansion. One year after his presentation he returned to playing competitive hockey, with no limitations and no respiratory symptoms. Four years later, he remained asymptomatic with no limitations in activity, no evidence of restrictive lung disease on PFTs (FVC 83%, TLC 94%), and a normal CXR. He remained on the same doses of HCQ and MMF with no clinical evidence of SLE disease activity, normal complement levels (C3 0.97), anti dsDNA 16, a SLEDAI of 2, and a follow renal biopsy showed no active nephritis.
Discussion
Shrinking lung syndrome is a rare complication of SLE with an incidence of approximately 1% in adult lupus patients [1, 5]. The incidence in pediatric SLE is unknown, but is likely even less common. As such, the diagnosis of SLS may not be considered or recognized in a child with SLE. Clinical features include progressive dyspnea, exercise intolerance, and pleuritic chest pain, all of which were described by our patient. Physical examination frequently reveals tachypnea with decreased air entry and the use of accessory respiratory muscles but is otherwise unremarkable. Findings on CXR often include significantly reduced lung volumes with elevated hemidiaphragms and may include pleural effusions, basal atelectasis, and pleural thickening. HRCT typically shows no parenchymal lung disease, though it may be more sensitive than CXR in demonstrating pleural effusions and atelectasis [4, 8]. PFTs show a restrictive pattern [4]. Reduced diaphragmatic excursion may be demonstrated on chest fluoroscopy, as was seen in our patient, or may be demonstrated using M-mode ultrasonography [8].
The pathogenesis of shrinking lung syndrome remains incompletely understood. When first described by Hoffbrand and Beck in 1965, the condition was thought to be due to surfactant deficiency causing microatelectasis [9]. Since then a number of mechanisms have been suggested, including phrenic nerve dysfunction, pleural inflammation and fibrosis, and diaphragmatic dysfunction due to myositis or neuropathy [3, 10]. Anti-SSa/Ro antibody positivity has been associated with both SLS and myositis, and has been suggested to support the theory that myositis contributes to diaphragmatic dysfunction in some patients [3, 11]. Of note, our patient was anti-SSa/Ro positive and had myositis as part of his SLE course. The frequent occurrence of pleuritic chest pain in up to 80% of patients with SLS has led to a more recently proposed mechanism of pleuritic pain leading to reflex inhibition of diaphragmatic activation and subsequent dysfunction in at least a subset of patients with SLS [1, 3]. Henderson et al. have proposed that pleural inflammation due to the underlying rheumatic disease may lead to activation of neural reflexes which inhibit deep inspiration and cause chronic lung hypoinflation. This is postulated to gradually reduce lung compliance and results in a positive feedback cycle [12]. Interestingly, our patient had developed pleuritic chest pain 2 months prior to his diagnosis of SLS, and had documented pleuritis associated with an RSV infection, and then associated with a flare of his SLE, which may have initiated the pathogenetic process leading to SLS.
There is no standard treatment for patients with SLS. Corticosteroids are the most frequently reported initial treatment of SLS, and can lead to full recovery in some patients [3, 5, 11, 13]. Immunosuppressive agents including cyclophosphamide, azathioprine, and methotrexate are often given along with corticosteroids or if corticosteroids alone are ineffective. There are also a few reports of theophylline and beta-agonists used effectively in SLS, and others advocate the use of analgesia to combat chest pain and pulmonary rehabilitation to improve lung expansion [1, 3, 5, 12, 13]. Although rare fatal cases have been described, the prognosis of SLS in adults is generally considered to be good, particularly in comparison with the progressive course and significant mortality associated with fibrotic interstitial lung disease in patients with SLE [1]. Some clinical improvement has been reported in most patients with SLS, however, recent literature makes it clear that despite treatment many patients do not achieve full recovery. Langenskiold et al., in a review of 35 cases with documented pre and post treatment PFTs, found that only 20% of patients with SLS regained normal lung function [4]. Duron et al. reported full recovery in only a minority of patients in their review of 155 patients with SLS, with 42.9% of patients showing chronic and persistent hemidiaphragm elevation [1]. A report of 20 cases from a large single center in 2018 showed a similar outcome, with 86.7% of patients showing continued restrictive defects on spirometry despite improved lung volumes [5]. The lack of full recovery in both adult and pediatric patients with SLS has led to 15 reports of rituximab use in adults and 2 reports in children with SLS complicating SLE [1, 3, 4, 6–8, 12, 14–16] (Table 1). Normal PFTs were reported in one child treated with rituximab [7], however the other child did not respond [12]. All 4 adult patients with well-documented post-treatment PFTs had normal or near normal findings [3, 4, 6]. Although the degree of objective improvement was not documented in the remaining 11 adult cases treated with rituximab, all were reported to have improved or stabilized. (Table 1). There has also been a recent report of a 19-year-old male with pediatric-onset SLE who developed SLS refractory to IVMP and cyclophosphamide and had some improvement with belimumab, a monoclonal antibody directed against BLyS receptors on B-cells, though long-term follow-up is still ongoing [11].
Table 1 Clinical features, treatment and outcome of patients with SLS associated with SLE who received treatment with rituximab
Reference Sex Age at SLE diagnosis Age at SLS diagnosis Clinical presentation Imaging findings at SLS diagnosis PFTs at SLS diagnosis Treatment Outcome
[1] F Unknown 61 Chest pain, history of pleurisy, dyspnea Elevated diaphragms, atelectasis, pleural thickening TLC 46%,
DLCO 25%, KCO 59%
CS + Beta-agonists + RTX (dose unknown) + Physiotherapy Improvement
[1] F Unknown 26 Chest pain, history of pleurisy, dyspnea Pleural thickening, reticulations FVC 41%,
TLC 68%,
DLCO 34%
CS + AZA + MMF + RTX (dose unknown) Improvement
[3] F 36 46 Dyspnea on exertion, orthopnea, pleuritic chest pain Elevated diaphragms, atelectasis, pleural thickening FVC 77%, TLC 68% CS + CYC + RTX (375 mg/m2 once weekly × 4 q6mo) Asymptomatic, normal PFTs
[4] F 28 28 (6 mo after diagnosis of SLE) Dyspnea, pleuritic chest pain, dry cough, orthopnea Elevated diaphragms FVC 61%, TLC 45% Beta-agonists + theophylline, RTX (1 g × 2, 2 weeks apart) + CYC Asymptomatic, normal PFTs
[6] F 38 38a Tachypnea, dyspnea Normal HRCT, elevated diaphragms FVC 64%, FEV1 73% CS + CYC without improvement; followed by RTX (1 g × 2, 2 weeks apart) Normal PFTs, normal CXR 6 months after treatment
[7] F 11 14 Dyspnea on exertion, chest pain Low lung volumes, small bilateral pleural effusions, small pericardial effusion, mild bibasilar atelectasis FVC 31%, TLC 32%, DLCO 96% CYC monthly × 1 year, then RTX (dose unknown) Clinical improvement,
PFTs 2 yrs. post: FVC 82%, TLC 80%
[14] F 22 27 Pleuritic chest pain, exertional dyspnea Elevated diaphragms, normal HRCT FVC 1.45 L (predicted value 4.20), TLC 2.35 (predicted value 5.76), DLCO 16.3 (predicted value 26.5) CS + RTX (375 mg/m2 × 2 doses 6 weeks apart) Initial clinical improvement, followed by re-presentation requiring second course of RTX. Improvement reported 2 yrs. later
[15] F 22 57 Dyspnea, dry cough, pleuritic chest pain Elevated diaphragms, bibasilar atelectasis FVC 43%, TLC 56%, DLCO 55% CS + beta-agonists + AZA + MMF, then 6 mo later RTX (1 g × 2 doses, 2 weeks apart, repeated q6mo) Clinical improvement. PFTs 5 years post: FVC 76%, TLC 79%, DLCO 53%
[16] F Unknown 28 Exercise intolerance, pleuritic chest pain Unknown FVC 0.99 L CS + MMF + RTX (2800 mg) Unlimited exercise tolerance, FVC 2.23 L
[12] F 12 14 Dyspnea, pleuritic chest pain, orthopnea Elevated right hemidiaphragm FVC 36%, TLC 39%, DLCO 102% CS + RTX (dose unknown) + CYC Active disease
[8] F 36 37 Dyspnea, pleuritic chest pain CXR: Bilateral diaphragmatic elevation with mild pleural effusion
HRCT: Mild pleural effusion
Restrictive pattern CS + MTX + beta-agonists + RTX (dose unknown) Restrictive defect improvement
[8] F 36 39 Dyspnea, pleuritic chest pain, fever CXR: Unilateral diaphragmatic elevation, left atelectasia
HRCT: Basal atelectasis
Restrictive pattern CS + MMF + beta-agonists + RTX (dose unknown) Restrictive defect stabilization. Developed ILD 4 yrs. later
[8] F 27 31 Dyspnea, pleuritic chest pain CXR: Unilateral diaphragmatic elevation, right atelectasia
HRCT: Basal atelectasis, mild pleural effusion
Restrictive pattern CS + theophylline + beta-agonists + RTX (dose unknown) Restrictive defect stabilization
[8] F 23 30 Dyspnea, pleuritic chest pain CXR: Unilateral diaphragmatic elevation
HRCT: Basal atelectasis
Restrictive pattern CS + MMF + beta-agonists + RTX (dose unknown) Restrictive defect improvement
[8] F 34 59 Dyspnea, pleuritic chest pain CXR: Bilateral diaphragmatic elevation, atelectasia
HRCT: Basal atelectasis
Restrictive pattern CS + MMF + RTX (dose unknown) + IVIG Restrictive defect stabilization
CS corticosteroids, RTX rituximab, CYC cyclophosphamide, AZA azathioprine, MMF mycophenolate mofetil, IVIG intravenous immunoglobulin, CXR chest X-ray, HRCT high-resolution computed tomography, PFTs pulmonary function tests, FEV1 forced expiratory volume in 1 s, FVC forced vital capacity, TLC total lung capacity, DLCO diffusing capacity for carbon monoxide, ILD interstitial lung disease. PFT results expressed in % predicted when available
a Diagnosis of SLS made at the time of diagnosis of SLE
Shrinking lung syndrome is extremely rare in pediatric lupus patients (defined as 16 years or less at diagnosis), with only 6 well-documented case reports identified in our literature review from 1984 to 2019 (Table 2). Age at onset of SLS ranged from 12 to 15 years, 5 were female, all presented with dyspnea, and 5 had associated chest pain. Interestingly, 3 of the 6 presented at the time of diagnosis of SLE, a much more frequent occurrence than that reported in adults with SLS. Of the 6 patients, only 2 reported a return to baseline respiratory function, both clinically and documented on PFTs [2, 7]. In addition to these 6 patients, our literature review identified 3 patients with pediatric onset SLE who developed SLS at age 19 or 20 [11, 19, 20]. Some improvement in lung function was documented in 2 of these patients, one treated with IVMP, cyclophosphamide and azathioprine, and 1 treated with belimumab. In addition, 7 SLE patients 16–18 years of age have been reported, most in case series of SLS, however very limited information was given on their disease course [1, 5, 12, 21, 22].
Table 2 Clinical features, treatment, and outcome of reported pediatric cases of SLS associated with SLE
Reference Sex Age at SLE diagnosis Age at SLS diagnosis Clinical presentation Imaging findings at SLS diagnosis PFTs at SLS diagnosis Treatment Outcome
[2] F 12 12a Prior diagnosis of mycoplasma pneumonia with recovery. Re-presented 6 months later with dyspnea CXR: Enlarged cardiac silhouette, low lung volumes, elevated diaphragms
HRCT: thoracic lymphadenopathy
FEV1 34%, FVC 27%, TLC 59% CS + CYC (q4weeks × 6 mo) Asymptomatic. Normal PFTs after 1 yr (FEV1 99%, FVC 97%, TLC 92%)
[7] F 11 14 Dyspnea on exertion, chest pain CXR: Low lung volumes, small pleural effusions, small pericardial effusion, mild bibasilar atelectasis FVC 31%, TLC 32%, DLCO 96% CYC monthly × 1 year, then RTX (dose unknown) Clinical improvement,
PFTs 2 yrs. post: FVC 82%, TLC 80%
[10] F 15 15a Pleuritic chest pain, dry cough, dyspnea on exertion Small lung fields, elevated bilateral hemidiaphragms, chest CT normal FEV1 26%, FVC 25%, TLC 31% Beta-agonist Clinical improvement. PFTs after 12d showed FEV1 increase of 58%, FVC increase of 50%, TLC increase of 47%
[17] M 11 14 Fatigue, dyspnea, pleuritic chest pain Enlarged cardiac silhouette, atelectasis, severely reduced diaphragmatic excursion on fluoroscopy FEV1 23%, FVC 20%, TLC 34% CS + AZA Follow-up 23 days later: FEV1 45%, FVC 45%, TLC 57%
[18] F 12 12a Pleuritic chest pain, dyspnea, fever, fatigue, anorexia CXR: Reduced lung volumes, elevated diaphragms, HRCT: pleural thickening Diaphragmatic fluoroscopy: minimal movement FVC 39%, TLC 60%, DLCO normal CS + HCQ 4 yrs. post: ongoing activity limitation, PFTs unchanged
[12] F 12 14 Dyspnea, pleuritic chest pain, orthopnea Elevated right hemidiaphragm FVC 36%, TLC 39%, DLCO 102% CS + RTX (dose unknown) + CYC Active disease
CS corticosteroids, RTX rituximab, CYC cyclophosphamide, AZA azathioprine, HCQ hydroxychloroquine, CXR chest X-ray, HRCT high-resolution computed tomography, PFTs pulmonary function tests, FEV1 forced expiratory volume in 1 s, FVC forced vital capacity, TLC total lung capacity, DLCO diffusing capacity for carbon monoxide. PFT results expressed in % predicted when available
a Diagnosis of SLS made at the time of diagnosis of SLE
Although extremely rare, it is important to recognize SLS as a possible cause of dyspnea and chest pain in a child with SLE, and be aware that in pediatric patients in particular, this complication may occur at the time of initial presentation of SLE. Our patient clearly stated that his goal for treatment was to return to competitive hockey. Recent literature on rituximab use in SLS, a review of pediatric SLS cases, and our case report suggest that additional therapy, including possible use of rituximab, should be considered in patients with SLS who have an incomplete response to initial immunosuppressive therapy. Careful documentation of the occurrence, treatment and outcome of patients with SLS utilizing large registries of adult and pediatric patients with SLE may help determine optimal treatment for this rare complication.
Abbreviations
SLSShrinking lung syndrome
SLESystemic lupus erythematosus
PFTPulmonary function test
FEV1Forced expiratory volume in 1 s
FVCForced vital capacity
TLCTotal lung capacity
RVResidual volume
RSVRespiratory syncytial virus
CXRChest x ray
dsDNADouble stranded DNA
ANAAntinuclear antibody
IVMPMethylprednisolone
PCRPolymerase chain reaction
HRCTHigh resolution computed tomography
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Acknowledgements
We thank the patient and family for participating in this report.
Authors’ contributions
CD and BL reviewed the patient’s medical record pertaining to this case and were major contributors in writing the manuscript. All authors read and approved the final manuscript.
Funding
None.
Availability of data and materials
Data sharing is not applicable to this article as no datasets were generated or analyzed during the current study.
Ethics approval and consent to participate
Research Ethics Board approval (#1024379) was obtained from the IWK Health Centre. Written and informed consent was also obtained from the patient.
Consent for publication
Written and informed consent was obtained from the patient to publish this material.
Competing interests
The authors declare that they have no competing interests. | AZATHIOPRINE, HYDROXYCHLOROQUINE, MYCOPHENOLATE MOFETIL, PREDNISONE | DrugsGivenReaction | CC BY | 33407629 | 18,886,056 | 2021-01-06 |
What was the administration route of drug 'PREDNISONE'? | Shrinking lung syndrome treated with rituximab in pediatric systemic lupus erythematosus: a case report and review of the literature.
BACKGROUND
Shrinking lung syndrome (SLS), a rare complication of systemic lupus erythematosus (SLE) characterized by dyspnea, low lung volumes, and a restrictive pattern on pulmonary function tests (PFTs), has only been reported in a few children. Given the rarity of SLS there is a paucity of literature regarding its optimal treatment. Outcomes are variable, with case reports documenting some improvement in most patients treated with corticosteroids, with or without additional immunosuppressive agents. However, most reported patients did not recover normal lung function. We report full recovery of a child with SLE and SLS following treatment with rituximab and review the current literature.
METHODS
An 11-year-old boy presented with a malar rash, myositis, arthritis, oral ulcers, leukopenia, anemia, positive lupus autoantibodies and Class II nephritis. He was diagnosed with SLE and treated with corticosteroids, hydroxychloroquine, azathioprine, and subsequently mycophenolate with symptom resolution. At age 14, his SLE flared coincident with a viral chest infection. He presented with a malar rash, polyarthritis, increased proteinuria and pleuritis which all improved with corticosteroids and ongoing treatment with mycophenolate. Six weeks later he presented with severe dyspnea, markedly decreased lung volumes, but otherwise normal chest X-ray (CXR) and high-resolution chest computed tomography (HRCT). He was found to have severely restricted PFTs (FEV1 27%, FVC 29%; TLC 43%). After additional investigations including echocardiography, pulmonary CT angiography, and diaphragmatic fluoroscopy, he was diagnosed with SLS and treated with rituximab and methylprednisolone. At 1 month his symptoms had improved, but he still had dyspnea with exertion and severely restricted PFTs. At 6 months his FVC and TLC had improved to 51 and 57% respectively, and were 83 and 94% respectively at 4 years. He had returned to all baseline activities, including competitive hockey.
CONCLUSIONS
Although extremely rare, it is important to recognize SLS as a possible cause of dyspnea and chest pain in a child with SLE. Optimal treatment strategies are unknown. This is the second reported case of a child treated with rituximab for SLS who recovered normal lung function. International lupus registries should carefully document the occurrence, treatment and outcome of patients with SLS to help determine the optimal treatment for this rare complication.
Background
Shrinking lung syndrome (SLS) is a rare complication of systemic lupus erythematosus (SLE) characterized by decreased lung volumes and a restrictive pattern on pulmonary function testing (PFTs). Patients typically present with progressive dyspnea and chest pain [1–3]. The diagnosis may be delayed, particularly in pediatric patients, because of failure to consider or recognize this disorder. The exact pathophysiology is unknown [1–3].
Given the rarity of SLS there is a paucity of literature regarding optimal treatment. Case reports and series have documented improvement in most patients treated with corticosteroids, with or without immunosuppressive agents. However, the majority of patients have an incomplete recovery [4, 5]. Recently, rituximab, a monoclonal antibody directed against the CD20 antigen found on the surface of B lymphocytes, has been used successfully in several adult patients and one child with SLE complicated by SLS [6, 7]. We report a child with SLE who developed SLS at age 14 and recovered fully following treatment with rituximab. We also review the literature on SLS in pediatric patients to increase awareness of this exceptionally rare complication, as well as review outcome of patients previously reported with SLS who were treated with rituximab.
Case presentation
At age 11 years, our patient was diagnosed with SLE after presenting with a malar rash, oral ulcers, polyarthritis, myositis, and anemia. His past history was remarkable only for mild asthma; family history was positive for maternal asthma and hypothyroidism. Work-up revealed leukopenia (WBC 2.5 10e9/L), hypocomplementemia (C3 0.23 g/L), positive anti-nuclear antibody, anti-dsDNA (633 IU/ml; normal less than10), anti-SSa/Ro, and anti-Smith antibodies, Class II lupus nephritis and a SLEDAI of 29. A baseline chest radiograph (CXR) was normal. He was treated with prednisone, hydroxychloroquine (HCQ), and azathioprine. A year later he had no symptoms of his SLE but was evaluated for an exercise-associated cough that was felt to be due to his asthma. A CXR was normal, PFTs showed moderate obstruction and symptoms resolved with a bronchodilator. Over the next few months, despite ongoing HCQ, azathioprine and low dose prednisone he had recurrence of malar rash and mild arthritis; a repeat renal biopsy showed Class III b lupus nephritis and azathioprine was replaced by mycophenolate mofetil (MMF) which was increased up to 700 mg/m2/dose BID, and subsequently decreased due to gastrointestinal side effects. This resulted in resolution of all symptoms but some ongoing nephritis (SLEDAI 12).
At age 14 he was admitted to his local hospital with fever, pleuritic chest pain, dyspnea, and cough. Bilateral pleural effusions were seen on CXR and he was given empiric antibiotics for possible pneumonia prior to transfer to our center, where he received a 3-day pulse of intravenous methylprednisolone (IVMP) for a suspected SLE flare (C3 0.70; anti dsDNA 95; SLEDAI 29). His chest symptoms resolved completely and respiratory syncytial virus (RSV) infection was subsequently confirmed by PCR and was thought to have triggered the flare. One month later, despite treatment with low dose prednisone and MMF (535 mg/m2/dose BID, although compliance was questionable), his SLE again flared. He presented with a malar rash, polyarthritis, as well as findings of pleuritis manifesting with chest pain, dyspnea, and a left pleural effusion. He was treated with pulse IVMP followed by increased MMF (625 mg/m2/dose BID) and daily oral prednisone (1 mg/kg/d).
Six weeks later his rash and arthritis had improved, but he reported increasing shortness of breath with marked exercise intolerance. On examination he was afebrile, his heart rate was 120, respiratory rate 40, and oxygen saturation 95% in room air. He appeared dyspneic with difficulty speaking in full sentences. Chest examination revealed shallow breathing and decreased air entry bilaterally. Physical examination was otherwise unremarkable. Work up for infection was negative. His SLEDAI had decreased to 14, C3 had normalized (0.97) and anti dsDNA had decreased to 39. CXR and high-resolution computed tomography (HRCT) showed severely reduced lung volumes with no pleural or interstitial disease; there was slight atelectasis but no other significant abnormalities (Figs. 1, 2). An echocardiogram was normal and a CT angiogram showed no evidence of pulmonary embolus. PFTs revealed a severe restrictive pattern with forced expiratory volume in 1 s (FEV1) of 27%, forced vital capacity (FVC) 29%, and total lung capacity (TLC) 43% (Fig. 3). Fluoroscopy documented significantly reduced diaphragmatic movement. He was diagnosed with SLS, and because of worsening dyspnea despite recently increased immunosuppression, he was treated with IVMP 1 g daily for 3 days followed by rituximab 1 g (2 doses, 2 weeks apart). He was also referred to physiotherapy for pulmonary rehabilitation.
Fig. 1 a Chest X-ray at presentation with SLS, showing decreased lung volumes and raised hemidiaphragms b Normal chest X-ray 3 years later
Fig. 2 High-resolution computed tomography (HRCT) of the chest at presentation with SLS, showing decreased lung volumes and slight atelectasis
Fig. 3 Pulmonary function tests (PFTs) over time in our patient with SLE and SLS; at diagnosis to 4 years following treatment with rituximab. FEV1, forced expiratory volume in 1 s; FVC, forced vital capacity; TLC, total lung capacity; RV, residual volume
One month later he reported some improvement in physical endurance, though he still had dyspnea with mild exertion and PFTs remained severely restrictive. At 6 months, however, he reported much improved exercise tolerance with ability to play some hockey. His FEV1 and FVC had improved to 42 and 51% respectively and TLC had increased to 57%. A planned second course of rituximab, (1 g, 2 doses, 2 weeks apart) was given at 6 months; preceding B cell counts were 8%. He was tapered off corticosteroids over the next 9 months and continued on HCQ (5 mg/kg/d) and MMF (600 mg/m2/dose BID). Serial CXRs showed gradual lung volume expansion. One year after his presentation he returned to playing competitive hockey, with no limitations and no respiratory symptoms. Four years later, he remained asymptomatic with no limitations in activity, no evidence of restrictive lung disease on PFTs (FVC 83%, TLC 94%), and a normal CXR. He remained on the same doses of HCQ and MMF with no clinical evidence of SLE disease activity, normal complement levels (C3 0.97), anti dsDNA 16, a SLEDAI of 2, and a follow renal biopsy showed no active nephritis.
Discussion
Shrinking lung syndrome is a rare complication of SLE with an incidence of approximately 1% in adult lupus patients [1, 5]. The incidence in pediatric SLE is unknown, but is likely even less common. As such, the diagnosis of SLS may not be considered or recognized in a child with SLE. Clinical features include progressive dyspnea, exercise intolerance, and pleuritic chest pain, all of which were described by our patient. Physical examination frequently reveals tachypnea with decreased air entry and the use of accessory respiratory muscles but is otherwise unremarkable. Findings on CXR often include significantly reduced lung volumes with elevated hemidiaphragms and may include pleural effusions, basal atelectasis, and pleural thickening. HRCT typically shows no parenchymal lung disease, though it may be more sensitive than CXR in demonstrating pleural effusions and atelectasis [4, 8]. PFTs show a restrictive pattern [4]. Reduced diaphragmatic excursion may be demonstrated on chest fluoroscopy, as was seen in our patient, or may be demonstrated using M-mode ultrasonography [8].
The pathogenesis of shrinking lung syndrome remains incompletely understood. When first described by Hoffbrand and Beck in 1965, the condition was thought to be due to surfactant deficiency causing microatelectasis [9]. Since then a number of mechanisms have been suggested, including phrenic nerve dysfunction, pleural inflammation and fibrosis, and diaphragmatic dysfunction due to myositis or neuropathy [3, 10]. Anti-SSa/Ro antibody positivity has been associated with both SLS and myositis, and has been suggested to support the theory that myositis contributes to diaphragmatic dysfunction in some patients [3, 11]. Of note, our patient was anti-SSa/Ro positive and had myositis as part of his SLE course. The frequent occurrence of pleuritic chest pain in up to 80% of patients with SLS has led to a more recently proposed mechanism of pleuritic pain leading to reflex inhibition of diaphragmatic activation and subsequent dysfunction in at least a subset of patients with SLS [1, 3]. Henderson et al. have proposed that pleural inflammation due to the underlying rheumatic disease may lead to activation of neural reflexes which inhibit deep inspiration and cause chronic lung hypoinflation. This is postulated to gradually reduce lung compliance and results in a positive feedback cycle [12]. Interestingly, our patient had developed pleuritic chest pain 2 months prior to his diagnosis of SLS, and had documented pleuritis associated with an RSV infection, and then associated with a flare of his SLE, which may have initiated the pathogenetic process leading to SLS.
There is no standard treatment for patients with SLS. Corticosteroids are the most frequently reported initial treatment of SLS, and can lead to full recovery in some patients [3, 5, 11, 13]. Immunosuppressive agents including cyclophosphamide, azathioprine, and methotrexate are often given along with corticosteroids or if corticosteroids alone are ineffective. There are also a few reports of theophylline and beta-agonists used effectively in SLS, and others advocate the use of analgesia to combat chest pain and pulmonary rehabilitation to improve lung expansion [1, 3, 5, 12, 13]. Although rare fatal cases have been described, the prognosis of SLS in adults is generally considered to be good, particularly in comparison with the progressive course and significant mortality associated with fibrotic interstitial lung disease in patients with SLE [1]. Some clinical improvement has been reported in most patients with SLS, however, recent literature makes it clear that despite treatment many patients do not achieve full recovery. Langenskiold et al., in a review of 35 cases with documented pre and post treatment PFTs, found that only 20% of patients with SLS regained normal lung function [4]. Duron et al. reported full recovery in only a minority of patients in their review of 155 patients with SLS, with 42.9% of patients showing chronic and persistent hemidiaphragm elevation [1]. A report of 20 cases from a large single center in 2018 showed a similar outcome, with 86.7% of patients showing continued restrictive defects on spirometry despite improved lung volumes [5]. The lack of full recovery in both adult and pediatric patients with SLS has led to 15 reports of rituximab use in adults and 2 reports in children with SLS complicating SLE [1, 3, 4, 6–8, 12, 14–16] (Table 1). Normal PFTs were reported in one child treated with rituximab [7], however the other child did not respond [12]. All 4 adult patients with well-documented post-treatment PFTs had normal or near normal findings [3, 4, 6]. Although the degree of objective improvement was not documented in the remaining 11 adult cases treated with rituximab, all were reported to have improved or stabilized. (Table 1). There has also been a recent report of a 19-year-old male with pediatric-onset SLE who developed SLS refractory to IVMP and cyclophosphamide and had some improvement with belimumab, a monoclonal antibody directed against BLyS receptors on B-cells, though long-term follow-up is still ongoing [11].
Table 1 Clinical features, treatment and outcome of patients with SLS associated with SLE who received treatment with rituximab
Reference Sex Age at SLE diagnosis Age at SLS diagnosis Clinical presentation Imaging findings at SLS diagnosis PFTs at SLS diagnosis Treatment Outcome
[1] F Unknown 61 Chest pain, history of pleurisy, dyspnea Elevated diaphragms, atelectasis, pleural thickening TLC 46%,
DLCO 25%, KCO 59%
CS + Beta-agonists + RTX (dose unknown) + Physiotherapy Improvement
[1] F Unknown 26 Chest pain, history of pleurisy, dyspnea Pleural thickening, reticulations FVC 41%,
TLC 68%,
DLCO 34%
CS + AZA + MMF + RTX (dose unknown) Improvement
[3] F 36 46 Dyspnea on exertion, orthopnea, pleuritic chest pain Elevated diaphragms, atelectasis, pleural thickening FVC 77%, TLC 68% CS + CYC + RTX (375 mg/m2 once weekly × 4 q6mo) Asymptomatic, normal PFTs
[4] F 28 28 (6 mo after diagnosis of SLE) Dyspnea, pleuritic chest pain, dry cough, orthopnea Elevated diaphragms FVC 61%, TLC 45% Beta-agonists + theophylline, RTX (1 g × 2, 2 weeks apart) + CYC Asymptomatic, normal PFTs
[6] F 38 38a Tachypnea, dyspnea Normal HRCT, elevated diaphragms FVC 64%, FEV1 73% CS + CYC without improvement; followed by RTX (1 g × 2, 2 weeks apart) Normal PFTs, normal CXR 6 months after treatment
[7] F 11 14 Dyspnea on exertion, chest pain Low lung volumes, small bilateral pleural effusions, small pericardial effusion, mild bibasilar atelectasis FVC 31%, TLC 32%, DLCO 96% CYC monthly × 1 year, then RTX (dose unknown) Clinical improvement,
PFTs 2 yrs. post: FVC 82%, TLC 80%
[14] F 22 27 Pleuritic chest pain, exertional dyspnea Elevated diaphragms, normal HRCT FVC 1.45 L (predicted value 4.20), TLC 2.35 (predicted value 5.76), DLCO 16.3 (predicted value 26.5) CS + RTX (375 mg/m2 × 2 doses 6 weeks apart) Initial clinical improvement, followed by re-presentation requiring second course of RTX. Improvement reported 2 yrs. later
[15] F 22 57 Dyspnea, dry cough, pleuritic chest pain Elevated diaphragms, bibasilar atelectasis FVC 43%, TLC 56%, DLCO 55% CS + beta-agonists + AZA + MMF, then 6 mo later RTX (1 g × 2 doses, 2 weeks apart, repeated q6mo) Clinical improvement. PFTs 5 years post: FVC 76%, TLC 79%, DLCO 53%
[16] F Unknown 28 Exercise intolerance, pleuritic chest pain Unknown FVC 0.99 L CS + MMF + RTX (2800 mg) Unlimited exercise tolerance, FVC 2.23 L
[12] F 12 14 Dyspnea, pleuritic chest pain, orthopnea Elevated right hemidiaphragm FVC 36%, TLC 39%, DLCO 102% CS + RTX (dose unknown) + CYC Active disease
[8] F 36 37 Dyspnea, pleuritic chest pain CXR: Bilateral diaphragmatic elevation with mild pleural effusion
HRCT: Mild pleural effusion
Restrictive pattern CS + MTX + beta-agonists + RTX (dose unknown) Restrictive defect improvement
[8] F 36 39 Dyspnea, pleuritic chest pain, fever CXR: Unilateral diaphragmatic elevation, left atelectasia
HRCT: Basal atelectasis
Restrictive pattern CS + MMF + beta-agonists + RTX (dose unknown) Restrictive defect stabilization. Developed ILD 4 yrs. later
[8] F 27 31 Dyspnea, pleuritic chest pain CXR: Unilateral diaphragmatic elevation, right atelectasia
HRCT: Basal atelectasis, mild pleural effusion
Restrictive pattern CS + theophylline + beta-agonists + RTX (dose unknown) Restrictive defect stabilization
[8] F 23 30 Dyspnea, pleuritic chest pain CXR: Unilateral diaphragmatic elevation
HRCT: Basal atelectasis
Restrictive pattern CS + MMF + beta-agonists + RTX (dose unknown) Restrictive defect improvement
[8] F 34 59 Dyspnea, pleuritic chest pain CXR: Bilateral diaphragmatic elevation, atelectasia
HRCT: Basal atelectasis
Restrictive pattern CS + MMF + RTX (dose unknown) + IVIG Restrictive defect stabilization
CS corticosteroids, RTX rituximab, CYC cyclophosphamide, AZA azathioprine, MMF mycophenolate mofetil, IVIG intravenous immunoglobulin, CXR chest X-ray, HRCT high-resolution computed tomography, PFTs pulmonary function tests, FEV1 forced expiratory volume in 1 s, FVC forced vital capacity, TLC total lung capacity, DLCO diffusing capacity for carbon monoxide, ILD interstitial lung disease. PFT results expressed in % predicted when available
a Diagnosis of SLS made at the time of diagnosis of SLE
Shrinking lung syndrome is extremely rare in pediatric lupus patients (defined as 16 years or less at diagnosis), with only 6 well-documented case reports identified in our literature review from 1984 to 2019 (Table 2). Age at onset of SLS ranged from 12 to 15 years, 5 were female, all presented with dyspnea, and 5 had associated chest pain. Interestingly, 3 of the 6 presented at the time of diagnosis of SLE, a much more frequent occurrence than that reported in adults with SLS. Of the 6 patients, only 2 reported a return to baseline respiratory function, both clinically and documented on PFTs [2, 7]. In addition to these 6 patients, our literature review identified 3 patients with pediatric onset SLE who developed SLS at age 19 or 20 [11, 19, 20]. Some improvement in lung function was documented in 2 of these patients, one treated with IVMP, cyclophosphamide and azathioprine, and 1 treated with belimumab. In addition, 7 SLE patients 16–18 years of age have been reported, most in case series of SLS, however very limited information was given on their disease course [1, 5, 12, 21, 22].
Table 2 Clinical features, treatment, and outcome of reported pediatric cases of SLS associated with SLE
Reference Sex Age at SLE diagnosis Age at SLS diagnosis Clinical presentation Imaging findings at SLS diagnosis PFTs at SLS diagnosis Treatment Outcome
[2] F 12 12a Prior diagnosis of mycoplasma pneumonia with recovery. Re-presented 6 months later with dyspnea CXR: Enlarged cardiac silhouette, low lung volumes, elevated diaphragms
HRCT: thoracic lymphadenopathy
FEV1 34%, FVC 27%, TLC 59% CS + CYC (q4weeks × 6 mo) Asymptomatic. Normal PFTs after 1 yr (FEV1 99%, FVC 97%, TLC 92%)
[7] F 11 14 Dyspnea on exertion, chest pain CXR: Low lung volumes, small pleural effusions, small pericardial effusion, mild bibasilar atelectasis FVC 31%, TLC 32%, DLCO 96% CYC monthly × 1 year, then RTX (dose unknown) Clinical improvement,
PFTs 2 yrs. post: FVC 82%, TLC 80%
[10] F 15 15a Pleuritic chest pain, dry cough, dyspnea on exertion Small lung fields, elevated bilateral hemidiaphragms, chest CT normal FEV1 26%, FVC 25%, TLC 31% Beta-agonist Clinical improvement. PFTs after 12d showed FEV1 increase of 58%, FVC increase of 50%, TLC increase of 47%
[17] M 11 14 Fatigue, dyspnea, pleuritic chest pain Enlarged cardiac silhouette, atelectasis, severely reduced diaphragmatic excursion on fluoroscopy FEV1 23%, FVC 20%, TLC 34% CS + AZA Follow-up 23 days later: FEV1 45%, FVC 45%, TLC 57%
[18] F 12 12a Pleuritic chest pain, dyspnea, fever, fatigue, anorexia CXR: Reduced lung volumes, elevated diaphragms, HRCT: pleural thickening Diaphragmatic fluoroscopy: minimal movement FVC 39%, TLC 60%, DLCO normal CS + HCQ 4 yrs. post: ongoing activity limitation, PFTs unchanged
[12] F 12 14 Dyspnea, pleuritic chest pain, orthopnea Elevated right hemidiaphragm FVC 36%, TLC 39%, DLCO 102% CS + RTX (dose unknown) + CYC Active disease
CS corticosteroids, RTX rituximab, CYC cyclophosphamide, AZA azathioprine, HCQ hydroxychloroquine, CXR chest X-ray, HRCT high-resolution computed tomography, PFTs pulmonary function tests, FEV1 forced expiratory volume in 1 s, FVC forced vital capacity, TLC total lung capacity, DLCO diffusing capacity for carbon monoxide. PFT results expressed in % predicted when available
a Diagnosis of SLS made at the time of diagnosis of SLE
Although extremely rare, it is important to recognize SLS as a possible cause of dyspnea and chest pain in a child with SLE, and be aware that in pediatric patients in particular, this complication may occur at the time of initial presentation of SLE. Our patient clearly stated that his goal for treatment was to return to competitive hockey. Recent literature on rituximab use in SLS, a review of pediatric SLS cases, and our case report suggest that additional therapy, including possible use of rituximab, should be considered in patients with SLS who have an incomplete response to initial immunosuppressive therapy. Careful documentation of the occurrence, treatment and outcome of patients with SLS utilizing large registries of adult and pediatric patients with SLE may help determine optimal treatment for this rare complication.
Abbreviations
SLSShrinking lung syndrome
SLESystemic lupus erythematosus
PFTPulmonary function test
FEV1Forced expiratory volume in 1 s
FVCForced vital capacity
TLCTotal lung capacity
RVResidual volume
RSVRespiratory syncytial virus
CXRChest x ray
dsDNADouble stranded DNA
ANAAntinuclear antibody
IVMPMethylprednisolone
PCRPolymerase chain reaction
HRCTHigh resolution computed tomography
Publisher’s Note
Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
Acknowledgements
We thank the patient and family for participating in this report.
Authors’ contributions
CD and BL reviewed the patient’s medical record pertaining to this case and were major contributors in writing the manuscript. All authors read and approved the final manuscript.
Funding
None.
Availability of data and materials
Data sharing is not applicable to this article as no datasets were generated or analyzed during the current study.
Ethics approval and consent to participate
Research Ethics Board approval (#1024379) was obtained from the IWK Health Centre. Written and informed consent was also obtained from the patient.
Consent for publication
Written and informed consent was obtained from the patient to publish this material.
Competing interests
The authors declare that they have no competing interests. | Oral | DrugAdministrationRoute | CC BY | 33407629 | 18,886,056 | 2021-01-06 |
What was the dosage of drug 'HYDROXYCHLOROQUINE'? | Shrinking lung syndrome treated with rituximab in pediatric systemic lupus erythematosus: a case report and review of the literature.
BACKGROUND
Shrinking lung syndrome (SLS), a rare complication of systemic lupus erythematosus (SLE) characterized by dyspnea, low lung volumes, and a restrictive pattern on pulmonary function tests (PFTs), has only been reported in a few children. Given the rarity of SLS there is a paucity of literature regarding its optimal treatment. Outcomes are variable, with case reports documenting some improvement in most patients treated with corticosteroids, with or without additional immunosuppressive agents. However, most reported patients did not recover normal lung function. We report full recovery of a child with SLE and SLS following treatment with rituximab and review the current literature.
METHODS
An 11-year-old boy presented with a malar rash, myositis, arthritis, oral ulcers, leukopenia, anemia, positive lupus autoantibodies and Class II nephritis. He was diagnosed with SLE and treated with corticosteroids, hydroxychloroquine, azathioprine, and subsequently mycophenolate with symptom resolution. At age 14, his SLE flared coincident with a viral chest infection. He presented with a malar rash, polyarthritis, increased proteinuria and pleuritis which all improved with corticosteroids and ongoing treatment with mycophenolate. Six weeks later he presented with severe dyspnea, markedly decreased lung volumes, but otherwise normal chest X-ray (CXR) and high-resolution chest computed tomography (HRCT). He was found to have severely restricted PFTs (FEV1 27%, FVC 29%; TLC 43%). After additional investigations including echocardiography, pulmonary CT angiography, and diaphragmatic fluoroscopy, he was diagnosed with SLS and treated with rituximab and methylprednisolone. At 1 month his symptoms had improved, but he still had dyspnea with exertion and severely restricted PFTs. At 6 months his FVC and TLC had improved to 51 and 57% respectively, and were 83 and 94% respectively at 4 years. He had returned to all baseline activities, including competitive hockey.
CONCLUSIONS
Although extremely rare, it is important to recognize SLS as a possible cause of dyspnea and chest pain in a child with SLE. Optimal treatment strategies are unknown. This is the second reported case of a child treated with rituximab for SLS who recovered normal lung function. International lupus registries should carefully document the occurrence, treatment and outcome of patients with SLS to help determine the optimal treatment for this rare complication.
Background
Shrinking lung syndrome (SLS) is a rare complication of systemic lupus erythematosus (SLE) characterized by decreased lung volumes and a restrictive pattern on pulmonary function testing (PFTs). Patients typically present with progressive dyspnea and chest pain [1–3]. The diagnosis may be delayed, particularly in pediatric patients, because of failure to consider or recognize this disorder. The exact pathophysiology is unknown [1–3].
Given the rarity of SLS there is a paucity of literature regarding optimal treatment. Case reports and series have documented improvement in most patients treated with corticosteroids, with or without immunosuppressive agents. However, the majority of patients have an incomplete recovery [4, 5]. Recently, rituximab, a monoclonal antibody directed against the CD20 antigen found on the surface of B lymphocytes, has been used successfully in several adult patients and one child with SLE complicated by SLS [6, 7]. We report a child with SLE who developed SLS at age 14 and recovered fully following treatment with rituximab. We also review the literature on SLS in pediatric patients to increase awareness of this exceptionally rare complication, as well as review outcome of patients previously reported with SLS who were treated with rituximab.
Case presentation
At age 11 years, our patient was diagnosed with SLE after presenting with a malar rash, oral ulcers, polyarthritis, myositis, and anemia. His past history was remarkable only for mild asthma; family history was positive for maternal asthma and hypothyroidism. Work-up revealed leukopenia (WBC 2.5 10e9/L), hypocomplementemia (C3 0.23 g/L), positive anti-nuclear antibody, anti-dsDNA (633 IU/ml; normal less than10), anti-SSa/Ro, and anti-Smith antibodies, Class II lupus nephritis and a SLEDAI of 29. A baseline chest radiograph (CXR) was normal. He was treated with prednisone, hydroxychloroquine (HCQ), and azathioprine. A year later he had no symptoms of his SLE but was evaluated for an exercise-associated cough that was felt to be due to his asthma. A CXR was normal, PFTs showed moderate obstruction and symptoms resolved with a bronchodilator. Over the next few months, despite ongoing HCQ, azathioprine and low dose prednisone he had recurrence of malar rash and mild arthritis; a repeat renal biopsy showed Class III b lupus nephritis and azathioprine was replaced by mycophenolate mofetil (MMF) which was increased up to 700 mg/m2/dose BID, and subsequently decreased due to gastrointestinal side effects. This resulted in resolution of all symptoms but some ongoing nephritis (SLEDAI 12).
At age 14 he was admitted to his local hospital with fever, pleuritic chest pain, dyspnea, and cough. Bilateral pleural effusions were seen on CXR and he was given empiric antibiotics for possible pneumonia prior to transfer to our center, where he received a 3-day pulse of intravenous methylprednisolone (IVMP) for a suspected SLE flare (C3 0.70; anti dsDNA 95; SLEDAI 29). His chest symptoms resolved completely and respiratory syncytial virus (RSV) infection was subsequently confirmed by PCR and was thought to have triggered the flare. One month later, despite treatment with low dose prednisone and MMF (535 mg/m2/dose BID, although compliance was questionable), his SLE again flared. He presented with a malar rash, polyarthritis, as well as findings of pleuritis manifesting with chest pain, dyspnea, and a left pleural effusion. He was treated with pulse IVMP followed by increased MMF (625 mg/m2/dose BID) and daily oral prednisone (1 mg/kg/d).
Six weeks later his rash and arthritis had improved, but he reported increasing shortness of breath with marked exercise intolerance. On examination he was afebrile, his heart rate was 120, respiratory rate 40, and oxygen saturation 95% in room air. He appeared dyspneic with difficulty speaking in full sentences. Chest examination revealed shallow breathing and decreased air entry bilaterally. Physical examination was otherwise unremarkable. Work up for infection was negative. His SLEDAI had decreased to 14, C3 had normalized (0.97) and anti dsDNA had decreased to 39. CXR and high-resolution computed tomography (HRCT) showed severely reduced lung volumes with no pleural or interstitial disease; there was slight atelectasis but no other significant abnormalities (Figs. 1, 2). An echocardiogram was normal and a CT angiogram showed no evidence of pulmonary embolus. PFTs revealed a severe restrictive pattern with forced expiratory volume in 1 s (FEV1) of 27%, forced vital capacity (FVC) 29%, and total lung capacity (TLC) 43% (Fig. 3). Fluoroscopy documented significantly reduced diaphragmatic movement. He was diagnosed with SLS, and because of worsening dyspnea despite recently increased immunosuppression, he was treated with IVMP 1 g daily for 3 days followed by rituximab 1 g (2 doses, 2 weeks apart). He was also referred to physiotherapy for pulmonary rehabilitation.
Fig. 1 a Chest X-ray at presentation with SLS, showing decreased lung volumes and raised hemidiaphragms b Normal chest X-ray 3 years later
Fig. 2 High-resolution computed tomography (HRCT) of the chest at presentation with SLS, showing decreased lung volumes and slight atelectasis
Fig. 3 Pulmonary function tests (PFTs) over time in our patient with SLE and SLS; at diagnosis to 4 years following treatment with rituximab. FEV1, forced expiratory volume in 1 s; FVC, forced vital capacity; TLC, total lung capacity; RV, residual volume
One month later he reported some improvement in physical endurance, though he still had dyspnea with mild exertion and PFTs remained severely restrictive. At 6 months, however, he reported much improved exercise tolerance with ability to play some hockey. His FEV1 and FVC had improved to 42 and 51% respectively and TLC had increased to 57%. A planned second course of rituximab, (1 g, 2 doses, 2 weeks apart) was given at 6 months; preceding B cell counts were 8%. He was tapered off corticosteroids over the next 9 months and continued on HCQ (5 mg/kg/d) and MMF (600 mg/m2/dose BID). Serial CXRs showed gradual lung volume expansion. One year after his presentation he returned to playing competitive hockey, with no limitations and no respiratory symptoms. Four years later, he remained asymptomatic with no limitations in activity, no evidence of restrictive lung disease on PFTs (FVC 83%, TLC 94%), and a normal CXR. He remained on the same doses of HCQ and MMF with no clinical evidence of SLE disease activity, normal complement levels (C3 0.97), anti dsDNA 16, a SLEDAI of 2, and a follow renal biopsy showed no active nephritis.
Discussion
Shrinking lung syndrome is a rare complication of SLE with an incidence of approximately 1% in adult lupus patients [1, 5]. The incidence in pediatric SLE is unknown, but is likely even less common. As such, the diagnosis of SLS may not be considered or recognized in a child with SLE. Clinical features include progressive dyspnea, exercise intolerance, and pleuritic chest pain, all of which were described by our patient. Physical examination frequently reveals tachypnea with decreased air entry and the use of accessory respiratory muscles but is otherwise unremarkable. Findings on CXR often include significantly reduced lung volumes with elevated hemidiaphragms and may include pleural effusions, basal atelectasis, and pleural thickening. HRCT typically shows no parenchymal lung disease, though it may be more sensitive than CXR in demonstrating pleural effusions and atelectasis [4, 8]. PFTs show a restrictive pattern [4]. Reduced diaphragmatic excursion may be demonstrated on chest fluoroscopy, as was seen in our patient, or may be demonstrated using M-mode ultrasonography [8].
The pathogenesis of shrinking lung syndrome remains incompletely understood. When first described by Hoffbrand and Beck in 1965, the condition was thought to be due to surfactant deficiency causing microatelectasis [9]. Since then a number of mechanisms have been suggested, including phrenic nerve dysfunction, pleural inflammation and fibrosis, and diaphragmatic dysfunction due to myositis or neuropathy [3, 10]. Anti-SSa/Ro antibody positivity has been associated with both SLS and myositis, and has been suggested to support the theory that myositis contributes to diaphragmatic dysfunction in some patients [3, 11]. Of note, our patient was anti-SSa/Ro positive and had myositis as part of his SLE course. The frequent occurrence of pleuritic chest pain in up to 80% of patients with SLS has led to a more recently proposed mechanism of pleuritic pain leading to reflex inhibition of diaphragmatic activation and subsequent dysfunction in at least a subset of patients with SLS [1, 3]. Henderson et al. have proposed that pleural inflammation due to the underlying rheumatic disease may lead to activation of neural reflexes which inhibit deep inspiration and cause chronic lung hypoinflation. This is postulated to gradually reduce lung compliance and results in a positive feedback cycle [12]. Interestingly, our patient had developed pleuritic chest pain 2 months prior to his diagnosis of SLS, and had documented pleuritis associated with an RSV infection, and then associated with a flare of his SLE, which may have initiated the pathogenetic process leading to SLS.
There is no standard treatment for patients with SLS. Corticosteroids are the most frequently reported initial treatment of SLS, and can lead to full recovery in some patients [3, 5, 11, 13]. Immunosuppressive agents including cyclophosphamide, azathioprine, and methotrexate are often given along with corticosteroids or if corticosteroids alone are ineffective. There are also a few reports of theophylline and beta-agonists used effectively in SLS, and others advocate the use of analgesia to combat chest pain and pulmonary rehabilitation to improve lung expansion [1, 3, 5, 12, 13]. Although rare fatal cases have been described, the prognosis of SLS in adults is generally considered to be good, particularly in comparison with the progressive course and significant mortality associated with fibrotic interstitial lung disease in patients with SLE [1]. Some clinical improvement has been reported in most patients with SLS, however, recent literature makes it clear that despite treatment many patients do not achieve full recovery. Langenskiold et al., in a review of 35 cases with documented pre and post treatment PFTs, found that only 20% of patients with SLS regained normal lung function [4]. Duron et al. reported full recovery in only a minority of patients in their review of 155 patients with SLS, with 42.9% of patients showing chronic and persistent hemidiaphragm elevation [1]. A report of 20 cases from a large single center in 2018 showed a similar outcome, with 86.7% of patients showing continued restrictive defects on spirometry despite improved lung volumes [5]. The lack of full recovery in both adult and pediatric patients with SLS has led to 15 reports of rituximab use in adults and 2 reports in children with SLS complicating SLE [1, 3, 4, 6–8, 12, 14–16] (Table 1). Normal PFTs were reported in one child treated with rituximab [7], however the other child did not respond [12]. All 4 adult patients with well-documented post-treatment PFTs had normal or near normal findings [3, 4, 6]. Although the degree of objective improvement was not documented in the remaining 11 adult cases treated with rituximab, all were reported to have improved or stabilized. (Table 1). There has also been a recent report of a 19-year-old male with pediatric-onset SLE who developed SLS refractory to IVMP and cyclophosphamide and had some improvement with belimumab, a monoclonal antibody directed against BLyS receptors on B-cells, though long-term follow-up is still ongoing [11].
Table 1 Clinical features, treatment and outcome of patients with SLS associated with SLE who received treatment with rituximab
Reference Sex Age at SLE diagnosis Age at SLS diagnosis Clinical presentation Imaging findings at SLS diagnosis PFTs at SLS diagnosis Treatment Outcome
[1] F Unknown 61 Chest pain, history of pleurisy, dyspnea Elevated diaphragms, atelectasis, pleural thickening TLC 46%,
DLCO 25%, KCO 59%
CS + Beta-agonists + RTX (dose unknown) + Physiotherapy Improvement
[1] F Unknown 26 Chest pain, history of pleurisy, dyspnea Pleural thickening, reticulations FVC 41%,
TLC 68%,
DLCO 34%
CS + AZA + MMF + RTX (dose unknown) Improvement
[3] F 36 46 Dyspnea on exertion, orthopnea, pleuritic chest pain Elevated diaphragms, atelectasis, pleural thickening FVC 77%, TLC 68% CS + CYC + RTX (375 mg/m2 once weekly × 4 q6mo) Asymptomatic, normal PFTs
[4] F 28 28 (6 mo after diagnosis of SLE) Dyspnea, pleuritic chest pain, dry cough, orthopnea Elevated diaphragms FVC 61%, TLC 45% Beta-agonists + theophylline, RTX (1 g × 2, 2 weeks apart) + CYC Asymptomatic, normal PFTs
[6] F 38 38a Tachypnea, dyspnea Normal HRCT, elevated diaphragms FVC 64%, FEV1 73% CS + CYC without improvement; followed by RTX (1 g × 2, 2 weeks apart) Normal PFTs, normal CXR 6 months after treatment
[7] F 11 14 Dyspnea on exertion, chest pain Low lung volumes, small bilateral pleural effusions, small pericardial effusion, mild bibasilar atelectasis FVC 31%, TLC 32%, DLCO 96% CYC monthly × 1 year, then RTX (dose unknown) Clinical improvement,
PFTs 2 yrs. post: FVC 82%, TLC 80%
[14] F 22 27 Pleuritic chest pain, exertional dyspnea Elevated diaphragms, normal HRCT FVC 1.45 L (predicted value 4.20), TLC 2.35 (predicted value 5.76), DLCO 16.3 (predicted value 26.5) CS + RTX (375 mg/m2 × 2 doses 6 weeks apart) Initial clinical improvement, followed by re-presentation requiring second course of RTX. Improvement reported 2 yrs. later
[15] F 22 57 Dyspnea, dry cough, pleuritic chest pain Elevated diaphragms, bibasilar atelectasis FVC 43%, TLC 56%, DLCO 55% CS + beta-agonists + AZA + MMF, then 6 mo later RTX (1 g × 2 doses, 2 weeks apart, repeated q6mo) Clinical improvement. PFTs 5 years post: FVC 76%, TLC 79%, DLCO 53%
[16] F Unknown 28 Exercise intolerance, pleuritic chest pain Unknown FVC 0.99 L CS + MMF + RTX (2800 mg) Unlimited exercise tolerance, FVC 2.23 L
[12] F 12 14 Dyspnea, pleuritic chest pain, orthopnea Elevated right hemidiaphragm FVC 36%, TLC 39%, DLCO 102% CS + RTX (dose unknown) + CYC Active disease
[8] F 36 37 Dyspnea, pleuritic chest pain CXR: Bilateral diaphragmatic elevation with mild pleural effusion
HRCT: Mild pleural effusion
Restrictive pattern CS + MTX + beta-agonists + RTX (dose unknown) Restrictive defect improvement
[8] F 36 39 Dyspnea, pleuritic chest pain, fever CXR: Unilateral diaphragmatic elevation, left atelectasia
HRCT: Basal atelectasis
Restrictive pattern CS + MMF + beta-agonists + RTX (dose unknown) Restrictive defect stabilization. Developed ILD 4 yrs. later
[8] F 27 31 Dyspnea, pleuritic chest pain CXR: Unilateral diaphragmatic elevation, right atelectasia
HRCT: Basal atelectasis, mild pleural effusion
Restrictive pattern CS + theophylline + beta-agonists + RTX (dose unknown) Restrictive defect stabilization
[8] F 23 30 Dyspnea, pleuritic chest pain CXR: Unilateral diaphragmatic elevation
HRCT: Basal atelectasis
Restrictive pattern CS + MMF + beta-agonists + RTX (dose unknown) Restrictive defect improvement
[8] F 34 59 Dyspnea, pleuritic chest pain CXR: Bilateral diaphragmatic elevation, atelectasia
HRCT: Basal atelectasis
Restrictive pattern CS + MMF + RTX (dose unknown) + IVIG Restrictive defect stabilization
CS corticosteroids, RTX rituximab, CYC cyclophosphamide, AZA azathioprine, MMF mycophenolate mofetil, IVIG intravenous immunoglobulin, CXR chest X-ray, HRCT high-resolution computed tomography, PFTs pulmonary function tests, FEV1 forced expiratory volume in 1 s, FVC forced vital capacity, TLC total lung capacity, DLCO diffusing capacity for carbon monoxide, ILD interstitial lung disease. PFT results expressed in % predicted when available
a Diagnosis of SLS made at the time of diagnosis of SLE
Shrinking lung syndrome is extremely rare in pediatric lupus patients (defined as 16 years or less at diagnosis), with only 6 well-documented case reports identified in our literature review from 1984 to 2019 (Table 2). Age at onset of SLS ranged from 12 to 15 years, 5 were female, all presented with dyspnea, and 5 had associated chest pain. Interestingly, 3 of the 6 presented at the time of diagnosis of SLE, a much more frequent occurrence than that reported in adults with SLS. Of the 6 patients, only 2 reported a return to baseline respiratory function, both clinically and documented on PFTs [2, 7]. In addition to these 6 patients, our literature review identified 3 patients with pediatric onset SLE who developed SLS at age 19 or 20 [11, 19, 20]. Some improvement in lung function was documented in 2 of these patients, one treated with IVMP, cyclophosphamide and azathioprine, and 1 treated with belimumab. In addition, 7 SLE patients 16–18 years of age have been reported, most in case series of SLS, however very limited information was given on their disease course [1, 5, 12, 21, 22].
Table 2 Clinical features, treatment, and outcome of reported pediatric cases of SLS associated with SLE
Reference Sex Age at SLE diagnosis Age at SLS diagnosis Clinical presentation Imaging findings at SLS diagnosis PFTs at SLS diagnosis Treatment Outcome
[2] F 12 12a Prior diagnosis of mycoplasma pneumonia with recovery. Re-presented 6 months later with dyspnea CXR: Enlarged cardiac silhouette, low lung volumes, elevated diaphragms
HRCT: thoracic lymphadenopathy
FEV1 34%, FVC 27%, TLC 59% CS + CYC (q4weeks × 6 mo) Asymptomatic. Normal PFTs after 1 yr (FEV1 99%, FVC 97%, TLC 92%)
[7] F 11 14 Dyspnea on exertion, chest pain CXR: Low lung volumes, small pleural effusions, small pericardial effusion, mild bibasilar atelectasis FVC 31%, TLC 32%, DLCO 96% CYC monthly × 1 year, then RTX (dose unknown) Clinical improvement,
PFTs 2 yrs. post: FVC 82%, TLC 80%
[10] F 15 15a Pleuritic chest pain, dry cough, dyspnea on exertion Small lung fields, elevated bilateral hemidiaphragms, chest CT normal FEV1 26%, FVC 25%, TLC 31% Beta-agonist Clinical improvement. PFTs after 12d showed FEV1 increase of 58%, FVC increase of 50%, TLC increase of 47%
[17] M 11 14 Fatigue, dyspnea, pleuritic chest pain Enlarged cardiac silhouette, atelectasis, severely reduced diaphragmatic excursion on fluoroscopy FEV1 23%, FVC 20%, TLC 34% CS + AZA Follow-up 23 days later: FEV1 45%, FVC 45%, TLC 57%
[18] F 12 12a Pleuritic chest pain, dyspnea, fever, fatigue, anorexia CXR: Reduced lung volumes, elevated diaphragms, HRCT: pleural thickening Diaphragmatic fluoroscopy: minimal movement FVC 39%, TLC 60%, DLCO normal CS + HCQ 4 yrs. post: ongoing activity limitation, PFTs unchanged
[12] F 12 14 Dyspnea, pleuritic chest pain, orthopnea Elevated right hemidiaphragm FVC 36%, TLC 39%, DLCO 102% CS + RTX (dose unknown) + CYC Active disease
CS corticosteroids, RTX rituximab, CYC cyclophosphamide, AZA azathioprine, HCQ hydroxychloroquine, CXR chest X-ray, HRCT high-resolution computed tomography, PFTs pulmonary function tests, FEV1 forced expiratory volume in 1 s, FVC forced vital capacity, TLC total lung capacity, DLCO diffusing capacity for carbon monoxide. PFT results expressed in % predicted when available
a Diagnosis of SLS made at the time of diagnosis of SLE
Although extremely rare, it is important to recognize SLS as a possible cause of dyspnea and chest pain in a child with SLE, and be aware that in pediatric patients in particular, this complication may occur at the time of initial presentation of SLE. Our patient clearly stated that his goal for treatment was to return to competitive hockey. Recent literature on rituximab use in SLS, a review of pediatric SLS cases, and our case report suggest that additional therapy, including possible use of rituximab, should be considered in patients with SLS who have an incomplete response to initial immunosuppressive therapy. Careful documentation of the occurrence, treatment and outcome of patients with SLS utilizing large registries of adult and pediatric patients with SLE may help determine optimal treatment for this rare complication.
Abbreviations
SLSShrinking lung syndrome
SLESystemic lupus erythematosus
PFTPulmonary function test
FEV1Forced expiratory volume in 1 s
FVCForced vital capacity
TLCTotal lung capacity
RVResidual volume
RSVRespiratory syncytial virus
CXRChest x ray
dsDNADouble stranded DNA
ANAAntinuclear antibody
IVMPMethylprednisolone
PCRPolymerase chain reaction
HRCTHigh resolution computed tomography
Publisher’s Note
Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
Acknowledgements
We thank the patient and family for participating in this report.
Authors’ contributions
CD and BL reviewed the patient’s medical record pertaining to this case and were major contributors in writing the manuscript. All authors read and approved the final manuscript.
Funding
None.
Availability of data and materials
Data sharing is not applicable to this article as no datasets were generated or analyzed during the current study.
Ethics approval and consent to participate
Research Ethics Board approval (#1024379) was obtained from the IWK Health Centre. Written and informed consent was also obtained from the patient.
Consent for publication
Written and informed consent was obtained from the patient to publish this material.
Competing interests
The authors declare that they have no competing interests. | 5 MILLIGRAM/KILOGRAM (5 MG/KG/D) | DrugDosageText | CC BY | 33407629 | 18,886,056 | 2021-01-06 |
What was the dosage of drug 'METHYLPREDNISOLONE'? | Shrinking lung syndrome treated with rituximab in pediatric systemic lupus erythematosus: a case report and review of the literature.
BACKGROUND
Shrinking lung syndrome (SLS), a rare complication of systemic lupus erythematosus (SLE) characterized by dyspnea, low lung volumes, and a restrictive pattern on pulmonary function tests (PFTs), has only been reported in a few children. Given the rarity of SLS there is a paucity of literature regarding its optimal treatment. Outcomes are variable, with case reports documenting some improvement in most patients treated with corticosteroids, with or without additional immunosuppressive agents. However, most reported patients did not recover normal lung function. We report full recovery of a child with SLE and SLS following treatment with rituximab and review the current literature.
METHODS
An 11-year-old boy presented with a malar rash, myositis, arthritis, oral ulcers, leukopenia, anemia, positive lupus autoantibodies and Class II nephritis. He was diagnosed with SLE and treated with corticosteroids, hydroxychloroquine, azathioprine, and subsequently mycophenolate with symptom resolution. At age 14, his SLE flared coincident with a viral chest infection. He presented with a malar rash, polyarthritis, increased proteinuria and pleuritis which all improved with corticosteroids and ongoing treatment with mycophenolate. Six weeks later he presented with severe dyspnea, markedly decreased lung volumes, but otherwise normal chest X-ray (CXR) and high-resolution chest computed tomography (HRCT). He was found to have severely restricted PFTs (FEV1 27%, FVC 29%; TLC 43%). After additional investigations including echocardiography, pulmonary CT angiography, and diaphragmatic fluoroscopy, he was diagnosed with SLS and treated with rituximab and methylprednisolone. At 1 month his symptoms had improved, but he still had dyspnea with exertion and severely restricted PFTs. At 6 months his FVC and TLC had improved to 51 and 57% respectively, and were 83 and 94% respectively at 4 years. He had returned to all baseline activities, including competitive hockey.
CONCLUSIONS
Although extremely rare, it is important to recognize SLS as a possible cause of dyspnea and chest pain in a child with SLE. Optimal treatment strategies are unknown. This is the second reported case of a child treated with rituximab for SLS who recovered normal lung function. International lupus registries should carefully document the occurrence, treatment and outcome of patients with SLS to help determine the optimal treatment for this rare complication.
Background
Shrinking lung syndrome (SLS) is a rare complication of systemic lupus erythematosus (SLE) characterized by decreased lung volumes and a restrictive pattern on pulmonary function testing (PFTs). Patients typically present with progressive dyspnea and chest pain [1–3]. The diagnosis may be delayed, particularly in pediatric patients, because of failure to consider or recognize this disorder. The exact pathophysiology is unknown [1–3].
Given the rarity of SLS there is a paucity of literature regarding optimal treatment. Case reports and series have documented improvement in most patients treated with corticosteroids, with or without immunosuppressive agents. However, the majority of patients have an incomplete recovery [4, 5]. Recently, rituximab, a monoclonal antibody directed against the CD20 antigen found on the surface of B lymphocytes, has been used successfully in several adult patients and one child with SLE complicated by SLS [6, 7]. We report a child with SLE who developed SLS at age 14 and recovered fully following treatment with rituximab. We also review the literature on SLS in pediatric patients to increase awareness of this exceptionally rare complication, as well as review outcome of patients previously reported with SLS who were treated with rituximab.
Case presentation
At age 11 years, our patient was diagnosed with SLE after presenting with a malar rash, oral ulcers, polyarthritis, myositis, and anemia. His past history was remarkable only for mild asthma; family history was positive for maternal asthma and hypothyroidism. Work-up revealed leukopenia (WBC 2.5 10e9/L), hypocomplementemia (C3 0.23 g/L), positive anti-nuclear antibody, anti-dsDNA (633 IU/ml; normal less than10), anti-SSa/Ro, and anti-Smith antibodies, Class II lupus nephritis and a SLEDAI of 29. A baseline chest radiograph (CXR) was normal. He was treated with prednisone, hydroxychloroquine (HCQ), and azathioprine. A year later he had no symptoms of his SLE but was evaluated for an exercise-associated cough that was felt to be due to his asthma. A CXR was normal, PFTs showed moderate obstruction and symptoms resolved with a bronchodilator. Over the next few months, despite ongoing HCQ, azathioprine and low dose prednisone he had recurrence of malar rash and mild arthritis; a repeat renal biopsy showed Class III b lupus nephritis and azathioprine was replaced by mycophenolate mofetil (MMF) which was increased up to 700 mg/m2/dose BID, and subsequently decreased due to gastrointestinal side effects. This resulted in resolution of all symptoms but some ongoing nephritis (SLEDAI 12).
At age 14 he was admitted to his local hospital with fever, pleuritic chest pain, dyspnea, and cough. Bilateral pleural effusions were seen on CXR and he was given empiric antibiotics for possible pneumonia prior to transfer to our center, where he received a 3-day pulse of intravenous methylprednisolone (IVMP) for a suspected SLE flare (C3 0.70; anti dsDNA 95; SLEDAI 29). His chest symptoms resolved completely and respiratory syncytial virus (RSV) infection was subsequently confirmed by PCR and was thought to have triggered the flare. One month later, despite treatment with low dose prednisone and MMF (535 mg/m2/dose BID, although compliance was questionable), his SLE again flared. He presented with a malar rash, polyarthritis, as well as findings of pleuritis manifesting with chest pain, dyspnea, and a left pleural effusion. He was treated with pulse IVMP followed by increased MMF (625 mg/m2/dose BID) and daily oral prednisone (1 mg/kg/d).
Six weeks later his rash and arthritis had improved, but he reported increasing shortness of breath with marked exercise intolerance. On examination he was afebrile, his heart rate was 120, respiratory rate 40, and oxygen saturation 95% in room air. He appeared dyspneic with difficulty speaking in full sentences. Chest examination revealed shallow breathing and decreased air entry bilaterally. Physical examination was otherwise unremarkable. Work up for infection was negative. His SLEDAI had decreased to 14, C3 had normalized (0.97) and anti dsDNA had decreased to 39. CXR and high-resolution computed tomography (HRCT) showed severely reduced lung volumes with no pleural or interstitial disease; there was slight atelectasis but no other significant abnormalities (Figs. 1, 2). An echocardiogram was normal and a CT angiogram showed no evidence of pulmonary embolus. PFTs revealed a severe restrictive pattern with forced expiratory volume in 1 s (FEV1) of 27%, forced vital capacity (FVC) 29%, and total lung capacity (TLC) 43% (Fig. 3). Fluoroscopy documented significantly reduced diaphragmatic movement. He was diagnosed with SLS, and because of worsening dyspnea despite recently increased immunosuppression, he was treated with IVMP 1 g daily for 3 days followed by rituximab 1 g (2 doses, 2 weeks apart). He was also referred to physiotherapy for pulmonary rehabilitation.
Fig. 1 a Chest X-ray at presentation with SLS, showing decreased lung volumes and raised hemidiaphragms b Normal chest X-ray 3 years later
Fig. 2 High-resolution computed tomography (HRCT) of the chest at presentation with SLS, showing decreased lung volumes and slight atelectasis
Fig. 3 Pulmonary function tests (PFTs) over time in our patient with SLE and SLS; at diagnosis to 4 years following treatment with rituximab. FEV1, forced expiratory volume in 1 s; FVC, forced vital capacity; TLC, total lung capacity; RV, residual volume
One month later he reported some improvement in physical endurance, though he still had dyspnea with mild exertion and PFTs remained severely restrictive. At 6 months, however, he reported much improved exercise tolerance with ability to play some hockey. His FEV1 and FVC had improved to 42 and 51% respectively and TLC had increased to 57%. A planned second course of rituximab, (1 g, 2 doses, 2 weeks apart) was given at 6 months; preceding B cell counts were 8%. He was tapered off corticosteroids over the next 9 months and continued on HCQ (5 mg/kg/d) and MMF (600 mg/m2/dose BID). Serial CXRs showed gradual lung volume expansion. One year after his presentation he returned to playing competitive hockey, with no limitations and no respiratory symptoms. Four years later, he remained asymptomatic with no limitations in activity, no evidence of restrictive lung disease on PFTs (FVC 83%, TLC 94%), and a normal CXR. He remained on the same doses of HCQ and MMF with no clinical evidence of SLE disease activity, normal complement levels (C3 0.97), anti dsDNA 16, a SLEDAI of 2, and a follow renal biopsy showed no active nephritis.
Discussion
Shrinking lung syndrome is a rare complication of SLE with an incidence of approximately 1% in adult lupus patients [1, 5]. The incidence in pediatric SLE is unknown, but is likely even less common. As such, the diagnosis of SLS may not be considered or recognized in a child with SLE. Clinical features include progressive dyspnea, exercise intolerance, and pleuritic chest pain, all of which were described by our patient. Physical examination frequently reveals tachypnea with decreased air entry and the use of accessory respiratory muscles but is otherwise unremarkable. Findings on CXR often include significantly reduced lung volumes with elevated hemidiaphragms and may include pleural effusions, basal atelectasis, and pleural thickening. HRCT typically shows no parenchymal lung disease, though it may be more sensitive than CXR in demonstrating pleural effusions and atelectasis [4, 8]. PFTs show a restrictive pattern [4]. Reduced diaphragmatic excursion may be demonstrated on chest fluoroscopy, as was seen in our patient, or may be demonstrated using M-mode ultrasonography [8].
The pathogenesis of shrinking lung syndrome remains incompletely understood. When first described by Hoffbrand and Beck in 1965, the condition was thought to be due to surfactant deficiency causing microatelectasis [9]. Since then a number of mechanisms have been suggested, including phrenic nerve dysfunction, pleural inflammation and fibrosis, and diaphragmatic dysfunction due to myositis or neuropathy [3, 10]. Anti-SSa/Ro antibody positivity has been associated with both SLS and myositis, and has been suggested to support the theory that myositis contributes to diaphragmatic dysfunction in some patients [3, 11]. Of note, our patient was anti-SSa/Ro positive and had myositis as part of his SLE course. The frequent occurrence of pleuritic chest pain in up to 80% of patients with SLS has led to a more recently proposed mechanism of pleuritic pain leading to reflex inhibition of diaphragmatic activation and subsequent dysfunction in at least a subset of patients with SLS [1, 3]. Henderson et al. have proposed that pleural inflammation due to the underlying rheumatic disease may lead to activation of neural reflexes which inhibit deep inspiration and cause chronic lung hypoinflation. This is postulated to gradually reduce lung compliance and results in a positive feedback cycle [12]. Interestingly, our patient had developed pleuritic chest pain 2 months prior to his diagnosis of SLS, and had documented pleuritis associated with an RSV infection, and then associated with a flare of his SLE, which may have initiated the pathogenetic process leading to SLS.
There is no standard treatment for patients with SLS. Corticosteroids are the most frequently reported initial treatment of SLS, and can lead to full recovery in some patients [3, 5, 11, 13]. Immunosuppressive agents including cyclophosphamide, azathioprine, and methotrexate are often given along with corticosteroids or if corticosteroids alone are ineffective. There are also a few reports of theophylline and beta-agonists used effectively in SLS, and others advocate the use of analgesia to combat chest pain and pulmonary rehabilitation to improve lung expansion [1, 3, 5, 12, 13]. Although rare fatal cases have been described, the prognosis of SLS in adults is generally considered to be good, particularly in comparison with the progressive course and significant mortality associated with fibrotic interstitial lung disease in patients with SLE [1]. Some clinical improvement has been reported in most patients with SLS, however, recent literature makes it clear that despite treatment many patients do not achieve full recovery. Langenskiold et al., in a review of 35 cases with documented pre and post treatment PFTs, found that only 20% of patients with SLS regained normal lung function [4]. Duron et al. reported full recovery in only a minority of patients in their review of 155 patients with SLS, with 42.9% of patients showing chronic and persistent hemidiaphragm elevation [1]. A report of 20 cases from a large single center in 2018 showed a similar outcome, with 86.7% of patients showing continued restrictive defects on spirometry despite improved lung volumes [5]. The lack of full recovery in both adult and pediatric patients with SLS has led to 15 reports of rituximab use in adults and 2 reports in children with SLS complicating SLE [1, 3, 4, 6–8, 12, 14–16] (Table 1). Normal PFTs were reported in one child treated with rituximab [7], however the other child did not respond [12]. All 4 adult patients with well-documented post-treatment PFTs had normal or near normal findings [3, 4, 6]. Although the degree of objective improvement was not documented in the remaining 11 adult cases treated with rituximab, all were reported to have improved or stabilized. (Table 1). There has also been a recent report of a 19-year-old male with pediatric-onset SLE who developed SLS refractory to IVMP and cyclophosphamide and had some improvement with belimumab, a monoclonal antibody directed against BLyS receptors on B-cells, though long-term follow-up is still ongoing [11].
Table 1 Clinical features, treatment and outcome of patients with SLS associated with SLE who received treatment with rituximab
Reference Sex Age at SLE diagnosis Age at SLS diagnosis Clinical presentation Imaging findings at SLS diagnosis PFTs at SLS diagnosis Treatment Outcome
[1] F Unknown 61 Chest pain, history of pleurisy, dyspnea Elevated diaphragms, atelectasis, pleural thickening TLC 46%,
DLCO 25%, KCO 59%
CS + Beta-agonists + RTX (dose unknown) + Physiotherapy Improvement
[1] F Unknown 26 Chest pain, history of pleurisy, dyspnea Pleural thickening, reticulations FVC 41%,
TLC 68%,
DLCO 34%
CS + AZA + MMF + RTX (dose unknown) Improvement
[3] F 36 46 Dyspnea on exertion, orthopnea, pleuritic chest pain Elevated diaphragms, atelectasis, pleural thickening FVC 77%, TLC 68% CS + CYC + RTX (375 mg/m2 once weekly × 4 q6mo) Asymptomatic, normal PFTs
[4] F 28 28 (6 mo after diagnosis of SLE) Dyspnea, pleuritic chest pain, dry cough, orthopnea Elevated diaphragms FVC 61%, TLC 45% Beta-agonists + theophylline, RTX (1 g × 2, 2 weeks apart) + CYC Asymptomatic, normal PFTs
[6] F 38 38a Tachypnea, dyspnea Normal HRCT, elevated diaphragms FVC 64%, FEV1 73% CS + CYC without improvement; followed by RTX (1 g × 2, 2 weeks apart) Normal PFTs, normal CXR 6 months after treatment
[7] F 11 14 Dyspnea on exertion, chest pain Low lung volumes, small bilateral pleural effusions, small pericardial effusion, mild bibasilar atelectasis FVC 31%, TLC 32%, DLCO 96% CYC monthly × 1 year, then RTX (dose unknown) Clinical improvement,
PFTs 2 yrs. post: FVC 82%, TLC 80%
[14] F 22 27 Pleuritic chest pain, exertional dyspnea Elevated diaphragms, normal HRCT FVC 1.45 L (predicted value 4.20), TLC 2.35 (predicted value 5.76), DLCO 16.3 (predicted value 26.5) CS + RTX (375 mg/m2 × 2 doses 6 weeks apart) Initial clinical improvement, followed by re-presentation requiring second course of RTX. Improvement reported 2 yrs. later
[15] F 22 57 Dyspnea, dry cough, pleuritic chest pain Elevated diaphragms, bibasilar atelectasis FVC 43%, TLC 56%, DLCO 55% CS + beta-agonists + AZA + MMF, then 6 mo later RTX (1 g × 2 doses, 2 weeks apart, repeated q6mo) Clinical improvement. PFTs 5 years post: FVC 76%, TLC 79%, DLCO 53%
[16] F Unknown 28 Exercise intolerance, pleuritic chest pain Unknown FVC 0.99 L CS + MMF + RTX (2800 mg) Unlimited exercise tolerance, FVC 2.23 L
[12] F 12 14 Dyspnea, pleuritic chest pain, orthopnea Elevated right hemidiaphragm FVC 36%, TLC 39%, DLCO 102% CS + RTX (dose unknown) + CYC Active disease
[8] F 36 37 Dyspnea, pleuritic chest pain CXR: Bilateral diaphragmatic elevation with mild pleural effusion
HRCT: Mild pleural effusion
Restrictive pattern CS + MTX + beta-agonists + RTX (dose unknown) Restrictive defect improvement
[8] F 36 39 Dyspnea, pleuritic chest pain, fever CXR: Unilateral diaphragmatic elevation, left atelectasia
HRCT: Basal atelectasis
Restrictive pattern CS + MMF + beta-agonists + RTX (dose unknown) Restrictive defect stabilization. Developed ILD 4 yrs. later
[8] F 27 31 Dyspnea, pleuritic chest pain CXR: Unilateral diaphragmatic elevation, right atelectasia
HRCT: Basal atelectasis, mild pleural effusion
Restrictive pattern CS + theophylline + beta-agonists + RTX (dose unknown) Restrictive defect stabilization
[8] F 23 30 Dyspnea, pleuritic chest pain CXR: Unilateral diaphragmatic elevation
HRCT: Basal atelectasis
Restrictive pattern CS + MMF + beta-agonists + RTX (dose unknown) Restrictive defect improvement
[8] F 34 59 Dyspnea, pleuritic chest pain CXR: Bilateral diaphragmatic elevation, atelectasia
HRCT: Basal atelectasis
Restrictive pattern CS + MMF + RTX (dose unknown) + IVIG Restrictive defect stabilization
CS corticosteroids, RTX rituximab, CYC cyclophosphamide, AZA azathioprine, MMF mycophenolate mofetil, IVIG intravenous immunoglobulin, CXR chest X-ray, HRCT high-resolution computed tomography, PFTs pulmonary function tests, FEV1 forced expiratory volume in 1 s, FVC forced vital capacity, TLC total lung capacity, DLCO diffusing capacity for carbon monoxide, ILD interstitial lung disease. PFT results expressed in % predicted when available
a Diagnosis of SLS made at the time of diagnosis of SLE
Shrinking lung syndrome is extremely rare in pediatric lupus patients (defined as 16 years or less at diagnosis), with only 6 well-documented case reports identified in our literature review from 1984 to 2019 (Table 2). Age at onset of SLS ranged from 12 to 15 years, 5 were female, all presented with dyspnea, and 5 had associated chest pain. Interestingly, 3 of the 6 presented at the time of diagnosis of SLE, a much more frequent occurrence than that reported in adults with SLS. Of the 6 patients, only 2 reported a return to baseline respiratory function, both clinically and documented on PFTs [2, 7]. In addition to these 6 patients, our literature review identified 3 patients with pediatric onset SLE who developed SLS at age 19 or 20 [11, 19, 20]. Some improvement in lung function was documented in 2 of these patients, one treated with IVMP, cyclophosphamide and azathioprine, and 1 treated with belimumab. In addition, 7 SLE patients 16–18 years of age have been reported, most in case series of SLS, however very limited information was given on their disease course [1, 5, 12, 21, 22].
Table 2 Clinical features, treatment, and outcome of reported pediatric cases of SLS associated with SLE
Reference Sex Age at SLE diagnosis Age at SLS diagnosis Clinical presentation Imaging findings at SLS diagnosis PFTs at SLS diagnosis Treatment Outcome
[2] F 12 12a Prior diagnosis of mycoplasma pneumonia with recovery. Re-presented 6 months later with dyspnea CXR: Enlarged cardiac silhouette, low lung volumes, elevated diaphragms
HRCT: thoracic lymphadenopathy
FEV1 34%, FVC 27%, TLC 59% CS + CYC (q4weeks × 6 mo) Asymptomatic. Normal PFTs after 1 yr (FEV1 99%, FVC 97%, TLC 92%)
[7] F 11 14 Dyspnea on exertion, chest pain CXR: Low lung volumes, small pleural effusions, small pericardial effusion, mild bibasilar atelectasis FVC 31%, TLC 32%, DLCO 96% CYC monthly × 1 year, then RTX (dose unknown) Clinical improvement,
PFTs 2 yrs. post: FVC 82%, TLC 80%
[10] F 15 15a Pleuritic chest pain, dry cough, dyspnea on exertion Small lung fields, elevated bilateral hemidiaphragms, chest CT normal FEV1 26%, FVC 25%, TLC 31% Beta-agonist Clinical improvement. PFTs after 12d showed FEV1 increase of 58%, FVC increase of 50%, TLC increase of 47%
[17] M 11 14 Fatigue, dyspnea, pleuritic chest pain Enlarged cardiac silhouette, atelectasis, severely reduced diaphragmatic excursion on fluoroscopy FEV1 23%, FVC 20%, TLC 34% CS + AZA Follow-up 23 days later: FEV1 45%, FVC 45%, TLC 57%
[18] F 12 12a Pleuritic chest pain, dyspnea, fever, fatigue, anorexia CXR: Reduced lung volumes, elevated diaphragms, HRCT: pleural thickening Diaphragmatic fluoroscopy: minimal movement FVC 39%, TLC 60%, DLCO normal CS + HCQ 4 yrs. post: ongoing activity limitation, PFTs unchanged
[12] F 12 14 Dyspnea, pleuritic chest pain, orthopnea Elevated right hemidiaphragm FVC 36%, TLC 39%, DLCO 102% CS + RTX (dose unknown) + CYC Active disease
CS corticosteroids, RTX rituximab, CYC cyclophosphamide, AZA azathioprine, HCQ hydroxychloroquine, CXR chest X-ray, HRCT high-resolution computed tomography, PFTs pulmonary function tests, FEV1 forced expiratory volume in 1 s, FVC forced vital capacity, TLC total lung capacity, DLCO diffusing capacity for carbon monoxide. PFT results expressed in % predicted when available
a Diagnosis of SLS made at the time of diagnosis of SLE
Although extremely rare, it is important to recognize SLS as a possible cause of dyspnea and chest pain in a child with SLE, and be aware that in pediatric patients in particular, this complication may occur at the time of initial presentation of SLE. Our patient clearly stated that his goal for treatment was to return to competitive hockey. Recent literature on rituximab use in SLS, a review of pediatric SLS cases, and our case report suggest that additional therapy, including possible use of rituximab, should be considered in patients with SLS who have an incomplete response to initial immunosuppressive therapy. Careful documentation of the occurrence, treatment and outcome of patients with SLS utilizing large registries of adult and pediatric patients with SLE may help determine optimal treatment for this rare complication.
Abbreviations
SLSShrinking lung syndrome
SLESystemic lupus erythematosus
PFTPulmonary function test
FEV1Forced expiratory volume in 1 s
FVCForced vital capacity
TLCTotal lung capacity
RVResidual volume
RSVRespiratory syncytial virus
CXRChest x ray
dsDNADouble stranded DNA
ANAAntinuclear antibody
IVMPMethylprednisolone
PCRPolymerase chain reaction
HRCTHigh resolution computed tomography
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Acknowledgements
We thank the patient and family for participating in this report.
Authors’ contributions
CD and BL reviewed the patient’s medical record pertaining to this case and were major contributors in writing the manuscript. All authors read and approved the final manuscript.
Funding
None.
Availability of data and materials
Data sharing is not applicable to this article as no datasets were generated or analyzed during the current study.
Ethics approval and consent to participate
Research Ethics Board approval (#1024379) was obtained from the IWK Health Centre. Written and informed consent was also obtained from the patient.
Consent for publication
Written and informed consent was obtained from the patient to publish this material.
Competing interests
The authors declare that they have no competing interests. | UNK (3 DAY PULSE) | DrugDosageText | CC BY | 33407629 | 18,908,879 | 2021-01-06 |
What was the outcome of reaction 'Arthritis'? | Shrinking lung syndrome treated with rituximab in pediatric systemic lupus erythematosus: a case report and review of the literature.
BACKGROUND
Shrinking lung syndrome (SLS), a rare complication of systemic lupus erythematosus (SLE) characterized by dyspnea, low lung volumes, and a restrictive pattern on pulmonary function tests (PFTs), has only been reported in a few children. Given the rarity of SLS there is a paucity of literature regarding its optimal treatment. Outcomes are variable, with case reports documenting some improvement in most patients treated with corticosteroids, with or without additional immunosuppressive agents. However, most reported patients did not recover normal lung function. We report full recovery of a child with SLE and SLS following treatment with rituximab and review the current literature.
METHODS
An 11-year-old boy presented with a malar rash, myositis, arthritis, oral ulcers, leukopenia, anemia, positive lupus autoantibodies and Class II nephritis. He was diagnosed with SLE and treated with corticosteroids, hydroxychloroquine, azathioprine, and subsequently mycophenolate with symptom resolution. At age 14, his SLE flared coincident with a viral chest infection. He presented with a malar rash, polyarthritis, increased proteinuria and pleuritis which all improved with corticosteroids and ongoing treatment with mycophenolate. Six weeks later he presented with severe dyspnea, markedly decreased lung volumes, but otherwise normal chest X-ray (CXR) and high-resolution chest computed tomography (HRCT). He was found to have severely restricted PFTs (FEV1 27%, FVC 29%; TLC 43%). After additional investigations including echocardiography, pulmonary CT angiography, and diaphragmatic fluoroscopy, he was diagnosed with SLS and treated with rituximab and methylprednisolone. At 1 month his symptoms had improved, but he still had dyspnea with exertion and severely restricted PFTs. At 6 months his FVC and TLC had improved to 51 and 57% respectively, and were 83 and 94% respectively at 4 years. He had returned to all baseline activities, including competitive hockey.
CONCLUSIONS
Although extremely rare, it is important to recognize SLS as a possible cause of dyspnea and chest pain in a child with SLE. Optimal treatment strategies are unknown. This is the second reported case of a child treated with rituximab for SLS who recovered normal lung function. International lupus registries should carefully document the occurrence, treatment and outcome of patients with SLS to help determine the optimal treatment for this rare complication.
Background
Shrinking lung syndrome (SLS) is a rare complication of systemic lupus erythematosus (SLE) characterized by decreased lung volumes and a restrictive pattern on pulmonary function testing (PFTs). Patients typically present with progressive dyspnea and chest pain [1–3]. The diagnosis may be delayed, particularly in pediatric patients, because of failure to consider or recognize this disorder. The exact pathophysiology is unknown [1–3].
Given the rarity of SLS there is a paucity of literature regarding optimal treatment. Case reports and series have documented improvement in most patients treated with corticosteroids, with or without immunosuppressive agents. However, the majority of patients have an incomplete recovery [4, 5]. Recently, rituximab, a monoclonal antibody directed against the CD20 antigen found on the surface of B lymphocytes, has been used successfully in several adult patients and one child with SLE complicated by SLS [6, 7]. We report a child with SLE who developed SLS at age 14 and recovered fully following treatment with rituximab. We also review the literature on SLS in pediatric patients to increase awareness of this exceptionally rare complication, as well as review outcome of patients previously reported with SLS who were treated with rituximab.
Case presentation
At age 11 years, our patient was diagnosed with SLE after presenting with a malar rash, oral ulcers, polyarthritis, myositis, and anemia. His past history was remarkable only for mild asthma; family history was positive for maternal asthma and hypothyroidism. Work-up revealed leukopenia (WBC 2.5 10e9/L), hypocomplementemia (C3 0.23 g/L), positive anti-nuclear antibody, anti-dsDNA (633 IU/ml; normal less than10), anti-SSa/Ro, and anti-Smith antibodies, Class II lupus nephritis and a SLEDAI of 29. A baseline chest radiograph (CXR) was normal. He was treated with prednisone, hydroxychloroquine (HCQ), and azathioprine. A year later he had no symptoms of his SLE but was evaluated for an exercise-associated cough that was felt to be due to his asthma. A CXR was normal, PFTs showed moderate obstruction and symptoms resolved with a bronchodilator. Over the next few months, despite ongoing HCQ, azathioprine and low dose prednisone he had recurrence of malar rash and mild arthritis; a repeat renal biopsy showed Class III b lupus nephritis and azathioprine was replaced by mycophenolate mofetil (MMF) which was increased up to 700 mg/m2/dose BID, and subsequently decreased due to gastrointestinal side effects. This resulted in resolution of all symptoms but some ongoing nephritis (SLEDAI 12).
At age 14 he was admitted to his local hospital with fever, pleuritic chest pain, dyspnea, and cough. Bilateral pleural effusions were seen on CXR and he was given empiric antibiotics for possible pneumonia prior to transfer to our center, where he received a 3-day pulse of intravenous methylprednisolone (IVMP) for a suspected SLE flare (C3 0.70; anti dsDNA 95; SLEDAI 29). His chest symptoms resolved completely and respiratory syncytial virus (RSV) infection was subsequently confirmed by PCR and was thought to have triggered the flare. One month later, despite treatment with low dose prednisone and MMF (535 mg/m2/dose BID, although compliance was questionable), his SLE again flared. He presented with a malar rash, polyarthritis, as well as findings of pleuritis manifesting with chest pain, dyspnea, and a left pleural effusion. He was treated with pulse IVMP followed by increased MMF (625 mg/m2/dose BID) and daily oral prednisone (1 mg/kg/d).
Six weeks later his rash and arthritis had improved, but he reported increasing shortness of breath with marked exercise intolerance. On examination he was afebrile, his heart rate was 120, respiratory rate 40, and oxygen saturation 95% in room air. He appeared dyspneic with difficulty speaking in full sentences. Chest examination revealed shallow breathing and decreased air entry bilaterally. Physical examination was otherwise unremarkable. Work up for infection was negative. His SLEDAI had decreased to 14, C3 had normalized (0.97) and anti dsDNA had decreased to 39. CXR and high-resolution computed tomography (HRCT) showed severely reduced lung volumes with no pleural or interstitial disease; there was slight atelectasis but no other significant abnormalities (Figs. 1, 2). An echocardiogram was normal and a CT angiogram showed no evidence of pulmonary embolus. PFTs revealed a severe restrictive pattern with forced expiratory volume in 1 s (FEV1) of 27%, forced vital capacity (FVC) 29%, and total lung capacity (TLC) 43% (Fig. 3). Fluoroscopy documented significantly reduced diaphragmatic movement. He was diagnosed with SLS, and because of worsening dyspnea despite recently increased immunosuppression, he was treated with IVMP 1 g daily for 3 days followed by rituximab 1 g (2 doses, 2 weeks apart). He was also referred to physiotherapy for pulmonary rehabilitation.
Fig. 1 a Chest X-ray at presentation with SLS, showing decreased lung volumes and raised hemidiaphragms b Normal chest X-ray 3 years later
Fig. 2 High-resolution computed tomography (HRCT) of the chest at presentation with SLS, showing decreased lung volumes and slight atelectasis
Fig. 3 Pulmonary function tests (PFTs) over time in our patient with SLE and SLS; at diagnosis to 4 years following treatment with rituximab. FEV1, forced expiratory volume in 1 s; FVC, forced vital capacity; TLC, total lung capacity; RV, residual volume
One month later he reported some improvement in physical endurance, though he still had dyspnea with mild exertion and PFTs remained severely restrictive. At 6 months, however, he reported much improved exercise tolerance with ability to play some hockey. His FEV1 and FVC had improved to 42 and 51% respectively and TLC had increased to 57%. A planned second course of rituximab, (1 g, 2 doses, 2 weeks apart) was given at 6 months; preceding B cell counts were 8%. He was tapered off corticosteroids over the next 9 months and continued on HCQ (5 mg/kg/d) and MMF (600 mg/m2/dose BID). Serial CXRs showed gradual lung volume expansion. One year after his presentation he returned to playing competitive hockey, with no limitations and no respiratory symptoms. Four years later, he remained asymptomatic with no limitations in activity, no evidence of restrictive lung disease on PFTs (FVC 83%, TLC 94%), and a normal CXR. He remained on the same doses of HCQ and MMF with no clinical evidence of SLE disease activity, normal complement levels (C3 0.97), anti dsDNA 16, a SLEDAI of 2, and a follow renal biopsy showed no active nephritis.
Discussion
Shrinking lung syndrome is a rare complication of SLE with an incidence of approximately 1% in adult lupus patients [1, 5]. The incidence in pediatric SLE is unknown, but is likely even less common. As such, the diagnosis of SLS may not be considered or recognized in a child with SLE. Clinical features include progressive dyspnea, exercise intolerance, and pleuritic chest pain, all of which were described by our patient. Physical examination frequently reveals tachypnea with decreased air entry and the use of accessory respiratory muscles but is otherwise unremarkable. Findings on CXR often include significantly reduced lung volumes with elevated hemidiaphragms and may include pleural effusions, basal atelectasis, and pleural thickening. HRCT typically shows no parenchymal lung disease, though it may be more sensitive than CXR in demonstrating pleural effusions and atelectasis [4, 8]. PFTs show a restrictive pattern [4]. Reduced diaphragmatic excursion may be demonstrated on chest fluoroscopy, as was seen in our patient, or may be demonstrated using M-mode ultrasonography [8].
The pathogenesis of shrinking lung syndrome remains incompletely understood. When first described by Hoffbrand and Beck in 1965, the condition was thought to be due to surfactant deficiency causing microatelectasis [9]. Since then a number of mechanisms have been suggested, including phrenic nerve dysfunction, pleural inflammation and fibrosis, and diaphragmatic dysfunction due to myositis or neuropathy [3, 10]. Anti-SSa/Ro antibody positivity has been associated with both SLS and myositis, and has been suggested to support the theory that myositis contributes to diaphragmatic dysfunction in some patients [3, 11]. Of note, our patient was anti-SSa/Ro positive and had myositis as part of his SLE course. The frequent occurrence of pleuritic chest pain in up to 80% of patients with SLS has led to a more recently proposed mechanism of pleuritic pain leading to reflex inhibition of diaphragmatic activation and subsequent dysfunction in at least a subset of patients with SLS [1, 3]. Henderson et al. have proposed that pleural inflammation due to the underlying rheumatic disease may lead to activation of neural reflexes which inhibit deep inspiration and cause chronic lung hypoinflation. This is postulated to gradually reduce lung compliance and results in a positive feedback cycle [12]. Interestingly, our patient had developed pleuritic chest pain 2 months prior to his diagnosis of SLS, and had documented pleuritis associated with an RSV infection, and then associated with a flare of his SLE, which may have initiated the pathogenetic process leading to SLS.
There is no standard treatment for patients with SLS. Corticosteroids are the most frequently reported initial treatment of SLS, and can lead to full recovery in some patients [3, 5, 11, 13]. Immunosuppressive agents including cyclophosphamide, azathioprine, and methotrexate are often given along with corticosteroids or if corticosteroids alone are ineffective. There are also a few reports of theophylline and beta-agonists used effectively in SLS, and others advocate the use of analgesia to combat chest pain and pulmonary rehabilitation to improve lung expansion [1, 3, 5, 12, 13]. Although rare fatal cases have been described, the prognosis of SLS in adults is generally considered to be good, particularly in comparison with the progressive course and significant mortality associated with fibrotic interstitial lung disease in patients with SLE [1]. Some clinical improvement has been reported in most patients with SLS, however, recent literature makes it clear that despite treatment many patients do not achieve full recovery. Langenskiold et al., in a review of 35 cases with documented pre and post treatment PFTs, found that only 20% of patients with SLS regained normal lung function [4]. Duron et al. reported full recovery in only a minority of patients in their review of 155 patients with SLS, with 42.9% of patients showing chronic and persistent hemidiaphragm elevation [1]. A report of 20 cases from a large single center in 2018 showed a similar outcome, with 86.7% of patients showing continued restrictive defects on spirometry despite improved lung volumes [5]. The lack of full recovery in both adult and pediatric patients with SLS has led to 15 reports of rituximab use in adults and 2 reports in children with SLS complicating SLE [1, 3, 4, 6–8, 12, 14–16] (Table 1). Normal PFTs were reported in one child treated with rituximab [7], however the other child did not respond [12]. All 4 adult patients with well-documented post-treatment PFTs had normal or near normal findings [3, 4, 6]. Although the degree of objective improvement was not documented in the remaining 11 adult cases treated with rituximab, all were reported to have improved or stabilized. (Table 1). There has also been a recent report of a 19-year-old male with pediatric-onset SLE who developed SLS refractory to IVMP and cyclophosphamide and had some improvement with belimumab, a monoclonal antibody directed against BLyS receptors on B-cells, though long-term follow-up is still ongoing [11].
Table 1 Clinical features, treatment and outcome of patients with SLS associated with SLE who received treatment with rituximab
Reference Sex Age at SLE diagnosis Age at SLS diagnosis Clinical presentation Imaging findings at SLS diagnosis PFTs at SLS diagnosis Treatment Outcome
[1] F Unknown 61 Chest pain, history of pleurisy, dyspnea Elevated diaphragms, atelectasis, pleural thickening TLC 46%,
DLCO 25%, KCO 59%
CS + Beta-agonists + RTX (dose unknown) + Physiotherapy Improvement
[1] F Unknown 26 Chest pain, history of pleurisy, dyspnea Pleural thickening, reticulations FVC 41%,
TLC 68%,
DLCO 34%
CS + AZA + MMF + RTX (dose unknown) Improvement
[3] F 36 46 Dyspnea on exertion, orthopnea, pleuritic chest pain Elevated diaphragms, atelectasis, pleural thickening FVC 77%, TLC 68% CS + CYC + RTX (375 mg/m2 once weekly × 4 q6mo) Asymptomatic, normal PFTs
[4] F 28 28 (6 mo after diagnosis of SLE) Dyspnea, pleuritic chest pain, dry cough, orthopnea Elevated diaphragms FVC 61%, TLC 45% Beta-agonists + theophylline, RTX (1 g × 2, 2 weeks apart) + CYC Asymptomatic, normal PFTs
[6] F 38 38a Tachypnea, dyspnea Normal HRCT, elevated diaphragms FVC 64%, FEV1 73% CS + CYC without improvement; followed by RTX (1 g × 2, 2 weeks apart) Normal PFTs, normal CXR 6 months after treatment
[7] F 11 14 Dyspnea on exertion, chest pain Low lung volumes, small bilateral pleural effusions, small pericardial effusion, mild bibasilar atelectasis FVC 31%, TLC 32%, DLCO 96% CYC monthly × 1 year, then RTX (dose unknown) Clinical improvement,
PFTs 2 yrs. post: FVC 82%, TLC 80%
[14] F 22 27 Pleuritic chest pain, exertional dyspnea Elevated diaphragms, normal HRCT FVC 1.45 L (predicted value 4.20), TLC 2.35 (predicted value 5.76), DLCO 16.3 (predicted value 26.5) CS + RTX (375 mg/m2 × 2 doses 6 weeks apart) Initial clinical improvement, followed by re-presentation requiring second course of RTX. Improvement reported 2 yrs. later
[15] F 22 57 Dyspnea, dry cough, pleuritic chest pain Elevated diaphragms, bibasilar atelectasis FVC 43%, TLC 56%, DLCO 55% CS + beta-agonists + AZA + MMF, then 6 mo later RTX (1 g × 2 doses, 2 weeks apart, repeated q6mo) Clinical improvement. PFTs 5 years post: FVC 76%, TLC 79%, DLCO 53%
[16] F Unknown 28 Exercise intolerance, pleuritic chest pain Unknown FVC 0.99 L CS + MMF + RTX (2800 mg) Unlimited exercise tolerance, FVC 2.23 L
[12] F 12 14 Dyspnea, pleuritic chest pain, orthopnea Elevated right hemidiaphragm FVC 36%, TLC 39%, DLCO 102% CS + RTX (dose unknown) + CYC Active disease
[8] F 36 37 Dyspnea, pleuritic chest pain CXR: Bilateral diaphragmatic elevation with mild pleural effusion
HRCT: Mild pleural effusion
Restrictive pattern CS + MTX + beta-agonists + RTX (dose unknown) Restrictive defect improvement
[8] F 36 39 Dyspnea, pleuritic chest pain, fever CXR: Unilateral diaphragmatic elevation, left atelectasia
HRCT: Basal atelectasis
Restrictive pattern CS + MMF + beta-agonists + RTX (dose unknown) Restrictive defect stabilization. Developed ILD 4 yrs. later
[8] F 27 31 Dyspnea, pleuritic chest pain CXR: Unilateral diaphragmatic elevation, right atelectasia
HRCT: Basal atelectasis, mild pleural effusion
Restrictive pattern CS + theophylline + beta-agonists + RTX (dose unknown) Restrictive defect stabilization
[8] F 23 30 Dyspnea, pleuritic chest pain CXR: Unilateral diaphragmatic elevation
HRCT: Basal atelectasis
Restrictive pattern CS + MMF + beta-agonists + RTX (dose unknown) Restrictive defect improvement
[8] F 34 59 Dyspnea, pleuritic chest pain CXR: Bilateral diaphragmatic elevation, atelectasia
HRCT: Basal atelectasis
Restrictive pattern CS + MMF + RTX (dose unknown) + IVIG Restrictive defect stabilization
CS corticosteroids, RTX rituximab, CYC cyclophosphamide, AZA azathioprine, MMF mycophenolate mofetil, IVIG intravenous immunoglobulin, CXR chest X-ray, HRCT high-resolution computed tomography, PFTs pulmonary function tests, FEV1 forced expiratory volume in 1 s, FVC forced vital capacity, TLC total lung capacity, DLCO diffusing capacity for carbon monoxide, ILD interstitial lung disease. PFT results expressed in % predicted when available
a Diagnosis of SLS made at the time of diagnosis of SLE
Shrinking lung syndrome is extremely rare in pediatric lupus patients (defined as 16 years or less at diagnosis), with only 6 well-documented case reports identified in our literature review from 1984 to 2019 (Table 2). Age at onset of SLS ranged from 12 to 15 years, 5 were female, all presented with dyspnea, and 5 had associated chest pain. Interestingly, 3 of the 6 presented at the time of diagnosis of SLE, a much more frequent occurrence than that reported in adults with SLS. Of the 6 patients, only 2 reported a return to baseline respiratory function, both clinically and documented on PFTs [2, 7]. In addition to these 6 patients, our literature review identified 3 patients with pediatric onset SLE who developed SLS at age 19 or 20 [11, 19, 20]. Some improvement in lung function was documented in 2 of these patients, one treated with IVMP, cyclophosphamide and azathioprine, and 1 treated with belimumab. In addition, 7 SLE patients 16–18 years of age have been reported, most in case series of SLS, however very limited information was given on their disease course [1, 5, 12, 21, 22].
Table 2 Clinical features, treatment, and outcome of reported pediatric cases of SLS associated with SLE
Reference Sex Age at SLE diagnosis Age at SLS diagnosis Clinical presentation Imaging findings at SLS diagnosis PFTs at SLS diagnosis Treatment Outcome
[2] F 12 12a Prior diagnosis of mycoplasma pneumonia with recovery. Re-presented 6 months later with dyspnea CXR: Enlarged cardiac silhouette, low lung volumes, elevated diaphragms
HRCT: thoracic lymphadenopathy
FEV1 34%, FVC 27%, TLC 59% CS + CYC (q4weeks × 6 mo) Asymptomatic. Normal PFTs after 1 yr (FEV1 99%, FVC 97%, TLC 92%)
[7] F 11 14 Dyspnea on exertion, chest pain CXR: Low lung volumes, small pleural effusions, small pericardial effusion, mild bibasilar atelectasis FVC 31%, TLC 32%, DLCO 96% CYC monthly × 1 year, then RTX (dose unknown) Clinical improvement,
PFTs 2 yrs. post: FVC 82%, TLC 80%
[10] F 15 15a Pleuritic chest pain, dry cough, dyspnea on exertion Small lung fields, elevated bilateral hemidiaphragms, chest CT normal FEV1 26%, FVC 25%, TLC 31% Beta-agonist Clinical improvement. PFTs after 12d showed FEV1 increase of 58%, FVC increase of 50%, TLC increase of 47%
[17] M 11 14 Fatigue, dyspnea, pleuritic chest pain Enlarged cardiac silhouette, atelectasis, severely reduced diaphragmatic excursion on fluoroscopy FEV1 23%, FVC 20%, TLC 34% CS + AZA Follow-up 23 days later: FEV1 45%, FVC 45%, TLC 57%
[18] F 12 12a Pleuritic chest pain, dyspnea, fever, fatigue, anorexia CXR: Reduced lung volumes, elevated diaphragms, HRCT: pleural thickening Diaphragmatic fluoroscopy: minimal movement FVC 39%, TLC 60%, DLCO normal CS + HCQ 4 yrs. post: ongoing activity limitation, PFTs unchanged
[12] F 12 14 Dyspnea, pleuritic chest pain, orthopnea Elevated right hemidiaphragm FVC 36%, TLC 39%, DLCO 102% CS + RTX (dose unknown) + CYC Active disease
CS corticosteroids, RTX rituximab, CYC cyclophosphamide, AZA azathioprine, HCQ hydroxychloroquine, CXR chest X-ray, HRCT high-resolution computed tomography, PFTs pulmonary function tests, FEV1 forced expiratory volume in 1 s, FVC forced vital capacity, TLC total lung capacity, DLCO diffusing capacity for carbon monoxide. PFT results expressed in % predicted when available
a Diagnosis of SLS made at the time of diagnosis of SLE
Although extremely rare, it is important to recognize SLS as a possible cause of dyspnea and chest pain in a child with SLE, and be aware that in pediatric patients in particular, this complication may occur at the time of initial presentation of SLE. Our patient clearly stated that his goal for treatment was to return to competitive hockey. Recent literature on rituximab use in SLS, a review of pediatric SLS cases, and our case report suggest that additional therapy, including possible use of rituximab, should be considered in patients with SLS who have an incomplete response to initial immunosuppressive therapy. Careful documentation of the occurrence, treatment and outcome of patients with SLS utilizing large registries of adult and pediatric patients with SLE may help determine optimal treatment for this rare complication.
Abbreviations
SLSShrinking lung syndrome
SLESystemic lupus erythematosus
PFTPulmonary function test
FEV1Forced expiratory volume in 1 s
FVCForced vital capacity
TLCTotal lung capacity
RVResidual volume
RSVRespiratory syncytial virus
CXRChest x ray
dsDNADouble stranded DNA
ANAAntinuclear antibody
IVMPMethylprednisolone
PCRPolymerase chain reaction
HRCTHigh resolution computed tomography
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Acknowledgements
We thank the patient and family for participating in this report.
Authors’ contributions
CD and BL reviewed the patient’s medical record pertaining to this case and were major contributors in writing the manuscript. All authors read and approved the final manuscript.
Funding
None.
Availability of data and materials
Data sharing is not applicable to this article as no datasets were generated or analyzed during the current study.
Ethics approval and consent to participate
Research Ethics Board approval (#1024379) was obtained from the IWK Health Centre. Written and informed consent was also obtained from the patient.
Consent for publication
Written and informed consent was obtained from the patient to publish this material.
Competing interests
The authors declare that they have no competing interests. | Recovered | ReactionOutcome | CC BY | 33407629 | 18,886,056 | 2021-01-06 |
What was the outcome of reaction 'Butterfly rash'? | Shrinking lung syndrome treated with rituximab in pediatric systemic lupus erythematosus: a case report and review of the literature.
BACKGROUND
Shrinking lung syndrome (SLS), a rare complication of systemic lupus erythematosus (SLE) characterized by dyspnea, low lung volumes, and a restrictive pattern on pulmonary function tests (PFTs), has only been reported in a few children. Given the rarity of SLS there is a paucity of literature regarding its optimal treatment. Outcomes are variable, with case reports documenting some improvement in most patients treated with corticosteroids, with or without additional immunosuppressive agents. However, most reported patients did not recover normal lung function. We report full recovery of a child with SLE and SLS following treatment with rituximab and review the current literature.
METHODS
An 11-year-old boy presented with a malar rash, myositis, arthritis, oral ulcers, leukopenia, anemia, positive lupus autoantibodies and Class II nephritis. He was diagnosed with SLE and treated with corticosteroids, hydroxychloroquine, azathioprine, and subsequently mycophenolate with symptom resolution. At age 14, his SLE flared coincident with a viral chest infection. He presented with a malar rash, polyarthritis, increased proteinuria and pleuritis which all improved with corticosteroids and ongoing treatment with mycophenolate. Six weeks later he presented with severe dyspnea, markedly decreased lung volumes, but otherwise normal chest X-ray (CXR) and high-resolution chest computed tomography (HRCT). He was found to have severely restricted PFTs (FEV1 27%, FVC 29%; TLC 43%). After additional investigations including echocardiography, pulmonary CT angiography, and diaphragmatic fluoroscopy, he was diagnosed with SLS and treated with rituximab and methylprednisolone. At 1 month his symptoms had improved, but he still had dyspnea with exertion and severely restricted PFTs. At 6 months his FVC and TLC had improved to 51 and 57% respectively, and were 83 and 94% respectively at 4 years. He had returned to all baseline activities, including competitive hockey.
CONCLUSIONS
Although extremely rare, it is important to recognize SLS as a possible cause of dyspnea and chest pain in a child with SLE. Optimal treatment strategies are unknown. This is the second reported case of a child treated with rituximab for SLS who recovered normal lung function. International lupus registries should carefully document the occurrence, treatment and outcome of patients with SLS to help determine the optimal treatment for this rare complication.
Background
Shrinking lung syndrome (SLS) is a rare complication of systemic lupus erythematosus (SLE) characterized by decreased lung volumes and a restrictive pattern on pulmonary function testing (PFTs). Patients typically present with progressive dyspnea and chest pain [1–3]. The diagnosis may be delayed, particularly in pediatric patients, because of failure to consider or recognize this disorder. The exact pathophysiology is unknown [1–3].
Given the rarity of SLS there is a paucity of literature regarding optimal treatment. Case reports and series have documented improvement in most patients treated with corticosteroids, with or without immunosuppressive agents. However, the majority of patients have an incomplete recovery [4, 5]. Recently, rituximab, a monoclonal antibody directed against the CD20 antigen found on the surface of B lymphocytes, has been used successfully in several adult patients and one child with SLE complicated by SLS [6, 7]. We report a child with SLE who developed SLS at age 14 and recovered fully following treatment with rituximab. We also review the literature on SLS in pediatric patients to increase awareness of this exceptionally rare complication, as well as review outcome of patients previously reported with SLS who were treated with rituximab.
Case presentation
At age 11 years, our patient was diagnosed with SLE after presenting with a malar rash, oral ulcers, polyarthritis, myositis, and anemia. His past history was remarkable only for mild asthma; family history was positive for maternal asthma and hypothyroidism. Work-up revealed leukopenia (WBC 2.5 10e9/L), hypocomplementemia (C3 0.23 g/L), positive anti-nuclear antibody, anti-dsDNA (633 IU/ml; normal less than10), anti-SSa/Ro, and anti-Smith antibodies, Class II lupus nephritis and a SLEDAI of 29. A baseline chest radiograph (CXR) was normal. He was treated with prednisone, hydroxychloroquine (HCQ), and azathioprine. A year later he had no symptoms of his SLE but was evaluated for an exercise-associated cough that was felt to be due to his asthma. A CXR was normal, PFTs showed moderate obstruction and symptoms resolved with a bronchodilator. Over the next few months, despite ongoing HCQ, azathioprine and low dose prednisone he had recurrence of malar rash and mild arthritis; a repeat renal biopsy showed Class III b lupus nephritis and azathioprine was replaced by mycophenolate mofetil (MMF) which was increased up to 700 mg/m2/dose BID, and subsequently decreased due to gastrointestinal side effects. This resulted in resolution of all symptoms but some ongoing nephritis (SLEDAI 12).
At age 14 he was admitted to his local hospital with fever, pleuritic chest pain, dyspnea, and cough. Bilateral pleural effusions were seen on CXR and he was given empiric antibiotics for possible pneumonia prior to transfer to our center, where he received a 3-day pulse of intravenous methylprednisolone (IVMP) for a suspected SLE flare (C3 0.70; anti dsDNA 95; SLEDAI 29). His chest symptoms resolved completely and respiratory syncytial virus (RSV) infection was subsequently confirmed by PCR and was thought to have triggered the flare. One month later, despite treatment with low dose prednisone and MMF (535 mg/m2/dose BID, although compliance was questionable), his SLE again flared. He presented with a malar rash, polyarthritis, as well as findings of pleuritis manifesting with chest pain, dyspnea, and a left pleural effusion. He was treated with pulse IVMP followed by increased MMF (625 mg/m2/dose BID) and daily oral prednisone (1 mg/kg/d).
Six weeks later his rash and arthritis had improved, but he reported increasing shortness of breath with marked exercise intolerance. On examination he was afebrile, his heart rate was 120, respiratory rate 40, and oxygen saturation 95% in room air. He appeared dyspneic with difficulty speaking in full sentences. Chest examination revealed shallow breathing and decreased air entry bilaterally. Physical examination was otherwise unremarkable. Work up for infection was negative. His SLEDAI had decreased to 14, C3 had normalized (0.97) and anti dsDNA had decreased to 39. CXR and high-resolution computed tomography (HRCT) showed severely reduced lung volumes with no pleural or interstitial disease; there was slight atelectasis but no other significant abnormalities (Figs. 1, 2). An echocardiogram was normal and a CT angiogram showed no evidence of pulmonary embolus. PFTs revealed a severe restrictive pattern with forced expiratory volume in 1 s (FEV1) of 27%, forced vital capacity (FVC) 29%, and total lung capacity (TLC) 43% (Fig. 3). Fluoroscopy documented significantly reduced diaphragmatic movement. He was diagnosed with SLS, and because of worsening dyspnea despite recently increased immunosuppression, he was treated with IVMP 1 g daily for 3 days followed by rituximab 1 g (2 doses, 2 weeks apart). He was also referred to physiotherapy for pulmonary rehabilitation.
Fig. 1 a Chest X-ray at presentation with SLS, showing decreased lung volumes and raised hemidiaphragms b Normal chest X-ray 3 years later
Fig. 2 High-resolution computed tomography (HRCT) of the chest at presentation with SLS, showing decreased lung volumes and slight atelectasis
Fig. 3 Pulmonary function tests (PFTs) over time in our patient with SLE and SLS; at diagnosis to 4 years following treatment with rituximab. FEV1, forced expiratory volume in 1 s; FVC, forced vital capacity; TLC, total lung capacity; RV, residual volume
One month later he reported some improvement in physical endurance, though he still had dyspnea with mild exertion and PFTs remained severely restrictive. At 6 months, however, he reported much improved exercise tolerance with ability to play some hockey. His FEV1 and FVC had improved to 42 and 51% respectively and TLC had increased to 57%. A planned second course of rituximab, (1 g, 2 doses, 2 weeks apart) was given at 6 months; preceding B cell counts were 8%. He was tapered off corticosteroids over the next 9 months and continued on HCQ (5 mg/kg/d) and MMF (600 mg/m2/dose BID). Serial CXRs showed gradual lung volume expansion. One year after his presentation he returned to playing competitive hockey, with no limitations and no respiratory symptoms. Four years later, he remained asymptomatic with no limitations in activity, no evidence of restrictive lung disease on PFTs (FVC 83%, TLC 94%), and a normal CXR. He remained on the same doses of HCQ and MMF with no clinical evidence of SLE disease activity, normal complement levels (C3 0.97), anti dsDNA 16, a SLEDAI of 2, and a follow renal biopsy showed no active nephritis.
Discussion
Shrinking lung syndrome is a rare complication of SLE with an incidence of approximately 1% in adult lupus patients [1, 5]. The incidence in pediatric SLE is unknown, but is likely even less common. As such, the diagnosis of SLS may not be considered or recognized in a child with SLE. Clinical features include progressive dyspnea, exercise intolerance, and pleuritic chest pain, all of which were described by our patient. Physical examination frequently reveals tachypnea with decreased air entry and the use of accessory respiratory muscles but is otherwise unremarkable. Findings on CXR often include significantly reduced lung volumes with elevated hemidiaphragms and may include pleural effusions, basal atelectasis, and pleural thickening. HRCT typically shows no parenchymal lung disease, though it may be more sensitive than CXR in demonstrating pleural effusions and atelectasis [4, 8]. PFTs show a restrictive pattern [4]. Reduced diaphragmatic excursion may be demonstrated on chest fluoroscopy, as was seen in our patient, or may be demonstrated using M-mode ultrasonography [8].
The pathogenesis of shrinking lung syndrome remains incompletely understood. When first described by Hoffbrand and Beck in 1965, the condition was thought to be due to surfactant deficiency causing microatelectasis [9]. Since then a number of mechanisms have been suggested, including phrenic nerve dysfunction, pleural inflammation and fibrosis, and diaphragmatic dysfunction due to myositis or neuropathy [3, 10]. Anti-SSa/Ro antibody positivity has been associated with both SLS and myositis, and has been suggested to support the theory that myositis contributes to diaphragmatic dysfunction in some patients [3, 11]. Of note, our patient was anti-SSa/Ro positive and had myositis as part of his SLE course. The frequent occurrence of pleuritic chest pain in up to 80% of patients with SLS has led to a more recently proposed mechanism of pleuritic pain leading to reflex inhibition of diaphragmatic activation and subsequent dysfunction in at least a subset of patients with SLS [1, 3]. Henderson et al. have proposed that pleural inflammation due to the underlying rheumatic disease may lead to activation of neural reflexes which inhibit deep inspiration and cause chronic lung hypoinflation. This is postulated to gradually reduce lung compliance and results in a positive feedback cycle [12]. Interestingly, our patient had developed pleuritic chest pain 2 months prior to his diagnosis of SLS, and had documented pleuritis associated with an RSV infection, and then associated with a flare of his SLE, which may have initiated the pathogenetic process leading to SLS.
There is no standard treatment for patients with SLS. Corticosteroids are the most frequently reported initial treatment of SLS, and can lead to full recovery in some patients [3, 5, 11, 13]. Immunosuppressive agents including cyclophosphamide, azathioprine, and methotrexate are often given along with corticosteroids or if corticosteroids alone are ineffective. There are also a few reports of theophylline and beta-agonists used effectively in SLS, and others advocate the use of analgesia to combat chest pain and pulmonary rehabilitation to improve lung expansion [1, 3, 5, 12, 13]. Although rare fatal cases have been described, the prognosis of SLS in adults is generally considered to be good, particularly in comparison with the progressive course and significant mortality associated with fibrotic interstitial lung disease in patients with SLE [1]. Some clinical improvement has been reported in most patients with SLS, however, recent literature makes it clear that despite treatment many patients do not achieve full recovery. Langenskiold et al., in a review of 35 cases with documented pre and post treatment PFTs, found that only 20% of patients with SLS regained normal lung function [4]. Duron et al. reported full recovery in only a minority of patients in their review of 155 patients with SLS, with 42.9% of patients showing chronic and persistent hemidiaphragm elevation [1]. A report of 20 cases from a large single center in 2018 showed a similar outcome, with 86.7% of patients showing continued restrictive defects on spirometry despite improved lung volumes [5]. The lack of full recovery in both adult and pediatric patients with SLS has led to 15 reports of rituximab use in adults and 2 reports in children with SLS complicating SLE [1, 3, 4, 6–8, 12, 14–16] (Table 1). Normal PFTs were reported in one child treated with rituximab [7], however the other child did not respond [12]. All 4 adult patients with well-documented post-treatment PFTs had normal or near normal findings [3, 4, 6]. Although the degree of objective improvement was not documented in the remaining 11 adult cases treated with rituximab, all were reported to have improved or stabilized. (Table 1). There has also been a recent report of a 19-year-old male with pediatric-onset SLE who developed SLS refractory to IVMP and cyclophosphamide and had some improvement with belimumab, a monoclonal antibody directed against BLyS receptors on B-cells, though long-term follow-up is still ongoing [11].
Table 1 Clinical features, treatment and outcome of patients with SLS associated with SLE who received treatment with rituximab
Reference Sex Age at SLE diagnosis Age at SLS diagnosis Clinical presentation Imaging findings at SLS diagnosis PFTs at SLS diagnosis Treatment Outcome
[1] F Unknown 61 Chest pain, history of pleurisy, dyspnea Elevated diaphragms, atelectasis, pleural thickening TLC 46%,
DLCO 25%, KCO 59%
CS + Beta-agonists + RTX (dose unknown) + Physiotherapy Improvement
[1] F Unknown 26 Chest pain, history of pleurisy, dyspnea Pleural thickening, reticulations FVC 41%,
TLC 68%,
DLCO 34%
CS + AZA + MMF + RTX (dose unknown) Improvement
[3] F 36 46 Dyspnea on exertion, orthopnea, pleuritic chest pain Elevated diaphragms, atelectasis, pleural thickening FVC 77%, TLC 68% CS + CYC + RTX (375 mg/m2 once weekly × 4 q6mo) Asymptomatic, normal PFTs
[4] F 28 28 (6 mo after diagnosis of SLE) Dyspnea, pleuritic chest pain, dry cough, orthopnea Elevated diaphragms FVC 61%, TLC 45% Beta-agonists + theophylline, RTX (1 g × 2, 2 weeks apart) + CYC Asymptomatic, normal PFTs
[6] F 38 38a Tachypnea, dyspnea Normal HRCT, elevated diaphragms FVC 64%, FEV1 73% CS + CYC without improvement; followed by RTX (1 g × 2, 2 weeks apart) Normal PFTs, normal CXR 6 months after treatment
[7] F 11 14 Dyspnea on exertion, chest pain Low lung volumes, small bilateral pleural effusions, small pericardial effusion, mild bibasilar atelectasis FVC 31%, TLC 32%, DLCO 96% CYC monthly × 1 year, then RTX (dose unknown) Clinical improvement,
PFTs 2 yrs. post: FVC 82%, TLC 80%
[14] F 22 27 Pleuritic chest pain, exertional dyspnea Elevated diaphragms, normal HRCT FVC 1.45 L (predicted value 4.20), TLC 2.35 (predicted value 5.76), DLCO 16.3 (predicted value 26.5) CS + RTX (375 mg/m2 × 2 doses 6 weeks apart) Initial clinical improvement, followed by re-presentation requiring second course of RTX. Improvement reported 2 yrs. later
[15] F 22 57 Dyspnea, dry cough, pleuritic chest pain Elevated diaphragms, bibasilar atelectasis FVC 43%, TLC 56%, DLCO 55% CS + beta-agonists + AZA + MMF, then 6 mo later RTX (1 g × 2 doses, 2 weeks apart, repeated q6mo) Clinical improvement. PFTs 5 years post: FVC 76%, TLC 79%, DLCO 53%
[16] F Unknown 28 Exercise intolerance, pleuritic chest pain Unknown FVC 0.99 L CS + MMF + RTX (2800 mg) Unlimited exercise tolerance, FVC 2.23 L
[12] F 12 14 Dyspnea, pleuritic chest pain, orthopnea Elevated right hemidiaphragm FVC 36%, TLC 39%, DLCO 102% CS + RTX (dose unknown) + CYC Active disease
[8] F 36 37 Dyspnea, pleuritic chest pain CXR: Bilateral diaphragmatic elevation with mild pleural effusion
HRCT: Mild pleural effusion
Restrictive pattern CS + MTX + beta-agonists + RTX (dose unknown) Restrictive defect improvement
[8] F 36 39 Dyspnea, pleuritic chest pain, fever CXR: Unilateral diaphragmatic elevation, left atelectasia
HRCT: Basal atelectasis
Restrictive pattern CS + MMF + beta-agonists + RTX (dose unknown) Restrictive defect stabilization. Developed ILD 4 yrs. later
[8] F 27 31 Dyspnea, pleuritic chest pain CXR: Unilateral diaphragmatic elevation, right atelectasia
HRCT: Basal atelectasis, mild pleural effusion
Restrictive pattern CS + theophylline + beta-agonists + RTX (dose unknown) Restrictive defect stabilization
[8] F 23 30 Dyspnea, pleuritic chest pain CXR: Unilateral diaphragmatic elevation
HRCT: Basal atelectasis
Restrictive pattern CS + MMF + beta-agonists + RTX (dose unknown) Restrictive defect improvement
[8] F 34 59 Dyspnea, pleuritic chest pain CXR: Bilateral diaphragmatic elevation, atelectasia
HRCT: Basal atelectasis
Restrictive pattern CS + MMF + RTX (dose unknown) + IVIG Restrictive defect stabilization
CS corticosteroids, RTX rituximab, CYC cyclophosphamide, AZA azathioprine, MMF mycophenolate mofetil, IVIG intravenous immunoglobulin, CXR chest X-ray, HRCT high-resolution computed tomography, PFTs pulmonary function tests, FEV1 forced expiratory volume in 1 s, FVC forced vital capacity, TLC total lung capacity, DLCO diffusing capacity for carbon monoxide, ILD interstitial lung disease. PFT results expressed in % predicted when available
a Diagnosis of SLS made at the time of diagnosis of SLE
Shrinking lung syndrome is extremely rare in pediatric lupus patients (defined as 16 years or less at diagnosis), with only 6 well-documented case reports identified in our literature review from 1984 to 2019 (Table 2). Age at onset of SLS ranged from 12 to 15 years, 5 were female, all presented with dyspnea, and 5 had associated chest pain. Interestingly, 3 of the 6 presented at the time of diagnosis of SLE, a much more frequent occurrence than that reported in adults with SLS. Of the 6 patients, only 2 reported a return to baseline respiratory function, both clinically and documented on PFTs [2, 7]. In addition to these 6 patients, our literature review identified 3 patients with pediatric onset SLE who developed SLS at age 19 or 20 [11, 19, 20]. Some improvement in lung function was documented in 2 of these patients, one treated with IVMP, cyclophosphamide and azathioprine, and 1 treated with belimumab. In addition, 7 SLE patients 16–18 years of age have been reported, most in case series of SLS, however very limited information was given on their disease course [1, 5, 12, 21, 22].
Table 2 Clinical features, treatment, and outcome of reported pediatric cases of SLS associated with SLE
Reference Sex Age at SLE diagnosis Age at SLS diagnosis Clinical presentation Imaging findings at SLS diagnosis PFTs at SLS diagnosis Treatment Outcome
[2] F 12 12a Prior diagnosis of mycoplasma pneumonia with recovery. Re-presented 6 months later with dyspnea CXR: Enlarged cardiac silhouette, low lung volumes, elevated diaphragms
HRCT: thoracic lymphadenopathy
FEV1 34%, FVC 27%, TLC 59% CS + CYC (q4weeks × 6 mo) Asymptomatic. Normal PFTs after 1 yr (FEV1 99%, FVC 97%, TLC 92%)
[7] F 11 14 Dyspnea on exertion, chest pain CXR: Low lung volumes, small pleural effusions, small pericardial effusion, mild bibasilar atelectasis FVC 31%, TLC 32%, DLCO 96% CYC monthly × 1 year, then RTX (dose unknown) Clinical improvement,
PFTs 2 yrs. post: FVC 82%, TLC 80%
[10] F 15 15a Pleuritic chest pain, dry cough, dyspnea on exertion Small lung fields, elevated bilateral hemidiaphragms, chest CT normal FEV1 26%, FVC 25%, TLC 31% Beta-agonist Clinical improvement. PFTs after 12d showed FEV1 increase of 58%, FVC increase of 50%, TLC increase of 47%
[17] M 11 14 Fatigue, dyspnea, pleuritic chest pain Enlarged cardiac silhouette, atelectasis, severely reduced diaphragmatic excursion on fluoroscopy FEV1 23%, FVC 20%, TLC 34% CS + AZA Follow-up 23 days later: FEV1 45%, FVC 45%, TLC 57%
[18] F 12 12a Pleuritic chest pain, dyspnea, fever, fatigue, anorexia CXR: Reduced lung volumes, elevated diaphragms, HRCT: pleural thickening Diaphragmatic fluoroscopy: minimal movement FVC 39%, TLC 60%, DLCO normal CS + HCQ 4 yrs. post: ongoing activity limitation, PFTs unchanged
[12] F 12 14 Dyspnea, pleuritic chest pain, orthopnea Elevated right hemidiaphragm FVC 36%, TLC 39%, DLCO 102% CS + RTX (dose unknown) + CYC Active disease
CS corticosteroids, RTX rituximab, CYC cyclophosphamide, AZA azathioprine, HCQ hydroxychloroquine, CXR chest X-ray, HRCT high-resolution computed tomography, PFTs pulmonary function tests, FEV1 forced expiratory volume in 1 s, FVC forced vital capacity, TLC total lung capacity, DLCO diffusing capacity for carbon monoxide. PFT results expressed in % predicted when available
a Diagnosis of SLS made at the time of diagnosis of SLE
Although extremely rare, it is important to recognize SLS as a possible cause of dyspnea and chest pain in a child with SLE, and be aware that in pediatric patients in particular, this complication may occur at the time of initial presentation of SLE. Our patient clearly stated that his goal for treatment was to return to competitive hockey. Recent literature on rituximab use in SLS, a review of pediatric SLS cases, and our case report suggest that additional therapy, including possible use of rituximab, should be considered in patients with SLS who have an incomplete response to initial immunosuppressive therapy. Careful documentation of the occurrence, treatment and outcome of patients with SLS utilizing large registries of adult and pediatric patients with SLE may help determine optimal treatment for this rare complication.
Abbreviations
SLSShrinking lung syndrome
SLESystemic lupus erythematosus
PFTPulmonary function test
FEV1Forced expiratory volume in 1 s
FVCForced vital capacity
TLCTotal lung capacity
RVResidual volume
RSVRespiratory syncytial virus
CXRChest x ray
dsDNADouble stranded DNA
ANAAntinuclear antibody
IVMPMethylprednisolone
PCRPolymerase chain reaction
HRCTHigh resolution computed tomography
Publisher’s Note
Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
Acknowledgements
We thank the patient and family for participating in this report.
Authors’ contributions
CD and BL reviewed the patient’s medical record pertaining to this case and were major contributors in writing the manuscript. All authors read and approved the final manuscript.
Funding
None.
Availability of data and materials
Data sharing is not applicable to this article as no datasets were generated or analyzed during the current study.
Ethics approval and consent to participate
Research Ethics Board approval (#1024379) was obtained from the IWK Health Centre. Written and informed consent was also obtained from the patient.
Consent for publication
Written and informed consent was obtained from the patient to publish this material.
Competing interests
The authors declare that they have no competing interests. | Recovered | ReactionOutcome | CC BY | 33407629 | 18,886,056 | 2021-01-06 |
What was the outcome of reaction 'Disease recurrence'? | Shrinking lung syndrome treated with rituximab in pediatric systemic lupus erythematosus: a case report and review of the literature.
BACKGROUND
Shrinking lung syndrome (SLS), a rare complication of systemic lupus erythematosus (SLE) characterized by dyspnea, low lung volumes, and a restrictive pattern on pulmonary function tests (PFTs), has only been reported in a few children. Given the rarity of SLS there is a paucity of literature regarding its optimal treatment. Outcomes are variable, with case reports documenting some improvement in most patients treated with corticosteroids, with or without additional immunosuppressive agents. However, most reported patients did not recover normal lung function. We report full recovery of a child with SLE and SLS following treatment with rituximab and review the current literature.
METHODS
An 11-year-old boy presented with a malar rash, myositis, arthritis, oral ulcers, leukopenia, anemia, positive lupus autoantibodies and Class II nephritis. He was diagnosed with SLE and treated with corticosteroids, hydroxychloroquine, azathioprine, and subsequently mycophenolate with symptom resolution. At age 14, his SLE flared coincident with a viral chest infection. He presented with a malar rash, polyarthritis, increased proteinuria and pleuritis which all improved with corticosteroids and ongoing treatment with mycophenolate. Six weeks later he presented with severe dyspnea, markedly decreased lung volumes, but otherwise normal chest X-ray (CXR) and high-resolution chest computed tomography (HRCT). He was found to have severely restricted PFTs (FEV1 27%, FVC 29%; TLC 43%). After additional investigations including echocardiography, pulmonary CT angiography, and diaphragmatic fluoroscopy, he was diagnosed with SLS and treated with rituximab and methylprednisolone. At 1 month his symptoms had improved, but he still had dyspnea with exertion and severely restricted PFTs. At 6 months his FVC and TLC had improved to 51 and 57% respectively, and were 83 and 94% respectively at 4 years. He had returned to all baseline activities, including competitive hockey.
CONCLUSIONS
Although extremely rare, it is important to recognize SLS as a possible cause of dyspnea and chest pain in a child with SLE. Optimal treatment strategies are unknown. This is the second reported case of a child treated with rituximab for SLS who recovered normal lung function. International lupus registries should carefully document the occurrence, treatment and outcome of patients with SLS to help determine the optimal treatment for this rare complication.
Background
Shrinking lung syndrome (SLS) is a rare complication of systemic lupus erythematosus (SLE) characterized by decreased lung volumes and a restrictive pattern on pulmonary function testing (PFTs). Patients typically present with progressive dyspnea and chest pain [1–3]. The diagnosis may be delayed, particularly in pediatric patients, because of failure to consider or recognize this disorder. The exact pathophysiology is unknown [1–3].
Given the rarity of SLS there is a paucity of literature regarding optimal treatment. Case reports and series have documented improvement in most patients treated with corticosteroids, with or without immunosuppressive agents. However, the majority of patients have an incomplete recovery [4, 5]. Recently, rituximab, a monoclonal antibody directed against the CD20 antigen found on the surface of B lymphocytes, has been used successfully in several adult patients and one child with SLE complicated by SLS [6, 7]. We report a child with SLE who developed SLS at age 14 and recovered fully following treatment with rituximab. We also review the literature on SLS in pediatric patients to increase awareness of this exceptionally rare complication, as well as review outcome of patients previously reported with SLS who were treated with rituximab.
Case presentation
At age 11 years, our patient was diagnosed with SLE after presenting with a malar rash, oral ulcers, polyarthritis, myositis, and anemia. His past history was remarkable only for mild asthma; family history was positive for maternal asthma and hypothyroidism. Work-up revealed leukopenia (WBC 2.5 10e9/L), hypocomplementemia (C3 0.23 g/L), positive anti-nuclear antibody, anti-dsDNA (633 IU/ml; normal less than10), anti-SSa/Ro, and anti-Smith antibodies, Class II lupus nephritis and a SLEDAI of 29. A baseline chest radiograph (CXR) was normal. He was treated with prednisone, hydroxychloroquine (HCQ), and azathioprine. A year later he had no symptoms of his SLE but was evaluated for an exercise-associated cough that was felt to be due to his asthma. A CXR was normal, PFTs showed moderate obstruction and symptoms resolved with a bronchodilator. Over the next few months, despite ongoing HCQ, azathioprine and low dose prednisone he had recurrence of malar rash and mild arthritis; a repeat renal biopsy showed Class III b lupus nephritis and azathioprine was replaced by mycophenolate mofetil (MMF) which was increased up to 700 mg/m2/dose BID, and subsequently decreased due to gastrointestinal side effects. This resulted in resolution of all symptoms but some ongoing nephritis (SLEDAI 12).
At age 14 he was admitted to his local hospital with fever, pleuritic chest pain, dyspnea, and cough. Bilateral pleural effusions were seen on CXR and he was given empiric antibiotics for possible pneumonia prior to transfer to our center, where he received a 3-day pulse of intravenous methylprednisolone (IVMP) for a suspected SLE flare (C3 0.70; anti dsDNA 95; SLEDAI 29). His chest symptoms resolved completely and respiratory syncytial virus (RSV) infection was subsequently confirmed by PCR and was thought to have triggered the flare. One month later, despite treatment with low dose prednisone and MMF (535 mg/m2/dose BID, although compliance was questionable), his SLE again flared. He presented with a malar rash, polyarthritis, as well as findings of pleuritis manifesting with chest pain, dyspnea, and a left pleural effusion. He was treated with pulse IVMP followed by increased MMF (625 mg/m2/dose BID) and daily oral prednisone (1 mg/kg/d).
Six weeks later his rash and arthritis had improved, but he reported increasing shortness of breath with marked exercise intolerance. On examination he was afebrile, his heart rate was 120, respiratory rate 40, and oxygen saturation 95% in room air. He appeared dyspneic with difficulty speaking in full sentences. Chest examination revealed shallow breathing and decreased air entry bilaterally. Physical examination was otherwise unremarkable. Work up for infection was negative. His SLEDAI had decreased to 14, C3 had normalized (0.97) and anti dsDNA had decreased to 39. CXR and high-resolution computed tomography (HRCT) showed severely reduced lung volumes with no pleural or interstitial disease; there was slight atelectasis but no other significant abnormalities (Figs. 1, 2). An echocardiogram was normal and a CT angiogram showed no evidence of pulmonary embolus. PFTs revealed a severe restrictive pattern with forced expiratory volume in 1 s (FEV1) of 27%, forced vital capacity (FVC) 29%, and total lung capacity (TLC) 43% (Fig. 3). Fluoroscopy documented significantly reduced diaphragmatic movement. He was diagnosed with SLS, and because of worsening dyspnea despite recently increased immunosuppression, he was treated with IVMP 1 g daily for 3 days followed by rituximab 1 g (2 doses, 2 weeks apart). He was also referred to physiotherapy for pulmonary rehabilitation.
Fig. 1 a Chest X-ray at presentation with SLS, showing decreased lung volumes and raised hemidiaphragms b Normal chest X-ray 3 years later
Fig. 2 High-resolution computed tomography (HRCT) of the chest at presentation with SLS, showing decreased lung volumes and slight atelectasis
Fig. 3 Pulmonary function tests (PFTs) over time in our patient with SLE and SLS; at diagnosis to 4 years following treatment with rituximab. FEV1, forced expiratory volume in 1 s; FVC, forced vital capacity; TLC, total lung capacity; RV, residual volume
One month later he reported some improvement in physical endurance, though he still had dyspnea with mild exertion and PFTs remained severely restrictive. At 6 months, however, he reported much improved exercise tolerance with ability to play some hockey. His FEV1 and FVC had improved to 42 and 51% respectively and TLC had increased to 57%. A planned second course of rituximab, (1 g, 2 doses, 2 weeks apart) was given at 6 months; preceding B cell counts were 8%. He was tapered off corticosteroids over the next 9 months and continued on HCQ (5 mg/kg/d) and MMF (600 mg/m2/dose BID). Serial CXRs showed gradual lung volume expansion. One year after his presentation he returned to playing competitive hockey, with no limitations and no respiratory symptoms. Four years later, he remained asymptomatic with no limitations in activity, no evidence of restrictive lung disease on PFTs (FVC 83%, TLC 94%), and a normal CXR. He remained on the same doses of HCQ and MMF with no clinical evidence of SLE disease activity, normal complement levels (C3 0.97), anti dsDNA 16, a SLEDAI of 2, and a follow renal biopsy showed no active nephritis.
Discussion
Shrinking lung syndrome is a rare complication of SLE with an incidence of approximately 1% in adult lupus patients [1, 5]. The incidence in pediatric SLE is unknown, but is likely even less common. As such, the diagnosis of SLS may not be considered or recognized in a child with SLE. Clinical features include progressive dyspnea, exercise intolerance, and pleuritic chest pain, all of which were described by our patient. Physical examination frequently reveals tachypnea with decreased air entry and the use of accessory respiratory muscles but is otherwise unremarkable. Findings on CXR often include significantly reduced lung volumes with elevated hemidiaphragms and may include pleural effusions, basal atelectasis, and pleural thickening. HRCT typically shows no parenchymal lung disease, though it may be more sensitive than CXR in demonstrating pleural effusions and atelectasis [4, 8]. PFTs show a restrictive pattern [4]. Reduced diaphragmatic excursion may be demonstrated on chest fluoroscopy, as was seen in our patient, or may be demonstrated using M-mode ultrasonography [8].
The pathogenesis of shrinking lung syndrome remains incompletely understood. When first described by Hoffbrand and Beck in 1965, the condition was thought to be due to surfactant deficiency causing microatelectasis [9]. Since then a number of mechanisms have been suggested, including phrenic nerve dysfunction, pleural inflammation and fibrosis, and diaphragmatic dysfunction due to myositis or neuropathy [3, 10]. Anti-SSa/Ro antibody positivity has been associated with both SLS and myositis, and has been suggested to support the theory that myositis contributes to diaphragmatic dysfunction in some patients [3, 11]. Of note, our patient was anti-SSa/Ro positive and had myositis as part of his SLE course. The frequent occurrence of pleuritic chest pain in up to 80% of patients with SLS has led to a more recently proposed mechanism of pleuritic pain leading to reflex inhibition of diaphragmatic activation and subsequent dysfunction in at least a subset of patients with SLS [1, 3]. Henderson et al. have proposed that pleural inflammation due to the underlying rheumatic disease may lead to activation of neural reflexes which inhibit deep inspiration and cause chronic lung hypoinflation. This is postulated to gradually reduce lung compliance and results in a positive feedback cycle [12]. Interestingly, our patient had developed pleuritic chest pain 2 months prior to his diagnosis of SLS, and had documented pleuritis associated with an RSV infection, and then associated with a flare of his SLE, which may have initiated the pathogenetic process leading to SLS.
There is no standard treatment for patients with SLS. Corticosteroids are the most frequently reported initial treatment of SLS, and can lead to full recovery in some patients [3, 5, 11, 13]. Immunosuppressive agents including cyclophosphamide, azathioprine, and methotrexate are often given along with corticosteroids or if corticosteroids alone are ineffective. There are also a few reports of theophylline and beta-agonists used effectively in SLS, and others advocate the use of analgesia to combat chest pain and pulmonary rehabilitation to improve lung expansion [1, 3, 5, 12, 13]. Although rare fatal cases have been described, the prognosis of SLS in adults is generally considered to be good, particularly in comparison with the progressive course and significant mortality associated with fibrotic interstitial lung disease in patients with SLE [1]. Some clinical improvement has been reported in most patients with SLS, however, recent literature makes it clear that despite treatment many patients do not achieve full recovery. Langenskiold et al., in a review of 35 cases with documented pre and post treatment PFTs, found that only 20% of patients with SLS regained normal lung function [4]. Duron et al. reported full recovery in only a minority of patients in their review of 155 patients with SLS, with 42.9% of patients showing chronic and persistent hemidiaphragm elevation [1]. A report of 20 cases from a large single center in 2018 showed a similar outcome, with 86.7% of patients showing continued restrictive defects on spirometry despite improved lung volumes [5]. The lack of full recovery in both adult and pediatric patients with SLS has led to 15 reports of rituximab use in adults and 2 reports in children with SLS complicating SLE [1, 3, 4, 6–8, 12, 14–16] (Table 1). Normal PFTs were reported in one child treated with rituximab [7], however the other child did not respond [12]. All 4 adult patients with well-documented post-treatment PFTs had normal or near normal findings [3, 4, 6]. Although the degree of objective improvement was not documented in the remaining 11 adult cases treated with rituximab, all were reported to have improved or stabilized. (Table 1). There has also been a recent report of a 19-year-old male with pediatric-onset SLE who developed SLS refractory to IVMP and cyclophosphamide and had some improvement with belimumab, a monoclonal antibody directed against BLyS receptors on B-cells, though long-term follow-up is still ongoing [11].
Table 1 Clinical features, treatment and outcome of patients with SLS associated with SLE who received treatment with rituximab
Reference Sex Age at SLE diagnosis Age at SLS diagnosis Clinical presentation Imaging findings at SLS diagnosis PFTs at SLS diagnosis Treatment Outcome
[1] F Unknown 61 Chest pain, history of pleurisy, dyspnea Elevated diaphragms, atelectasis, pleural thickening TLC 46%,
DLCO 25%, KCO 59%
CS + Beta-agonists + RTX (dose unknown) + Physiotherapy Improvement
[1] F Unknown 26 Chest pain, history of pleurisy, dyspnea Pleural thickening, reticulations FVC 41%,
TLC 68%,
DLCO 34%
CS + AZA + MMF + RTX (dose unknown) Improvement
[3] F 36 46 Dyspnea on exertion, orthopnea, pleuritic chest pain Elevated diaphragms, atelectasis, pleural thickening FVC 77%, TLC 68% CS + CYC + RTX (375 mg/m2 once weekly × 4 q6mo) Asymptomatic, normal PFTs
[4] F 28 28 (6 mo after diagnosis of SLE) Dyspnea, pleuritic chest pain, dry cough, orthopnea Elevated diaphragms FVC 61%, TLC 45% Beta-agonists + theophylline, RTX (1 g × 2, 2 weeks apart) + CYC Asymptomatic, normal PFTs
[6] F 38 38a Tachypnea, dyspnea Normal HRCT, elevated diaphragms FVC 64%, FEV1 73% CS + CYC without improvement; followed by RTX (1 g × 2, 2 weeks apart) Normal PFTs, normal CXR 6 months after treatment
[7] F 11 14 Dyspnea on exertion, chest pain Low lung volumes, small bilateral pleural effusions, small pericardial effusion, mild bibasilar atelectasis FVC 31%, TLC 32%, DLCO 96% CYC monthly × 1 year, then RTX (dose unknown) Clinical improvement,
PFTs 2 yrs. post: FVC 82%, TLC 80%
[14] F 22 27 Pleuritic chest pain, exertional dyspnea Elevated diaphragms, normal HRCT FVC 1.45 L (predicted value 4.20), TLC 2.35 (predicted value 5.76), DLCO 16.3 (predicted value 26.5) CS + RTX (375 mg/m2 × 2 doses 6 weeks apart) Initial clinical improvement, followed by re-presentation requiring second course of RTX. Improvement reported 2 yrs. later
[15] F 22 57 Dyspnea, dry cough, pleuritic chest pain Elevated diaphragms, bibasilar atelectasis FVC 43%, TLC 56%, DLCO 55% CS + beta-agonists + AZA + MMF, then 6 mo later RTX (1 g × 2 doses, 2 weeks apart, repeated q6mo) Clinical improvement. PFTs 5 years post: FVC 76%, TLC 79%, DLCO 53%
[16] F Unknown 28 Exercise intolerance, pleuritic chest pain Unknown FVC 0.99 L CS + MMF + RTX (2800 mg) Unlimited exercise tolerance, FVC 2.23 L
[12] F 12 14 Dyspnea, pleuritic chest pain, orthopnea Elevated right hemidiaphragm FVC 36%, TLC 39%, DLCO 102% CS + RTX (dose unknown) + CYC Active disease
[8] F 36 37 Dyspnea, pleuritic chest pain CXR: Bilateral diaphragmatic elevation with mild pleural effusion
HRCT: Mild pleural effusion
Restrictive pattern CS + MTX + beta-agonists + RTX (dose unknown) Restrictive defect improvement
[8] F 36 39 Dyspnea, pleuritic chest pain, fever CXR: Unilateral diaphragmatic elevation, left atelectasia
HRCT: Basal atelectasis
Restrictive pattern CS + MMF + beta-agonists + RTX (dose unknown) Restrictive defect stabilization. Developed ILD 4 yrs. later
[8] F 27 31 Dyspnea, pleuritic chest pain CXR: Unilateral diaphragmatic elevation, right atelectasia
HRCT: Basal atelectasis, mild pleural effusion
Restrictive pattern CS + theophylline + beta-agonists + RTX (dose unknown) Restrictive defect stabilization
[8] F 23 30 Dyspnea, pleuritic chest pain CXR: Unilateral diaphragmatic elevation
HRCT: Basal atelectasis
Restrictive pattern CS + MMF + beta-agonists + RTX (dose unknown) Restrictive defect improvement
[8] F 34 59 Dyspnea, pleuritic chest pain CXR: Bilateral diaphragmatic elevation, atelectasia
HRCT: Basal atelectasis
Restrictive pattern CS + MMF + RTX (dose unknown) + IVIG Restrictive defect stabilization
CS corticosteroids, RTX rituximab, CYC cyclophosphamide, AZA azathioprine, MMF mycophenolate mofetil, IVIG intravenous immunoglobulin, CXR chest X-ray, HRCT high-resolution computed tomography, PFTs pulmonary function tests, FEV1 forced expiratory volume in 1 s, FVC forced vital capacity, TLC total lung capacity, DLCO diffusing capacity for carbon monoxide, ILD interstitial lung disease. PFT results expressed in % predicted when available
a Diagnosis of SLS made at the time of diagnosis of SLE
Shrinking lung syndrome is extremely rare in pediatric lupus patients (defined as 16 years or less at diagnosis), with only 6 well-documented case reports identified in our literature review from 1984 to 2019 (Table 2). Age at onset of SLS ranged from 12 to 15 years, 5 were female, all presented with dyspnea, and 5 had associated chest pain. Interestingly, 3 of the 6 presented at the time of diagnosis of SLE, a much more frequent occurrence than that reported in adults with SLS. Of the 6 patients, only 2 reported a return to baseline respiratory function, both clinically and documented on PFTs [2, 7]. In addition to these 6 patients, our literature review identified 3 patients with pediatric onset SLE who developed SLS at age 19 or 20 [11, 19, 20]. Some improvement in lung function was documented in 2 of these patients, one treated with IVMP, cyclophosphamide and azathioprine, and 1 treated with belimumab. In addition, 7 SLE patients 16–18 years of age have been reported, most in case series of SLS, however very limited information was given on their disease course [1, 5, 12, 21, 22].
Table 2 Clinical features, treatment, and outcome of reported pediatric cases of SLS associated with SLE
Reference Sex Age at SLE diagnosis Age at SLS diagnosis Clinical presentation Imaging findings at SLS diagnosis PFTs at SLS diagnosis Treatment Outcome
[2] F 12 12a Prior diagnosis of mycoplasma pneumonia with recovery. Re-presented 6 months later with dyspnea CXR: Enlarged cardiac silhouette, low lung volumes, elevated diaphragms
HRCT: thoracic lymphadenopathy
FEV1 34%, FVC 27%, TLC 59% CS + CYC (q4weeks × 6 mo) Asymptomatic. Normal PFTs after 1 yr (FEV1 99%, FVC 97%, TLC 92%)
[7] F 11 14 Dyspnea on exertion, chest pain CXR: Low lung volumes, small pleural effusions, small pericardial effusion, mild bibasilar atelectasis FVC 31%, TLC 32%, DLCO 96% CYC monthly × 1 year, then RTX (dose unknown) Clinical improvement,
PFTs 2 yrs. post: FVC 82%, TLC 80%
[10] F 15 15a Pleuritic chest pain, dry cough, dyspnea on exertion Small lung fields, elevated bilateral hemidiaphragms, chest CT normal FEV1 26%, FVC 25%, TLC 31% Beta-agonist Clinical improvement. PFTs after 12d showed FEV1 increase of 58%, FVC increase of 50%, TLC increase of 47%
[17] M 11 14 Fatigue, dyspnea, pleuritic chest pain Enlarged cardiac silhouette, atelectasis, severely reduced diaphragmatic excursion on fluoroscopy FEV1 23%, FVC 20%, TLC 34% CS + AZA Follow-up 23 days later: FEV1 45%, FVC 45%, TLC 57%
[18] F 12 12a Pleuritic chest pain, dyspnea, fever, fatigue, anorexia CXR: Reduced lung volumes, elevated diaphragms, HRCT: pleural thickening Diaphragmatic fluoroscopy: minimal movement FVC 39%, TLC 60%, DLCO normal CS + HCQ 4 yrs. post: ongoing activity limitation, PFTs unchanged
[12] F 12 14 Dyspnea, pleuritic chest pain, orthopnea Elevated right hemidiaphragm FVC 36%, TLC 39%, DLCO 102% CS + RTX (dose unknown) + CYC Active disease
CS corticosteroids, RTX rituximab, CYC cyclophosphamide, AZA azathioprine, HCQ hydroxychloroquine, CXR chest X-ray, HRCT high-resolution computed tomography, PFTs pulmonary function tests, FEV1 forced expiratory volume in 1 s, FVC forced vital capacity, TLC total lung capacity, DLCO diffusing capacity for carbon monoxide. PFT results expressed in % predicted when available
a Diagnosis of SLS made at the time of diagnosis of SLE
Although extremely rare, it is important to recognize SLS as a possible cause of dyspnea and chest pain in a child with SLE, and be aware that in pediatric patients in particular, this complication may occur at the time of initial presentation of SLE. Our patient clearly stated that his goal for treatment was to return to competitive hockey. Recent literature on rituximab use in SLS, a review of pediatric SLS cases, and our case report suggest that additional therapy, including possible use of rituximab, should be considered in patients with SLS who have an incomplete response to initial immunosuppressive therapy. Careful documentation of the occurrence, treatment and outcome of patients with SLS utilizing large registries of adult and pediatric patients with SLE may help determine optimal treatment for this rare complication.
Abbreviations
SLSShrinking lung syndrome
SLESystemic lupus erythematosus
PFTPulmonary function test
FEV1Forced expiratory volume in 1 s
FVCForced vital capacity
TLCTotal lung capacity
RVResidual volume
RSVRespiratory syncytial virus
CXRChest x ray
dsDNADouble stranded DNA
ANAAntinuclear antibody
IVMPMethylprednisolone
PCRPolymerase chain reaction
HRCTHigh resolution computed tomography
Publisher’s Note
Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
Acknowledgements
We thank the patient and family for participating in this report.
Authors’ contributions
CD and BL reviewed the patient’s medical record pertaining to this case and were major contributors in writing the manuscript. All authors read and approved the final manuscript.
Funding
None.
Availability of data and materials
Data sharing is not applicable to this article as no datasets were generated or analyzed during the current study.
Ethics approval and consent to participate
Research Ethics Board approval (#1024379) was obtained from the IWK Health Centre. Written and informed consent was also obtained from the patient.
Consent for publication
Written and informed consent was obtained from the patient to publish this material.
Competing interests
The authors declare that they have no competing interests. | Recovered | ReactionOutcome | CC BY | 33407629 | 18,886,056 | 2021-01-06 |
What was the outcome of reaction 'Lupus nephritis'? | Shrinking lung syndrome treated with rituximab in pediatric systemic lupus erythematosus: a case report and review of the literature.
BACKGROUND
Shrinking lung syndrome (SLS), a rare complication of systemic lupus erythematosus (SLE) characterized by dyspnea, low lung volumes, and a restrictive pattern on pulmonary function tests (PFTs), has only been reported in a few children. Given the rarity of SLS there is a paucity of literature regarding its optimal treatment. Outcomes are variable, with case reports documenting some improvement in most patients treated with corticosteroids, with or without additional immunosuppressive agents. However, most reported patients did not recover normal lung function. We report full recovery of a child with SLE and SLS following treatment with rituximab and review the current literature.
METHODS
An 11-year-old boy presented with a malar rash, myositis, arthritis, oral ulcers, leukopenia, anemia, positive lupus autoantibodies and Class II nephritis. He was diagnosed with SLE and treated with corticosteroids, hydroxychloroquine, azathioprine, and subsequently mycophenolate with symptom resolution. At age 14, his SLE flared coincident with a viral chest infection. He presented with a malar rash, polyarthritis, increased proteinuria and pleuritis which all improved with corticosteroids and ongoing treatment with mycophenolate. Six weeks later he presented with severe dyspnea, markedly decreased lung volumes, but otherwise normal chest X-ray (CXR) and high-resolution chest computed tomography (HRCT). He was found to have severely restricted PFTs (FEV1 27%, FVC 29%; TLC 43%). After additional investigations including echocardiography, pulmonary CT angiography, and diaphragmatic fluoroscopy, he was diagnosed with SLS and treated with rituximab and methylprednisolone. At 1 month his symptoms had improved, but he still had dyspnea with exertion and severely restricted PFTs. At 6 months his FVC and TLC had improved to 51 and 57% respectively, and were 83 and 94% respectively at 4 years. He had returned to all baseline activities, including competitive hockey.
CONCLUSIONS
Although extremely rare, it is important to recognize SLS as a possible cause of dyspnea and chest pain in a child with SLE. Optimal treatment strategies are unknown. This is the second reported case of a child treated with rituximab for SLS who recovered normal lung function. International lupus registries should carefully document the occurrence, treatment and outcome of patients with SLS to help determine the optimal treatment for this rare complication.
Background
Shrinking lung syndrome (SLS) is a rare complication of systemic lupus erythematosus (SLE) characterized by decreased lung volumes and a restrictive pattern on pulmonary function testing (PFTs). Patients typically present with progressive dyspnea and chest pain [1–3]. The diagnosis may be delayed, particularly in pediatric patients, because of failure to consider or recognize this disorder. The exact pathophysiology is unknown [1–3].
Given the rarity of SLS there is a paucity of literature regarding optimal treatment. Case reports and series have documented improvement in most patients treated with corticosteroids, with or without immunosuppressive agents. However, the majority of patients have an incomplete recovery [4, 5]. Recently, rituximab, a monoclonal antibody directed against the CD20 antigen found on the surface of B lymphocytes, has been used successfully in several adult patients and one child with SLE complicated by SLS [6, 7]. We report a child with SLE who developed SLS at age 14 and recovered fully following treatment with rituximab. We also review the literature on SLS in pediatric patients to increase awareness of this exceptionally rare complication, as well as review outcome of patients previously reported with SLS who were treated with rituximab.
Case presentation
At age 11 years, our patient was diagnosed with SLE after presenting with a malar rash, oral ulcers, polyarthritis, myositis, and anemia. His past history was remarkable only for mild asthma; family history was positive for maternal asthma and hypothyroidism. Work-up revealed leukopenia (WBC 2.5 10e9/L), hypocomplementemia (C3 0.23 g/L), positive anti-nuclear antibody, anti-dsDNA (633 IU/ml; normal less than10), anti-SSa/Ro, and anti-Smith antibodies, Class II lupus nephritis and a SLEDAI of 29. A baseline chest radiograph (CXR) was normal. He was treated with prednisone, hydroxychloroquine (HCQ), and azathioprine. A year later he had no symptoms of his SLE but was evaluated for an exercise-associated cough that was felt to be due to his asthma. A CXR was normal, PFTs showed moderate obstruction and symptoms resolved with a bronchodilator. Over the next few months, despite ongoing HCQ, azathioprine and low dose prednisone he had recurrence of malar rash and mild arthritis; a repeat renal biopsy showed Class III b lupus nephritis and azathioprine was replaced by mycophenolate mofetil (MMF) which was increased up to 700 mg/m2/dose BID, and subsequently decreased due to gastrointestinal side effects. This resulted in resolution of all symptoms but some ongoing nephritis (SLEDAI 12).
At age 14 he was admitted to his local hospital with fever, pleuritic chest pain, dyspnea, and cough. Bilateral pleural effusions were seen on CXR and he was given empiric antibiotics for possible pneumonia prior to transfer to our center, where he received a 3-day pulse of intravenous methylprednisolone (IVMP) for a suspected SLE flare (C3 0.70; anti dsDNA 95; SLEDAI 29). His chest symptoms resolved completely and respiratory syncytial virus (RSV) infection was subsequently confirmed by PCR and was thought to have triggered the flare. One month later, despite treatment with low dose prednisone and MMF (535 mg/m2/dose BID, although compliance was questionable), his SLE again flared. He presented with a malar rash, polyarthritis, as well as findings of pleuritis manifesting with chest pain, dyspnea, and a left pleural effusion. He was treated with pulse IVMP followed by increased MMF (625 mg/m2/dose BID) and daily oral prednisone (1 mg/kg/d).
Six weeks later his rash and arthritis had improved, but he reported increasing shortness of breath with marked exercise intolerance. On examination he was afebrile, his heart rate was 120, respiratory rate 40, and oxygen saturation 95% in room air. He appeared dyspneic with difficulty speaking in full sentences. Chest examination revealed shallow breathing and decreased air entry bilaterally. Physical examination was otherwise unremarkable. Work up for infection was negative. His SLEDAI had decreased to 14, C3 had normalized (0.97) and anti dsDNA had decreased to 39. CXR and high-resolution computed tomography (HRCT) showed severely reduced lung volumes with no pleural or interstitial disease; there was slight atelectasis but no other significant abnormalities (Figs. 1, 2). An echocardiogram was normal and a CT angiogram showed no evidence of pulmonary embolus. PFTs revealed a severe restrictive pattern with forced expiratory volume in 1 s (FEV1) of 27%, forced vital capacity (FVC) 29%, and total lung capacity (TLC) 43% (Fig. 3). Fluoroscopy documented significantly reduced diaphragmatic movement. He was diagnosed with SLS, and because of worsening dyspnea despite recently increased immunosuppression, he was treated with IVMP 1 g daily for 3 days followed by rituximab 1 g (2 doses, 2 weeks apart). He was also referred to physiotherapy for pulmonary rehabilitation.
Fig. 1 a Chest X-ray at presentation with SLS, showing decreased lung volumes and raised hemidiaphragms b Normal chest X-ray 3 years later
Fig. 2 High-resolution computed tomography (HRCT) of the chest at presentation with SLS, showing decreased lung volumes and slight atelectasis
Fig. 3 Pulmonary function tests (PFTs) over time in our patient with SLE and SLS; at diagnosis to 4 years following treatment with rituximab. FEV1, forced expiratory volume in 1 s; FVC, forced vital capacity; TLC, total lung capacity; RV, residual volume
One month later he reported some improvement in physical endurance, though he still had dyspnea with mild exertion and PFTs remained severely restrictive. At 6 months, however, he reported much improved exercise tolerance with ability to play some hockey. His FEV1 and FVC had improved to 42 and 51% respectively and TLC had increased to 57%. A planned second course of rituximab, (1 g, 2 doses, 2 weeks apart) was given at 6 months; preceding B cell counts were 8%. He was tapered off corticosteroids over the next 9 months and continued on HCQ (5 mg/kg/d) and MMF (600 mg/m2/dose BID). Serial CXRs showed gradual lung volume expansion. One year after his presentation he returned to playing competitive hockey, with no limitations and no respiratory symptoms. Four years later, he remained asymptomatic with no limitations in activity, no evidence of restrictive lung disease on PFTs (FVC 83%, TLC 94%), and a normal CXR. He remained on the same doses of HCQ and MMF with no clinical evidence of SLE disease activity, normal complement levels (C3 0.97), anti dsDNA 16, a SLEDAI of 2, and a follow renal biopsy showed no active nephritis.
Discussion
Shrinking lung syndrome is a rare complication of SLE with an incidence of approximately 1% in adult lupus patients [1, 5]. The incidence in pediatric SLE is unknown, but is likely even less common. As such, the diagnosis of SLS may not be considered or recognized in a child with SLE. Clinical features include progressive dyspnea, exercise intolerance, and pleuritic chest pain, all of which were described by our patient. Physical examination frequently reveals tachypnea with decreased air entry and the use of accessory respiratory muscles but is otherwise unremarkable. Findings on CXR often include significantly reduced lung volumes with elevated hemidiaphragms and may include pleural effusions, basal atelectasis, and pleural thickening. HRCT typically shows no parenchymal lung disease, though it may be more sensitive than CXR in demonstrating pleural effusions and atelectasis [4, 8]. PFTs show a restrictive pattern [4]. Reduced diaphragmatic excursion may be demonstrated on chest fluoroscopy, as was seen in our patient, or may be demonstrated using M-mode ultrasonography [8].
The pathogenesis of shrinking lung syndrome remains incompletely understood. When first described by Hoffbrand and Beck in 1965, the condition was thought to be due to surfactant deficiency causing microatelectasis [9]. Since then a number of mechanisms have been suggested, including phrenic nerve dysfunction, pleural inflammation and fibrosis, and diaphragmatic dysfunction due to myositis or neuropathy [3, 10]. Anti-SSa/Ro antibody positivity has been associated with both SLS and myositis, and has been suggested to support the theory that myositis contributes to diaphragmatic dysfunction in some patients [3, 11]. Of note, our patient was anti-SSa/Ro positive and had myositis as part of his SLE course. The frequent occurrence of pleuritic chest pain in up to 80% of patients with SLS has led to a more recently proposed mechanism of pleuritic pain leading to reflex inhibition of diaphragmatic activation and subsequent dysfunction in at least a subset of patients with SLS [1, 3]. Henderson et al. have proposed that pleural inflammation due to the underlying rheumatic disease may lead to activation of neural reflexes which inhibit deep inspiration and cause chronic lung hypoinflation. This is postulated to gradually reduce lung compliance and results in a positive feedback cycle [12]. Interestingly, our patient had developed pleuritic chest pain 2 months prior to his diagnosis of SLS, and had documented pleuritis associated with an RSV infection, and then associated with a flare of his SLE, which may have initiated the pathogenetic process leading to SLS.
There is no standard treatment for patients with SLS. Corticosteroids are the most frequently reported initial treatment of SLS, and can lead to full recovery in some patients [3, 5, 11, 13]. Immunosuppressive agents including cyclophosphamide, azathioprine, and methotrexate are often given along with corticosteroids or if corticosteroids alone are ineffective. There are also a few reports of theophylline and beta-agonists used effectively in SLS, and others advocate the use of analgesia to combat chest pain and pulmonary rehabilitation to improve lung expansion [1, 3, 5, 12, 13]. Although rare fatal cases have been described, the prognosis of SLS in adults is generally considered to be good, particularly in comparison with the progressive course and significant mortality associated with fibrotic interstitial lung disease in patients with SLE [1]. Some clinical improvement has been reported in most patients with SLS, however, recent literature makes it clear that despite treatment many patients do not achieve full recovery. Langenskiold et al., in a review of 35 cases with documented pre and post treatment PFTs, found that only 20% of patients with SLS regained normal lung function [4]. Duron et al. reported full recovery in only a minority of patients in their review of 155 patients with SLS, with 42.9% of patients showing chronic and persistent hemidiaphragm elevation [1]. A report of 20 cases from a large single center in 2018 showed a similar outcome, with 86.7% of patients showing continued restrictive defects on spirometry despite improved lung volumes [5]. The lack of full recovery in both adult and pediatric patients with SLS has led to 15 reports of rituximab use in adults and 2 reports in children with SLS complicating SLE [1, 3, 4, 6–8, 12, 14–16] (Table 1). Normal PFTs were reported in one child treated with rituximab [7], however the other child did not respond [12]. All 4 adult patients with well-documented post-treatment PFTs had normal or near normal findings [3, 4, 6]. Although the degree of objective improvement was not documented in the remaining 11 adult cases treated with rituximab, all were reported to have improved or stabilized. (Table 1). There has also been a recent report of a 19-year-old male with pediatric-onset SLE who developed SLS refractory to IVMP and cyclophosphamide and had some improvement with belimumab, a monoclonal antibody directed against BLyS receptors on B-cells, though long-term follow-up is still ongoing [11].
Table 1 Clinical features, treatment and outcome of patients with SLS associated with SLE who received treatment with rituximab
Reference Sex Age at SLE diagnosis Age at SLS diagnosis Clinical presentation Imaging findings at SLS diagnosis PFTs at SLS diagnosis Treatment Outcome
[1] F Unknown 61 Chest pain, history of pleurisy, dyspnea Elevated diaphragms, atelectasis, pleural thickening TLC 46%,
DLCO 25%, KCO 59%
CS + Beta-agonists + RTX (dose unknown) + Physiotherapy Improvement
[1] F Unknown 26 Chest pain, history of pleurisy, dyspnea Pleural thickening, reticulations FVC 41%,
TLC 68%,
DLCO 34%
CS + AZA + MMF + RTX (dose unknown) Improvement
[3] F 36 46 Dyspnea on exertion, orthopnea, pleuritic chest pain Elevated diaphragms, atelectasis, pleural thickening FVC 77%, TLC 68% CS + CYC + RTX (375 mg/m2 once weekly × 4 q6mo) Asymptomatic, normal PFTs
[4] F 28 28 (6 mo after diagnosis of SLE) Dyspnea, pleuritic chest pain, dry cough, orthopnea Elevated diaphragms FVC 61%, TLC 45% Beta-agonists + theophylline, RTX (1 g × 2, 2 weeks apart) + CYC Asymptomatic, normal PFTs
[6] F 38 38a Tachypnea, dyspnea Normal HRCT, elevated diaphragms FVC 64%, FEV1 73% CS + CYC without improvement; followed by RTX (1 g × 2, 2 weeks apart) Normal PFTs, normal CXR 6 months after treatment
[7] F 11 14 Dyspnea on exertion, chest pain Low lung volumes, small bilateral pleural effusions, small pericardial effusion, mild bibasilar atelectasis FVC 31%, TLC 32%, DLCO 96% CYC monthly × 1 year, then RTX (dose unknown) Clinical improvement,
PFTs 2 yrs. post: FVC 82%, TLC 80%
[14] F 22 27 Pleuritic chest pain, exertional dyspnea Elevated diaphragms, normal HRCT FVC 1.45 L (predicted value 4.20), TLC 2.35 (predicted value 5.76), DLCO 16.3 (predicted value 26.5) CS + RTX (375 mg/m2 × 2 doses 6 weeks apart) Initial clinical improvement, followed by re-presentation requiring second course of RTX. Improvement reported 2 yrs. later
[15] F 22 57 Dyspnea, dry cough, pleuritic chest pain Elevated diaphragms, bibasilar atelectasis FVC 43%, TLC 56%, DLCO 55% CS + beta-agonists + AZA + MMF, then 6 mo later RTX (1 g × 2 doses, 2 weeks apart, repeated q6mo) Clinical improvement. PFTs 5 years post: FVC 76%, TLC 79%, DLCO 53%
[16] F Unknown 28 Exercise intolerance, pleuritic chest pain Unknown FVC 0.99 L CS + MMF + RTX (2800 mg) Unlimited exercise tolerance, FVC 2.23 L
[12] F 12 14 Dyspnea, pleuritic chest pain, orthopnea Elevated right hemidiaphragm FVC 36%, TLC 39%, DLCO 102% CS + RTX (dose unknown) + CYC Active disease
[8] F 36 37 Dyspnea, pleuritic chest pain CXR: Bilateral diaphragmatic elevation with mild pleural effusion
HRCT: Mild pleural effusion
Restrictive pattern CS + MTX + beta-agonists + RTX (dose unknown) Restrictive defect improvement
[8] F 36 39 Dyspnea, pleuritic chest pain, fever CXR: Unilateral diaphragmatic elevation, left atelectasia
HRCT: Basal atelectasis
Restrictive pattern CS + MMF + beta-agonists + RTX (dose unknown) Restrictive defect stabilization. Developed ILD 4 yrs. later
[8] F 27 31 Dyspnea, pleuritic chest pain CXR: Unilateral diaphragmatic elevation, right atelectasia
HRCT: Basal atelectasis, mild pleural effusion
Restrictive pattern CS + theophylline + beta-agonists + RTX (dose unknown) Restrictive defect stabilization
[8] F 23 30 Dyspnea, pleuritic chest pain CXR: Unilateral diaphragmatic elevation
HRCT: Basal atelectasis
Restrictive pattern CS + MMF + beta-agonists + RTX (dose unknown) Restrictive defect improvement
[8] F 34 59 Dyspnea, pleuritic chest pain CXR: Bilateral diaphragmatic elevation, atelectasia
HRCT: Basal atelectasis
Restrictive pattern CS + MMF + RTX (dose unknown) + IVIG Restrictive defect stabilization
CS corticosteroids, RTX rituximab, CYC cyclophosphamide, AZA azathioprine, MMF mycophenolate mofetil, IVIG intravenous immunoglobulin, CXR chest X-ray, HRCT high-resolution computed tomography, PFTs pulmonary function tests, FEV1 forced expiratory volume in 1 s, FVC forced vital capacity, TLC total lung capacity, DLCO diffusing capacity for carbon monoxide, ILD interstitial lung disease. PFT results expressed in % predicted when available
a Diagnosis of SLS made at the time of diagnosis of SLE
Shrinking lung syndrome is extremely rare in pediatric lupus patients (defined as 16 years or less at diagnosis), with only 6 well-documented case reports identified in our literature review from 1984 to 2019 (Table 2). Age at onset of SLS ranged from 12 to 15 years, 5 were female, all presented with dyspnea, and 5 had associated chest pain. Interestingly, 3 of the 6 presented at the time of diagnosis of SLE, a much more frequent occurrence than that reported in adults with SLS. Of the 6 patients, only 2 reported a return to baseline respiratory function, both clinically and documented on PFTs [2, 7]. In addition to these 6 patients, our literature review identified 3 patients with pediatric onset SLE who developed SLS at age 19 or 20 [11, 19, 20]. Some improvement in lung function was documented in 2 of these patients, one treated with IVMP, cyclophosphamide and azathioprine, and 1 treated with belimumab. In addition, 7 SLE patients 16–18 years of age have been reported, most in case series of SLS, however very limited information was given on their disease course [1, 5, 12, 21, 22].
Table 2 Clinical features, treatment, and outcome of reported pediatric cases of SLS associated with SLE
Reference Sex Age at SLE diagnosis Age at SLS diagnosis Clinical presentation Imaging findings at SLS diagnosis PFTs at SLS diagnosis Treatment Outcome
[2] F 12 12a Prior diagnosis of mycoplasma pneumonia with recovery. Re-presented 6 months later with dyspnea CXR: Enlarged cardiac silhouette, low lung volumes, elevated diaphragms
HRCT: thoracic lymphadenopathy
FEV1 34%, FVC 27%, TLC 59% CS + CYC (q4weeks × 6 mo) Asymptomatic. Normal PFTs after 1 yr (FEV1 99%, FVC 97%, TLC 92%)
[7] F 11 14 Dyspnea on exertion, chest pain CXR: Low lung volumes, small pleural effusions, small pericardial effusion, mild bibasilar atelectasis FVC 31%, TLC 32%, DLCO 96% CYC monthly × 1 year, then RTX (dose unknown) Clinical improvement,
PFTs 2 yrs. post: FVC 82%, TLC 80%
[10] F 15 15a Pleuritic chest pain, dry cough, dyspnea on exertion Small lung fields, elevated bilateral hemidiaphragms, chest CT normal FEV1 26%, FVC 25%, TLC 31% Beta-agonist Clinical improvement. PFTs after 12d showed FEV1 increase of 58%, FVC increase of 50%, TLC increase of 47%
[17] M 11 14 Fatigue, dyspnea, pleuritic chest pain Enlarged cardiac silhouette, atelectasis, severely reduced diaphragmatic excursion on fluoroscopy FEV1 23%, FVC 20%, TLC 34% CS + AZA Follow-up 23 days later: FEV1 45%, FVC 45%, TLC 57%
[18] F 12 12a Pleuritic chest pain, dyspnea, fever, fatigue, anorexia CXR: Reduced lung volumes, elevated diaphragms, HRCT: pleural thickening Diaphragmatic fluoroscopy: minimal movement FVC 39%, TLC 60%, DLCO normal CS + HCQ 4 yrs. post: ongoing activity limitation, PFTs unchanged
[12] F 12 14 Dyspnea, pleuritic chest pain, orthopnea Elevated right hemidiaphragm FVC 36%, TLC 39%, DLCO 102% CS + RTX (dose unknown) + CYC Active disease
CS corticosteroids, RTX rituximab, CYC cyclophosphamide, AZA azathioprine, HCQ hydroxychloroquine, CXR chest X-ray, HRCT high-resolution computed tomography, PFTs pulmonary function tests, FEV1 forced expiratory volume in 1 s, FVC forced vital capacity, TLC total lung capacity, DLCO diffusing capacity for carbon monoxide. PFT results expressed in % predicted when available
a Diagnosis of SLS made at the time of diagnosis of SLE
Although extremely rare, it is important to recognize SLS as a possible cause of dyspnea and chest pain in a child with SLE, and be aware that in pediatric patients in particular, this complication may occur at the time of initial presentation of SLE. Our patient clearly stated that his goal for treatment was to return to competitive hockey. Recent literature on rituximab use in SLS, a review of pediatric SLS cases, and our case report suggest that additional therapy, including possible use of rituximab, should be considered in patients with SLS who have an incomplete response to initial immunosuppressive therapy. Careful documentation of the occurrence, treatment and outcome of patients with SLS utilizing large registries of adult and pediatric patients with SLE may help determine optimal treatment for this rare complication.
Abbreviations
SLSShrinking lung syndrome
SLESystemic lupus erythematosus
PFTPulmonary function test
FEV1Forced expiratory volume in 1 s
FVCForced vital capacity
TLCTotal lung capacity
RVResidual volume
RSVRespiratory syncytial virus
CXRChest x ray
dsDNADouble stranded DNA
ANAAntinuclear antibody
IVMPMethylprednisolone
PCRPolymerase chain reaction
HRCTHigh resolution computed tomography
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Acknowledgements
We thank the patient and family for participating in this report.
Authors’ contributions
CD and BL reviewed the patient’s medical record pertaining to this case and were major contributors in writing the manuscript. All authors read and approved the final manuscript.
Funding
None.
Availability of data and materials
Data sharing is not applicable to this article as no datasets were generated or analyzed during the current study.
Ethics approval and consent to participate
Research Ethics Board approval (#1024379) was obtained from the IWK Health Centre. Written and informed consent was also obtained from the patient.
Consent for publication
Written and informed consent was obtained from the patient to publish this material.
Competing interests
The authors declare that they have no competing interests. | Recovered | ReactionOutcome | CC BY | 33407629 | 18,886,056 | 2021-01-06 |
What was the outcome of reaction 'Pneumonia'? | Shrinking lung syndrome treated with rituximab in pediatric systemic lupus erythematosus: a case report and review of the literature.
BACKGROUND
Shrinking lung syndrome (SLS), a rare complication of systemic lupus erythematosus (SLE) characterized by dyspnea, low lung volumes, and a restrictive pattern on pulmonary function tests (PFTs), has only been reported in a few children. Given the rarity of SLS there is a paucity of literature regarding its optimal treatment. Outcomes are variable, with case reports documenting some improvement in most patients treated with corticosteroids, with or without additional immunosuppressive agents. However, most reported patients did not recover normal lung function. We report full recovery of a child with SLE and SLS following treatment with rituximab and review the current literature.
METHODS
An 11-year-old boy presented with a malar rash, myositis, arthritis, oral ulcers, leukopenia, anemia, positive lupus autoantibodies and Class II nephritis. He was diagnosed with SLE and treated with corticosteroids, hydroxychloroquine, azathioprine, and subsequently mycophenolate with symptom resolution. At age 14, his SLE flared coincident with a viral chest infection. He presented with a malar rash, polyarthritis, increased proteinuria and pleuritis which all improved with corticosteroids and ongoing treatment with mycophenolate. Six weeks later he presented with severe dyspnea, markedly decreased lung volumes, but otherwise normal chest X-ray (CXR) and high-resolution chest computed tomography (HRCT). He was found to have severely restricted PFTs (FEV1 27%, FVC 29%; TLC 43%). After additional investigations including echocardiography, pulmonary CT angiography, and diaphragmatic fluoroscopy, he was diagnosed with SLS and treated with rituximab and methylprednisolone. At 1 month his symptoms had improved, but he still had dyspnea with exertion and severely restricted PFTs. At 6 months his FVC and TLC had improved to 51 and 57% respectively, and were 83 and 94% respectively at 4 years. He had returned to all baseline activities, including competitive hockey.
CONCLUSIONS
Although extremely rare, it is important to recognize SLS as a possible cause of dyspnea and chest pain in a child with SLE. Optimal treatment strategies are unknown. This is the second reported case of a child treated with rituximab for SLS who recovered normal lung function. International lupus registries should carefully document the occurrence, treatment and outcome of patients with SLS to help determine the optimal treatment for this rare complication.
Background
Shrinking lung syndrome (SLS) is a rare complication of systemic lupus erythematosus (SLE) characterized by decreased lung volumes and a restrictive pattern on pulmonary function testing (PFTs). Patients typically present with progressive dyspnea and chest pain [1–3]. The diagnosis may be delayed, particularly in pediatric patients, because of failure to consider or recognize this disorder. The exact pathophysiology is unknown [1–3].
Given the rarity of SLS there is a paucity of literature regarding optimal treatment. Case reports and series have documented improvement in most patients treated with corticosteroids, with or without immunosuppressive agents. However, the majority of patients have an incomplete recovery [4, 5]. Recently, rituximab, a monoclonal antibody directed against the CD20 antigen found on the surface of B lymphocytes, has been used successfully in several adult patients and one child with SLE complicated by SLS [6, 7]. We report a child with SLE who developed SLS at age 14 and recovered fully following treatment with rituximab. We also review the literature on SLS in pediatric patients to increase awareness of this exceptionally rare complication, as well as review outcome of patients previously reported with SLS who were treated with rituximab.
Case presentation
At age 11 years, our patient was diagnosed with SLE after presenting with a malar rash, oral ulcers, polyarthritis, myositis, and anemia. His past history was remarkable only for mild asthma; family history was positive for maternal asthma and hypothyroidism. Work-up revealed leukopenia (WBC 2.5 10e9/L), hypocomplementemia (C3 0.23 g/L), positive anti-nuclear antibody, anti-dsDNA (633 IU/ml; normal less than10), anti-SSa/Ro, and anti-Smith antibodies, Class II lupus nephritis and a SLEDAI of 29. A baseline chest radiograph (CXR) was normal. He was treated with prednisone, hydroxychloroquine (HCQ), and azathioprine. A year later he had no symptoms of his SLE but was evaluated for an exercise-associated cough that was felt to be due to his asthma. A CXR was normal, PFTs showed moderate obstruction and symptoms resolved with a bronchodilator. Over the next few months, despite ongoing HCQ, azathioprine and low dose prednisone he had recurrence of malar rash and mild arthritis; a repeat renal biopsy showed Class III b lupus nephritis and azathioprine was replaced by mycophenolate mofetil (MMF) which was increased up to 700 mg/m2/dose BID, and subsequently decreased due to gastrointestinal side effects. This resulted in resolution of all symptoms but some ongoing nephritis (SLEDAI 12).
At age 14 he was admitted to his local hospital with fever, pleuritic chest pain, dyspnea, and cough. Bilateral pleural effusions were seen on CXR and he was given empiric antibiotics for possible pneumonia prior to transfer to our center, where he received a 3-day pulse of intravenous methylprednisolone (IVMP) for a suspected SLE flare (C3 0.70; anti dsDNA 95; SLEDAI 29). His chest symptoms resolved completely and respiratory syncytial virus (RSV) infection was subsequently confirmed by PCR and was thought to have triggered the flare. One month later, despite treatment with low dose prednisone and MMF (535 mg/m2/dose BID, although compliance was questionable), his SLE again flared. He presented with a malar rash, polyarthritis, as well as findings of pleuritis manifesting with chest pain, dyspnea, and a left pleural effusion. He was treated with pulse IVMP followed by increased MMF (625 mg/m2/dose BID) and daily oral prednisone (1 mg/kg/d).
Six weeks later his rash and arthritis had improved, but he reported increasing shortness of breath with marked exercise intolerance. On examination he was afebrile, his heart rate was 120, respiratory rate 40, and oxygen saturation 95% in room air. He appeared dyspneic with difficulty speaking in full sentences. Chest examination revealed shallow breathing and decreased air entry bilaterally. Physical examination was otherwise unremarkable. Work up for infection was negative. His SLEDAI had decreased to 14, C3 had normalized (0.97) and anti dsDNA had decreased to 39. CXR and high-resolution computed tomography (HRCT) showed severely reduced lung volumes with no pleural or interstitial disease; there was slight atelectasis but no other significant abnormalities (Figs. 1, 2). An echocardiogram was normal and a CT angiogram showed no evidence of pulmonary embolus. PFTs revealed a severe restrictive pattern with forced expiratory volume in 1 s (FEV1) of 27%, forced vital capacity (FVC) 29%, and total lung capacity (TLC) 43% (Fig. 3). Fluoroscopy documented significantly reduced diaphragmatic movement. He was diagnosed with SLS, and because of worsening dyspnea despite recently increased immunosuppression, he was treated with IVMP 1 g daily for 3 days followed by rituximab 1 g (2 doses, 2 weeks apart). He was also referred to physiotherapy for pulmonary rehabilitation.
Fig. 1 a Chest X-ray at presentation with SLS, showing decreased lung volumes and raised hemidiaphragms b Normal chest X-ray 3 years later
Fig. 2 High-resolution computed tomography (HRCT) of the chest at presentation with SLS, showing decreased lung volumes and slight atelectasis
Fig. 3 Pulmonary function tests (PFTs) over time in our patient with SLE and SLS; at diagnosis to 4 years following treatment with rituximab. FEV1, forced expiratory volume in 1 s; FVC, forced vital capacity; TLC, total lung capacity; RV, residual volume
One month later he reported some improvement in physical endurance, though he still had dyspnea with mild exertion and PFTs remained severely restrictive. At 6 months, however, he reported much improved exercise tolerance with ability to play some hockey. His FEV1 and FVC had improved to 42 and 51% respectively and TLC had increased to 57%. A planned second course of rituximab, (1 g, 2 doses, 2 weeks apart) was given at 6 months; preceding B cell counts were 8%. He was tapered off corticosteroids over the next 9 months and continued on HCQ (5 mg/kg/d) and MMF (600 mg/m2/dose BID). Serial CXRs showed gradual lung volume expansion. One year after his presentation he returned to playing competitive hockey, with no limitations and no respiratory symptoms. Four years later, he remained asymptomatic with no limitations in activity, no evidence of restrictive lung disease on PFTs (FVC 83%, TLC 94%), and a normal CXR. He remained on the same doses of HCQ and MMF with no clinical evidence of SLE disease activity, normal complement levels (C3 0.97), anti dsDNA 16, a SLEDAI of 2, and a follow renal biopsy showed no active nephritis.
Discussion
Shrinking lung syndrome is a rare complication of SLE with an incidence of approximately 1% in adult lupus patients [1, 5]. The incidence in pediatric SLE is unknown, but is likely even less common. As such, the diagnosis of SLS may not be considered or recognized in a child with SLE. Clinical features include progressive dyspnea, exercise intolerance, and pleuritic chest pain, all of which were described by our patient. Physical examination frequently reveals tachypnea with decreased air entry and the use of accessory respiratory muscles but is otherwise unremarkable. Findings on CXR often include significantly reduced lung volumes with elevated hemidiaphragms and may include pleural effusions, basal atelectasis, and pleural thickening. HRCT typically shows no parenchymal lung disease, though it may be more sensitive than CXR in demonstrating pleural effusions and atelectasis [4, 8]. PFTs show a restrictive pattern [4]. Reduced diaphragmatic excursion may be demonstrated on chest fluoroscopy, as was seen in our patient, or may be demonstrated using M-mode ultrasonography [8].
The pathogenesis of shrinking lung syndrome remains incompletely understood. When first described by Hoffbrand and Beck in 1965, the condition was thought to be due to surfactant deficiency causing microatelectasis [9]. Since then a number of mechanisms have been suggested, including phrenic nerve dysfunction, pleural inflammation and fibrosis, and diaphragmatic dysfunction due to myositis or neuropathy [3, 10]. Anti-SSa/Ro antibody positivity has been associated with both SLS and myositis, and has been suggested to support the theory that myositis contributes to diaphragmatic dysfunction in some patients [3, 11]. Of note, our patient was anti-SSa/Ro positive and had myositis as part of his SLE course. The frequent occurrence of pleuritic chest pain in up to 80% of patients with SLS has led to a more recently proposed mechanism of pleuritic pain leading to reflex inhibition of diaphragmatic activation and subsequent dysfunction in at least a subset of patients with SLS [1, 3]. Henderson et al. have proposed that pleural inflammation due to the underlying rheumatic disease may lead to activation of neural reflexes which inhibit deep inspiration and cause chronic lung hypoinflation. This is postulated to gradually reduce lung compliance and results in a positive feedback cycle [12]. Interestingly, our patient had developed pleuritic chest pain 2 months prior to his diagnosis of SLS, and had documented pleuritis associated with an RSV infection, and then associated with a flare of his SLE, which may have initiated the pathogenetic process leading to SLS.
There is no standard treatment for patients with SLS. Corticosteroids are the most frequently reported initial treatment of SLS, and can lead to full recovery in some patients [3, 5, 11, 13]. Immunosuppressive agents including cyclophosphamide, azathioprine, and methotrexate are often given along with corticosteroids or if corticosteroids alone are ineffective. There are also a few reports of theophylline and beta-agonists used effectively in SLS, and others advocate the use of analgesia to combat chest pain and pulmonary rehabilitation to improve lung expansion [1, 3, 5, 12, 13]. Although rare fatal cases have been described, the prognosis of SLS in adults is generally considered to be good, particularly in comparison with the progressive course and significant mortality associated with fibrotic interstitial lung disease in patients with SLE [1]. Some clinical improvement has been reported in most patients with SLS, however, recent literature makes it clear that despite treatment many patients do not achieve full recovery. Langenskiold et al., in a review of 35 cases with documented pre and post treatment PFTs, found that only 20% of patients with SLS regained normal lung function [4]. Duron et al. reported full recovery in only a minority of patients in their review of 155 patients with SLS, with 42.9% of patients showing chronic and persistent hemidiaphragm elevation [1]. A report of 20 cases from a large single center in 2018 showed a similar outcome, with 86.7% of patients showing continued restrictive defects on spirometry despite improved lung volumes [5]. The lack of full recovery in both adult and pediatric patients with SLS has led to 15 reports of rituximab use in adults and 2 reports in children with SLS complicating SLE [1, 3, 4, 6–8, 12, 14–16] (Table 1). Normal PFTs were reported in one child treated with rituximab [7], however the other child did not respond [12]. All 4 adult patients with well-documented post-treatment PFTs had normal or near normal findings [3, 4, 6]. Although the degree of objective improvement was not documented in the remaining 11 adult cases treated with rituximab, all were reported to have improved or stabilized. (Table 1). There has also been a recent report of a 19-year-old male with pediatric-onset SLE who developed SLS refractory to IVMP and cyclophosphamide and had some improvement with belimumab, a monoclonal antibody directed against BLyS receptors on B-cells, though long-term follow-up is still ongoing [11].
Table 1 Clinical features, treatment and outcome of patients with SLS associated with SLE who received treatment with rituximab
Reference Sex Age at SLE diagnosis Age at SLS diagnosis Clinical presentation Imaging findings at SLS diagnosis PFTs at SLS diagnosis Treatment Outcome
[1] F Unknown 61 Chest pain, history of pleurisy, dyspnea Elevated diaphragms, atelectasis, pleural thickening TLC 46%,
DLCO 25%, KCO 59%
CS + Beta-agonists + RTX (dose unknown) + Physiotherapy Improvement
[1] F Unknown 26 Chest pain, history of pleurisy, dyspnea Pleural thickening, reticulations FVC 41%,
TLC 68%,
DLCO 34%
CS + AZA + MMF + RTX (dose unknown) Improvement
[3] F 36 46 Dyspnea on exertion, orthopnea, pleuritic chest pain Elevated diaphragms, atelectasis, pleural thickening FVC 77%, TLC 68% CS + CYC + RTX (375 mg/m2 once weekly × 4 q6mo) Asymptomatic, normal PFTs
[4] F 28 28 (6 mo after diagnosis of SLE) Dyspnea, pleuritic chest pain, dry cough, orthopnea Elevated diaphragms FVC 61%, TLC 45% Beta-agonists + theophylline, RTX (1 g × 2, 2 weeks apart) + CYC Asymptomatic, normal PFTs
[6] F 38 38a Tachypnea, dyspnea Normal HRCT, elevated diaphragms FVC 64%, FEV1 73% CS + CYC without improvement; followed by RTX (1 g × 2, 2 weeks apart) Normal PFTs, normal CXR 6 months after treatment
[7] F 11 14 Dyspnea on exertion, chest pain Low lung volumes, small bilateral pleural effusions, small pericardial effusion, mild bibasilar atelectasis FVC 31%, TLC 32%, DLCO 96% CYC monthly × 1 year, then RTX (dose unknown) Clinical improvement,
PFTs 2 yrs. post: FVC 82%, TLC 80%
[14] F 22 27 Pleuritic chest pain, exertional dyspnea Elevated diaphragms, normal HRCT FVC 1.45 L (predicted value 4.20), TLC 2.35 (predicted value 5.76), DLCO 16.3 (predicted value 26.5) CS + RTX (375 mg/m2 × 2 doses 6 weeks apart) Initial clinical improvement, followed by re-presentation requiring second course of RTX. Improvement reported 2 yrs. later
[15] F 22 57 Dyspnea, dry cough, pleuritic chest pain Elevated diaphragms, bibasilar atelectasis FVC 43%, TLC 56%, DLCO 55% CS + beta-agonists + AZA + MMF, then 6 mo later RTX (1 g × 2 doses, 2 weeks apart, repeated q6mo) Clinical improvement. PFTs 5 years post: FVC 76%, TLC 79%, DLCO 53%
[16] F Unknown 28 Exercise intolerance, pleuritic chest pain Unknown FVC 0.99 L CS + MMF + RTX (2800 mg) Unlimited exercise tolerance, FVC 2.23 L
[12] F 12 14 Dyspnea, pleuritic chest pain, orthopnea Elevated right hemidiaphragm FVC 36%, TLC 39%, DLCO 102% CS + RTX (dose unknown) + CYC Active disease
[8] F 36 37 Dyspnea, pleuritic chest pain CXR: Bilateral diaphragmatic elevation with mild pleural effusion
HRCT: Mild pleural effusion
Restrictive pattern CS + MTX + beta-agonists + RTX (dose unknown) Restrictive defect improvement
[8] F 36 39 Dyspnea, pleuritic chest pain, fever CXR: Unilateral diaphragmatic elevation, left atelectasia
HRCT: Basal atelectasis
Restrictive pattern CS + MMF + beta-agonists + RTX (dose unknown) Restrictive defect stabilization. Developed ILD 4 yrs. later
[8] F 27 31 Dyspnea, pleuritic chest pain CXR: Unilateral diaphragmatic elevation, right atelectasia
HRCT: Basal atelectasis, mild pleural effusion
Restrictive pattern CS + theophylline + beta-agonists + RTX (dose unknown) Restrictive defect stabilization
[8] F 23 30 Dyspnea, pleuritic chest pain CXR: Unilateral diaphragmatic elevation
HRCT: Basal atelectasis
Restrictive pattern CS + MMF + beta-agonists + RTX (dose unknown) Restrictive defect improvement
[8] F 34 59 Dyspnea, pleuritic chest pain CXR: Bilateral diaphragmatic elevation, atelectasia
HRCT: Basal atelectasis
Restrictive pattern CS + MMF + RTX (dose unknown) + IVIG Restrictive defect stabilization
CS corticosteroids, RTX rituximab, CYC cyclophosphamide, AZA azathioprine, MMF mycophenolate mofetil, IVIG intravenous immunoglobulin, CXR chest X-ray, HRCT high-resolution computed tomography, PFTs pulmonary function tests, FEV1 forced expiratory volume in 1 s, FVC forced vital capacity, TLC total lung capacity, DLCO diffusing capacity for carbon monoxide, ILD interstitial lung disease. PFT results expressed in % predicted when available
a Diagnosis of SLS made at the time of diagnosis of SLE
Shrinking lung syndrome is extremely rare in pediatric lupus patients (defined as 16 years or less at diagnosis), with only 6 well-documented case reports identified in our literature review from 1984 to 2019 (Table 2). Age at onset of SLS ranged from 12 to 15 years, 5 were female, all presented with dyspnea, and 5 had associated chest pain. Interestingly, 3 of the 6 presented at the time of diagnosis of SLE, a much more frequent occurrence than that reported in adults with SLS. Of the 6 patients, only 2 reported a return to baseline respiratory function, both clinically and documented on PFTs [2, 7]. In addition to these 6 patients, our literature review identified 3 patients with pediatric onset SLE who developed SLS at age 19 or 20 [11, 19, 20]. Some improvement in lung function was documented in 2 of these patients, one treated with IVMP, cyclophosphamide and azathioprine, and 1 treated with belimumab. In addition, 7 SLE patients 16–18 years of age have been reported, most in case series of SLS, however very limited information was given on their disease course [1, 5, 12, 21, 22].
Table 2 Clinical features, treatment, and outcome of reported pediatric cases of SLS associated with SLE
Reference Sex Age at SLE diagnosis Age at SLS diagnosis Clinical presentation Imaging findings at SLS diagnosis PFTs at SLS diagnosis Treatment Outcome
[2] F 12 12a Prior diagnosis of mycoplasma pneumonia with recovery. Re-presented 6 months later with dyspnea CXR: Enlarged cardiac silhouette, low lung volumes, elevated diaphragms
HRCT: thoracic lymphadenopathy
FEV1 34%, FVC 27%, TLC 59% CS + CYC (q4weeks × 6 mo) Asymptomatic. Normal PFTs after 1 yr (FEV1 99%, FVC 97%, TLC 92%)
[7] F 11 14 Dyspnea on exertion, chest pain CXR: Low lung volumes, small pleural effusions, small pericardial effusion, mild bibasilar atelectasis FVC 31%, TLC 32%, DLCO 96% CYC monthly × 1 year, then RTX (dose unknown) Clinical improvement,
PFTs 2 yrs. post: FVC 82%, TLC 80%
[10] F 15 15a Pleuritic chest pain, dry cough, dyspnea on exertion Small lung fields, elevated bilateral hemidiaphragms, chest CT normal FEV1 26%, FVC 25%, TLC 31% Beta-agonist Clinical improvement. PFTs after 12d showed FEV1 increase of 58%, FVC increase of 50%, TLC increase of 47%
[17] M 11 14 Fatigue, dyspnea, pleuritic chest pain Enlarged cardiac silhouette, atelectasis, severely reduced diaphragmatic excursion on fluoroscopy FEV1 23%, FVC 20%, TLC 34% CS + AZA Follow-up 23 days later: FEV1 45%, FVC 45%, TLC 57%
[18] F 12 12a Pleuritic chest pain, dyspnea, fever, fatigue, anorexia CXR: Reduced lung volumes, elevated diaphragms, HRCT: pleural thickening Diaphragmatic fluoroscopy: minimal movement FVC 39%, TLC 60%, DLCO normal CS + HCQ 4 yrs. post: ongoing activity limitation, PFTs unchanged
[12] F 12 14 Dyspnea, pleuritic chest pain, orthopnea Elevated right hemidiaphragm FVC 36%, TLC 39%, DLCO 102% CS + RTX (dose unknown) + CYC Active disease
CS corticosteroids, RTX rituximab, CYC cyclophosphamide, AZA azathioprine, HCQ hydroxychloroquine, CXR chest X-ray, HRCT high-resolution computed tomography, PFTs pulmonary function tests, FEV1 forced expiratory volume in 1 s, FVC forced vital capacity, TLC total lung capacity, DLCO diffusing capacity for carbon monoxide. PFT results expressed in % predicted when available
a Diagnosis of SLS made at the time of diagnosis of SLE
Although extremely rare, it is important to recognize SLS as a possible cause of dyspnea and chest pain in a child with SLE, and be aware that in pediatric patients in particular, this complication may occur at the time of initial presentation of SLE. Our patient clearly stated that his goal for treatment was to return to competitive hockey. Recent literature on rituximab use in SLS, a review of pediatric SLS cases, and our case report suggest that additional therapy, including possible use of rituximab, should be considered in patients with SLS who have an incomplete response to initial immunosuppressive therapy. Careful documentation of the occurrence, treatment and outcome of patients with SLS utilizing large registries of adult and pediatric patients with SLE may help determine optimal treatment for this rare complication.
Abbreviations
SLSShrinking lung syndrome
SLESystemic lupus erythematosus
PFTPulmonary function test
FEV1Forced expiratory volume in 1 s
FVCForced vital capacity
TLCTotal lung capacity
RVResidual volume
RSVRespiratory syncytial virus
CXRChest x ray
dsDNADouble stranded DNA
ANAAntinuclear antibody
IVMPMethylprednisolone
PCRPolymerase chain reaction
HRCTHigh resolution computed tomography
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Acknowledgements
We thank the patient and family for participating in this report.
Authors’ contributions
CD and BL reviewed the patient’s medical record pertaining to this case and were major contributors in writing the manuscript. All authors read and approved the final manuscript.
Funding
None.
Availability of data and materials
Data sharing is not applicable to this article as no datasets were generated or analyzed during the current study.
Ethics approval and consent to participate
Research Ethics Board approval (#1024379) was obtained from the IWK Health Centre. Written and informed consent was also obtained from the patient.
Consent for publication
Written and informed consent was obtained from the patient to publish this material.
Competing interests
The authors declare that they have no competing interests. | Recovered | ReactionOutcome | CC BY | 33407629 | 18,886,056 | 2021-01-06 |
What was the outcome of reaction 'Respiratory syncytial virus infection'? | Shrinking lung syndrome treated with rituximab in pediatric systemic lupus erythematosus: a case report and review of the literature.
BACKGROUND
Shrinking lung syndrome (SLS), a rare complication of systemic lupus erythematosus (SLE) characterized by dyspnea, low lung volumes, and a restrictive pattern on pulmonary function tests (PFTs), has only been reported in a few children. Given the rarity of SLS there is a paucity of literature regarding its optimal treatment. Outcomes are variable, with case reports documenting some improvement in most patients treated with corticosteroids, with or without additional immunosuppressive agents. However, most reported patients did not recover normal lung function. We report full recovery of a child with SLE and SLS following treatment with rituximab and review the current literature.
METHODS
An 11-year-old boy presented with a malar rash, myositis, arthritis, oral ulcers, leukopenia, anemia, positive lupus autoantibodies and Class II nephritis. He was diagnosed with SLE and treated with corticosteroids, hydroxychloroquine, azathioprine, and subsequently mycophenolate with symptom resolution. At age 14, his SLE flared coincident with a viral chest infection. He presented with a malar rash, polyarthritis, increased proteinuria and pleuritis which all improved with corticosteroids and ongoing treatment with mycophenolate. Six weeks later he presented with severe dyspnea, markedly decreased lung volumes, but otherwise normal chest X-ray (CXR) and high-resolution chest computed tomography (HRCT). He was found to have severely restricted PFTs (FEV1 27%, FVC 29%; TLC 43%). After additional investigations including echocardiography, pulmonary CT angiography, and diaphragmatic fluoroscopy, he was diagnosed with SLS and treated with rituximab and methylprednisolone. At 1 month his symptoms had improved, but he still had dyspnea with exertion and severely restricted PFTs. At 6 months his FVC and TLC had improved to 51 and 57% respectively, and were 83 and 94% respectively at 4 years. He had returned to all baseline activities, including competitive hockey.
CONCLUSIONS
Although extremely rare, it is important to recognize SLS as a possible cause of dyspnea and chest pain in a child with SLE. Optimal treatment strategies are unknown. This is the second reported case of a child treated with rituximab for SLS who recovered normal lung function. International lupus registries should carefully document the occurrence, treatment and outcome of patients with SLS to help determine the optimal treatment for this rare complication.
Background
Shrinking lung syndrome (SLS) is a rare complication of systemic lupus erythematosus (SLE) characterized by decreased lung volumes and a restrictive pattern on pulmonary function testing (PFTs). Patients typically present with progressive dyspnea and chest pain [1–3]. The diagnosis may be delayed, particularly in pediatric patients, because of failure to consider or recognize this disorder. The exact pathophysiology is unknown [1–3].
Given the rarity of SLS there is a paucity of literature regarding optimal treatment. Case reports and series have documented improvement in most patients treated with corticosteroids, with or without immunosuppressive agents. However, the majority of patients have an incomplete recovery [4, 5]. Recently, rituximab, a monoclonal antibody directed against the CD20 antigen found on the surface of B lymphocytes, has been used successfully in several adult patients and one child with SLE complicated by SLS [6, 7]. We report a child with SLE who developed SLS at age 14 and recovered fully following treatment with rituximab. We also review the literature on SLS in pediatric patients to increase awareness of this exceptionally rare complication, as well as review outcome of patients previously reported with SLS who were treated with rituximab.
Case presentation
At age 11 years, our patient was diagnosed with SLE after presenting with a malar rash, oral ulcers, polyarthritis, myositis, and anemia. His past history was remarkable only for mild asthma; family history was positive for maternal asthma and hypothyroidism. Work-up revealed leukopenia (WBC 2.5 10e9/L), hypocomplementemia (C3 0.23 g/L), positive anti-nuclear antibody, anti-dsDNA (633 IU/ml; normal less than10), anti-SSa/Ro, and anti-Smith antibodies, Class II lupus nephritis and a SLEDAI of 29. A baseline chest radiograph (CXR) was normal. He was treated with prednisone, hydroxychloroquine (HCQ), and azathioprine. A year later he had no symptoms of his SLE but was evaluated for an exercise-associated cough that was felt to be due to his asthma. A CXR was normal, PFTs showed moderate obstruction and symptoms resolved with a bronchodilator. Over the next few months, despite ongoing HCQ, azathioprine and low dose prednisone he had recurrence of malar rash and mild arthritis; a repeat renal biopsy showed Class III b lupus nephritis and azathioprine was replaced by mycophenolate mofetil (MMF) which was increased up to 700 mg/m2/dose BID, and subsequently decreased due to gastrointestinal side effects. This resulted in resolution of all symptoms but some ongoing nephritis (SLEDAI 12).
At age 14 he was admitted to his local hospital with fever, pleuritic chest pain, dyspnea, and cough. Bilateral pleural effusions were seen on CXR and he was given empiric antibiotics for possible pneumonia prior to transfer to our center, where he received a 3-day pulse of intravenous methylprednisolone (IVMP) for a suspected SLE flare (C3 0.70; anti dsDNA 95; SLEDAI 29). His chest symptoms resolved completely and respiratory syncytial virus (RSV) infection was subsequently confirmed by PCR and was thought to have triggered the flare. One month later, despite treatment with low dose prednisone and MMF (535 mg/m2/dose BID, although compliance was questionable), his SLE again flared. He presented with a malar rash, polyarthritis, as well as findings of pleuritis manifesting with chest pain, dyspnea, and a left pleural effusion. He was treated with pulse IVMP followed by increased MMF (625 mg/m2/dose BID) and daily oral prednisone (1 mg/kg/d).
Six weeks later his rash and arthritis had improved, but he reported increasing shortness of breath with marked exercise intolerance. On examination he was afebrile, his heart rate was 120, respiratory rate 40, and oxygen saturation 95% in room air. He appeared dyspneic with difficulty speaking in full sentences. Chest examination revealed shallow breathing and decreased air entry bilaterally. Physical examination was otherwise unremarkable. Work up for infection was negative. His SLEDAI had decreased to 14, C3 had normalized (0.97) and anti dsDNA had decreased to 39. CXR and high-resolution computed tomography (HRCT) showed severely reduced lung volumes with no pleural or interstitial disease; there was slight atelectasis but no other significant abnormalities (Figs. 1, 2). An echocardiogram was normal and a CT angiogram showed no evidence of pulmonary embolus. PFTs revealed a severe restrictive pattern with forced expiratory volume in 1 s (FEV1) of 27%, forced vital capacity (FVC) 29%, and total lung capacity (TLC) 43% (Fig. 3). Fluoroscopy documented significantly reduced diaphragmatic movement. He was diagnosed with SLS, and because of worsening dyspnea despite recently increased immunosuppression, he was treated with IVMP 1 g daily for 3 days followed by rituximab 1 g (2 doses, 2 weeks apart). He was also referred to physiotherapy for pulmonary rehabilitation.
Fig. 1 a Chest X-ray at presentation with SLS, showing decreased lung volumes and raised hemidiaphragms b Normal chest X-ray 3 years later
Fig. 2 High-resolution computed tomography (HRCT) of the chest at presentation with SLS, showing decreased lung volumes and slight atelectasis
Fig. 3 Pulmonary function tests (PFTs) over time in our patient with SLE and SLS; at diagnosis to 4 years following treatment with rituximab. FEV1, forced expiratory volume in 1 s; FVC, forced vital capacity; TLC, total lung capacity; RV, residual volume
One month later he reported some improvement in physical endurance, though he still had dyspnea with mild exertion and PFTs remained severely restrictive. At 6 months, however, he reported much improved exercise tolerance with ability to play some hockey. His FEV1 and FVC had improved to 42 and 51% respectively and TLC had increased to 57%. A planned second course of rituximab, (1 g, 2 doses, 2 weeks apart) was given at 6 months; preceding B cell counts were 8%. He was tapered off corticosteroids over the next 9 months and continued on HCQ (5 mg/kg/d) and MMF (600 mg/m2/dose BID). Serial CXRs showed gradual lung volume expansion. One year after his presentation he returned to playing competitive hockey, with no limitations and no respiratory symptoms. Four years later, he remained asymptomatic with no limitations in activity, no evidence of restrictive lung disease on PFTs (FVC 83%, TLC 94%), and a normal CXR. He remained on the same doses of HCQ and MMF with no clinical evidence of SLE disease activity, normal complement levels (C3 0.97), anti dsDNA 16, a SLEDAI of 2, and a follow renal biopsy showed no active nephritis.
Discussion
Shrinking lung syndrome is a rare complication of SLE with an incidence of approximately 1% in adult lupus patients [1, 5]. The incidence in pediatric SLE is unknown, but is likely even less common. As such, the diagnosis of SLS may not be considered or recognized in a child with SLE. Clinical features include progressive dyspnea, exercise intolerance, and pleuritic chest pain, all of which were described by our patient. Physical examination frequently reveals tachypnea with decreased air entry and the use of accessory respiratory muscles but is otherwise unremarkable. Findings on CXR often include significantly reduced lung volumes with elevated hemidiaphragms and may include pleural effusions, basal atelectasis, and pleural thickening. HRCT typically shows no parenchymal lung disease, though it may be more sensitive than CXR in demonstrating pleural effusions and atelectasis [4, 8]. PFTs show a restrictive pattern [4]. Reduced diaphragmatic excursion may be demonstrated on chest fluoroscopy, as was seen in our patient, or may be demonstrated using M-mode ultrasonography [8].
The pathogenesis of shrinking lung syndrome remains incompletely understood. When first described by Hoffbrand and Beck in 1965, the condition was thought to be due to surfactant deficiency causing microatelectasis [9]. Since then a number of mechanisms have been suggested, including phrenic nerve dysfunction, pleural inflammation and fibrosis, and diaphragmatic dysfunction due to myositis or neuropathy [3, 10]. Anti-SSa/Ro antibody positivity has been associated with both SLS and myositis, and has been suggested to support the theory that myositis contributes to diaphragmatic dysfunction in some patients [3, 11]. Of note, our patient was anti-SSa/Ro positive and had myositis as part of his SLE course. The frequent occurrence of pleuritic chest pain in up to 80% of patients with SLS has led to a more recently proposed mechanism of pleuritic pain leading to reflex inhibition of diaphragmatic activation and subsequent dysfunction in at least a subset of patients with SLS [1, 3]. Henderson et al. have proposed that pleural inflammation due to the underlying rheumatic disease may lead to activation of neural reflexes which inhibit deep inspiration and cause chronic lung hypoinflation. This is postulated to gradually reduce lung compliance and results in a positive feedback cycle [12]. Interestingly, our patient had developed pleuritic chest pain 2 months prior to his diagnosis of SLS, and had documented pleuritis associated with an RSV infection, and then associated with a flare of his SLE, which may have initiated the pathogenetic process leading to SLS.
There is no standard treatment for patients with SLS. Corticosteroids are the most frequently reported initial treatment of SLS, and can lead to full recovery in some patients [3, 5, 11, 13]. Immunosuppressive agents including cyclophosphamide, azathioprine, and methotrexate are often given along with corticosteroids or if corticosteroids alone are ineffective. There are also a few reports of theophylline and beta-agonists used effectively in SLS, and others advocate the use of analgesia to combat chest pain and pulmonary rehabilitation to improve lung expansion [1, 3, 5, 12, 13]. Although rare fatal cases have been described, the prognosis of SLS in adults is generally considered to be good, particularly in comparison with the progressive course and significant mortality associated with fibrotic interstitial lung disease in patients with SLE [1]. Some clinical improvement has been reported in most patients with SLS, however, recent literature makes it clear that despite treatment many patients do not achieve full recovery. Langenskiold et al., in a review of 35 cases with documented pre and post treatment PFTs, found that only 20% of patients with SLS regained normal lung function [4]. Duron et al. reported full recovery in only a minority of patients in their review of 155 patients with SLS, with 42.9% of patients showing chronic and persistent hemidiaphragm elevation [1]. A report of 20 cases from a large single center in 2018 showed a similar outcome, with 86.7% of patients showing continued restrictive defects on spirometry despite improved lung volumes [5]. The lack of full recovery in both adult and pediatric patients with SLS has led to 15 reports of rituximab use in adults and 2 reports in children with SLS complicating SLE [1, 3, 4, 6–8, 12, 14–16] (Table 1). Normal PFTs were reported in one child treated with rituximab [7], however the other child did not respond [12]. All 4 adult patients with well-documented post-treatment PFTs had normal or near normal findings [3, 4, 6]. Although the degree of objective improvement was not documented in the remaining 11 adult cases treated with rituximab, all were reported to have improved or stabilized. (Table 1). There has also been a recent report of a 19-year-old male with pediatric-onset SLE who developed SLS refractory to IVMP and cyclophosphamide and had some improvement with belimumab, a monoclonal antibody directed against BLyS receptors on B-cells, though long-term follow-up is still ongoing [11].
Table 1 Clinical features, treatment and outcome of patients with SLS associated with SLE who received treatment with rituximab
Reference Sex Age at SLE diagnosis Age at SLS diagnosis Clinical presentation Imaging findings at SLS diagnosis PFTs at SLS diagnosis Treatment Outcome
[1] F Unknown 61 Chest pain, history of pleurisy, dyspnea Elevated diaphragms, atelectasis, pleural thickening TLC 46%,
DLCO 25%, KCO 59%
CS + Beta-agonists + RTX (dose unknown) + Physiotherapy Improvement
[1] F Unknown 26 Chest pain, history of pleurisy, dyspnea Pleural thickening, reticulations FVC 41%,
TLC 68%,
DLCO 34%
CS + AZA + MMF + RTX (dose unknown) Improvement
[3] F 36 46 Dyspnea on exertion, orthopnea, pleuritic chest pain Elevated diaphragms, atelectasis, pleural thickening FVC 77%, TLC 68% CS + CYC + RTX (375 mg/m2 once weekly × 4 q6mo) Asymptomatic, normal PFTs
[4] F 28 28 (6 mo after diagnosis of SLE) Dyspnea, pleuritic chest pain, dry cough, orthopnea Elevated diaphragms FVC 61%, TLC 45% Beta-agonists + theophylline, RTX (1 g × 2, 2 weeks apart) + CYC Asymptomatic, normal PFTs
[6] F 38 38a Tachypnea, dyspnea Normal HRCT, elevated diaphragms FVC 64%, FEV1 73% CS + CYC without improvement; followed by RTX (1 g × 2, 2 weeks apart) Normal PFTs, normal CXR 6 months after treatment
[7] F 11 14 Dyspnea on exertion, chest pain Low lung volumes, small bilateral pleural effusions, small pericardial effusion, mild bibasilar atelectasis FVC 31%, TLC 32%, DLCO 96% CYC monthly × 1 year, then RTX (dose unknown) Clinical improvement,
PFTs 2 yrs. post: FVC 82%, TLC 80%
[14] F 22 27 Pleuritic chest pain, exertional dyspnea Elevated diaphragms, normal HRCT FVC 1.45 L (predicted value 4.20), TLC 2.35 (predicted value 5.76), DLCO 16.3 (predicted value 26.5) CS + RTX (375 mg/m2 × 2 doses 6 weeks apart) Initial clinical improvement, followed by re-presentation requiring second course of RTX. Improvement reported 2 yrs. later
[15] F 22 57 Dyspnea, dry cough, pleuritic chest pain Elevated diaphragms, bibasilar atelectasis FVC 43%, TLC 56%, DLCO 55% CS + beta-agonists + AZA + MMF, then 6 mo later RTX (1 g × 2 doses, 2 weeks apart, repeated q6mo) Clinical improvement. PFTs 5 years post: FVC 76%, TLC 79%, DLCO 53%
[16] F Unknown 28 Exercise intolerance, pleuritic chest pain Unknown FVC 0.99 L CS + MMF + RTX (2800 mg) Unlimited exercise tolerance, FVC 2.23 L
[12] F 12 14 Dyspnea, pleuritic chest pain, orthopnea Elevated right hemidiaphragm FVC 36%, TLC 39%, DLCO 102% CS + RTX (dose unknown) + CYC Active disease
[8] F 36 37 Dyspnea, pleuritic chest pain CXR: Bilateral diaphragmatic elevation with mild pleural effusion
HRCT: Mild pleural effusion
Restrictive pattern CS + MTX + beta-agonists + RTX (dose unknown) Restrictive defect improvement
[8] F 36 39 Dyspnea, pleuritic chest pain, fever CXR: Unilateral diaphragmatic elevation, left atelectasia
HRCT: Basal atelectasis
Restrictive pattern CS + MMF + beta-agonists + RTX (dose unknown) Restrictive defect stabilization. Developed ILD 4 yrs. later
[8] F 27 31 Dyspnea, pleuritic chest pain CXR: Unilateral diaphragmatic elevation, right atelectasia
HRCT: Basal atelectasis, mild pleural effusion
Restrictive pattern CS + theophylline + beta-agonists + RTX (dose unknown) Restrictive defect stabilization
[8] F 23 30 Dyspnea, pleuritic chest pain CXR: Unilateral diaphragmatic elevation
HRCT: Basal atelectasis
Restrictive pattern CS + MMF + beta-agonists + RTX (dose unknown) Restrictive defect improvement
[8] F 34 59 Dyspnea, pleuritic chest pain CXR: Bilateral diaphragmatic elevation, atelectasia
HRCT: Basal atelectasis
Restrictive pattern CS + MMF + RTX (dose unknown) + IVIG Restrictive defect stabilization
CS corticosteroids, RTX rituximab, CYC cyclophosphamide, AZA azathioprine, MMF mycophenolate mofetil, IVIG intravenous immunoglobulin, CXR chest X-ray, HRCT high-resolution computed tomography, PFTs pulmonary function tests, FEV1 forced expiratory volume in 1 s, FVC forced vital capacity, TLC total lung capacity, DLCO diffusing capacity for carbon monoxide, ILD interstitial lung disease. PFT results expressed in % predicted when available
a Diagnosis of SLS made at the time of diagnosis of SLE
Shrinking lung syndrome is extremely rare in pediatric lupus patients (defined as 16 years or less at diagnosis), with only 6 well-documented case reports identified in our literature review from 1984 to 2019 (Table 2). Age at onset of SLS ranged from 12 to 15 years, 5 were female, all presented with dyspnea, and 5 had associated chest pain. Interestingly, 3 of the 6 presented at the time of diagnosis of SLE, a much more frequent occurrence than that reported in adults with SLS. Of the 6 patients, only 2 reported a return to baseline respiratory function, both clinically and documented on PFTs [2, 7]. In addition to these 6 patients, our literature review identified 3 patients with pediatric onset SLE who developed SLS at age 19 or 20 [11, 19, 20]. Some improvement in lung function was documented in 2 of these patients, one treated with IVMP, cyclophosphamide and azathioprine, and 1 treated with belimumab. In addition, 7 SLE patients 16–18 years of age have been reported, most in case series of SLS, however very limited information was given on their disease course [1, 5, 12, 21, 22].
Table 2 Clinical features, treatment, and outcome of reported pediatric cases of SLS associated with SLE
Reference Sex Age at SLE diagnosis Age at SLS diagnosis Clinical presentation Imaging findings at SLS diagnosis PFTs at SLS diagnosis Treatment Outcome
[2] F 12 12a Prior diagnosis of mycoplasma pneumonia with recovery. Re-presented 6 months later with dyspnea CXR: Enlarged cardiac silhouette, low lung volumes, elevated diaphragms
HRCT: thoracic lymphadenopathy
FEV1 34%, FVC 27%, TLC 59% CS + CYC (q4weeks × 6 mo) Asymptomatic. Normal PFTs after 1 yr (FEV1 99%, FVC 97%, TLC 92%)
[7] F 11 14 Dyspnea on exertion, chest pain CXR: Low lung volumes, small pleural effusions, small pericardial effusion, mild bibasilar atelectasis FVC 31%, TLC 32%, DLCO 96% CYC monthly × 1 year, then RTX (dose unknown) Clinical improvement,
PFTs 2 yrs. post: FVC 82%, TLC 80%
[10] F 15 15a Pleuritic chest pain, dry cough, dyspnea on exertion Small lung fields, elevated bilateral hemidiaphragms, chest CT normal FEV1 26%, FVC 25%, TLC 31% Beta-agonist Clinical improvement. PFTs after 12d showed FEV1 increase of 58%, FVC increase of 50%, TLC increase of 47%
[17] M 11 14 Fatigue, dyspnea, pleuritic chest pain Enlarged cardiac silhouette, atelectasis, severely reduced diaphragmatic excursion on fluoroscopy FEV1 23%, FVC 20%, TLC 34% CS + AZA Follow-up 23 days later: FEV1 45%, FVC 45%, TLC 57%
[18] F 12 12a Pleuritic chest pain, dyspnea, fever, fatigue, anorexia CXR: Reduced lung volumes, elevated diaphragms, HRCT: pleural thickening Diaphragmatic fluoroscopy: minimal movement FVC 39%, TLC 60%, DLCO normal CS + HCQ 4 yrs. post: ongoing activity limitation, PFTs unchanged
[12] F 12 14 Dyspnea, pleuritic chest pain, orthopnea Elevated right hemidiaphragm FVC 36%, TLC 39%, DLCO 102% CS + RTX (dose unknown) + CYC Active disease
CS corticosteroids, RTX rituximab, CYC cyclophosphamide, AZA azathioprine, HCQ hydroxychloroquine, CXR chest X-ray, HRCT high-resolution computed tomography, PFTs pulmonary function tests, FEV1 forced expiratory volume in 1 s, FVC forced vital capacity, TLC total lung capacity, DLCO diffusing capacity for carbon monoxide. PFT results expressed in % predicted when available
a Diagnosis of SLS made at the time of diagnosis of SLE
Although extremely rare, it is important to recognize SLS as a possible cause of dyspnea and chest pain in a child with SLE, and be aware that in pediatric patients in particular, this complication may occur at the time of initial presentation of SLE. Our patient clearly stated that his goal for treatment was to return to competitive hockey. Recent literature on rituximab use in SLS, a review of pediatric SLS cases, and our case report suggest that additional therapy, including possible use of rituximab, should be considered in patients with SLS who have an incomplete response to initial immunosuppressive therapy. Careful documentation of the occurrence, treatment and outcome of patients with SLS utilizing large registries of adult and pediatric patients with SLE may help determine optimal treatment for this rare complication.
Abbreviations
SLSShrinking lung syndrome
SLESystemic lupus erythematosus
PFTPulmonary function test
FEV1Forced expiratory volume in 1 s
FVCForced vital capacity
TLCTotal lung capacity
RVResidual volume
RSVRespiratory syncytial virus
CXRChest x ray
dsDNADouble stranded DNA
ANAAntinuclear antibody
IVMPMethylprednisolone
PCRPolymerase chain reaction
HRCTHigh resolution computed tomography
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Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
Acknowledgements
We thank the patient and family for participating in this report.
Authors’ contributions
CD and BL reviewed the patient’s medical record pertaining to this case and were major contributors in writing the manuscript. All authors read and approved the final manuscript.
Funding
None.
Availability of data and materials
Data sharing is not applicable to this article as no datasets were generated or analyzed during the current study.
Ethics approval and consent to participate
Research Ethics Board approval (#1024379) was obtained from the IWK Health Centre. Written and informed consent was also obtained from the patient.
Consent for publication
Written and informed consent was obtained from the patient to publish this material.
Competing interests
The authors declare that they have no competing interests. | Recovered | ReactionOutcome | CC BY | 33407629 | 18,886,056 | 2021-01-06 |
Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Antinuclear antibody positive'. | ANCA-negative microscopic polyangiitis with diffuse alveolar hemorrhage masquerading as congestive heart failure.
BACKGROUND
Microscopic polyangiitis (MPA) is a subtype of anti-neutrophil cytoplasmic antibody-associated vasculitis (AAV), involving small and medium sized vessels, often affecting the kidneys and lungs. Anti-neutrophil cytoplasmic antibody (ANCA) is detected in up to 90% of cases of MPA and its detection helps guide diagnosis, however cases of ANCA-negative MPA have been reported, hence definitive diagnosis relies on tissue biopsy.
METHODS
A 23-year-old man was evaluated for dyspnea and pleuritic chest pain, and found to have bilateral intra-alveolar opacities and hilar adenopathy. Diagnostic work up revealed positive anti-nuclear antibodies (ANA) and negative ANCA, which in the setting of a non-classical presentation, delayed diagnosis and appropriate treatment. Due to persistent symptoms and a high suspicion for autoimmune disease with pulmonary-renal syndrome, he underwent lung biopsy which revealed intra-alveolar hemorrhage and capillaritis indicative of microscopic polyangiitis (MPA). Surprisingly, kidney biopsy was not typical of classic MPA, but revealed less common features. Due to therapeutic noncompliance he was readmitted multiple times thereafter with rare complications of MPA such as acute pancreatitis and hemorrhagic pericardial effusion with tamponade.
CONCLUSIONS
This case serves as an important clinical reminder to consider AAV even in those with negative ANCA serologies and a high suspicion for pulmonary-renal syndrome. It also demonstrates the high morbidity in cases of diagnostic delay and inadequate treatment.
Background
The 2012 Chapel Hill Consensus guideline recognizes microscopic polyangiitis (MPA) as a subset of ANCA-associated vasculitis (AAV), a group of necrotizing pauci-immune vasculitides that predominantly affects small vessels—capillaries, venules, and arterioles—with few or no immune deposits [1]. AAV commonly affects the renal and pulmonary parenchyma to varying degrees, and is characterized by the presence of antibodies against neutrophilic cytoplasmic components, Proteinase-3 (PR3, c-ANCA) and Myeloperoxidase (MPO, p-ANCA). AAV include Microscopic Polyangiitis (MPA), Granulomatosis with polyangiitis (GPA; Wegener’s) and Eosinophilic granulomatosis with angiitis (EGPA; Churg-Strauss), as well as a variety of additional AAV-associated syndromes (drug-induced vasculitis, renal-limited vasculitis (RLV)), each characterized by the presence of distinct clinical presentation, ANCA subtypes, histopathological findings, and associated laboratory findings [1–4].
MPA is characterized by the presence of anti-MPO (p-ANCA) antibodies, renal and pulmonary involvement, and the absence of granulomatous inflammation on histopathology, a defining feature when compared to GPA and EGPA which, while demonstrating both renal and pulmonary involvement, are characterized by the presence of anti-PR3 (c-ANCA) and granulomatous disease. Though a widely accepted marker for AAV, the presence of ANCA is variable and not detected in all cases. ANCA is detected in 80–90% of cases of MPA and its detection has become integral in the diagnostic workup as well as classification and prognostication of all AAV [3, 4]. While current evidence indicates that ANCA plays a role in pathogenesis of MPA and other AAV, cases of ANCA-negative vasculitis, including cases of ANCA-negative MPA, GPA, and EGPA have been reported [1–7]. We present a case of ANCA-negative MPA in a young man who presented with hemoptysis and was found to have diffuse bilateral lung infiltrates, acute kidney injury, and heart failure. Following a circuitous diagnostic course masked by symptoms of heart failure, he was eventually diagnosed with MPA, however the course of his disease was further complicated by medication non-compliance as well as rare complications of AAV, including acute pancreatitis, pancreatic pseudoaneurysm, and cardiac tamponade.
Case report
A 23-year-old African-American man with past medical history of G6PD-deficiency and obesity presented with dyspnea and pleuritic chest pain that improved upon leaning forward and scant hemoptysis of two weeks duration. He was notably hypertensive to the 220/110 s mmHg and tachycardic to the 120 s, but had a preserved respiratory rate and oxygen saturation. Physical exam was remarkable for bilateral diffuse wheezing throughout all lung fields. Other parts of the exam including cardiovascular, nasopharynx, skin and musculoskeletal systems were unremarkable. Additional pertinent history was remarkable only for marijuana smoking. Electrocardiogram was unremarkable except for left atrial enlargement. Chest X-ray revealed bilateral pulmonary infiltrates, cardiomegaly, and mediastinal enlargement suggestive of bulky hilar adenopathy. Computed tomography (CT) scan of the chest with contrast was performed which was negative for pulmonary embolism, but revealed bilateral centrilobular opacities, hilar/mediastinal lymphadenopathy, and a trivial pericardial effusion (Fig. 1a). Initial laboratory diagnostics were significant for acute kidney injury with a serum creatinine of 2.03 (mg/dL), trace proteinuria, troponin elevation to 0.232 (ng/mL), and a D-Dimer of 1.3 (mcg/mL). Complete blood count revealed no leukocytosis, but concomitant eosinophilia, with no evidence of anemia. The patient was subsequently admitted to the medicine wards and a therapeutic regimen of antihypertensive agents as well as intravenous ceftriaxone and azithromycin for presumed community acquired pneumonia was initiated.Fig. 1 CT scans of the chest. a CT Scan of the chest on first day of presentation demonstrating bilateral centrilobular opacities, hilar/mediastinal lymphadenopathy, moderate cardiomegaly, a trivial pericardial effusion and enlargement of the main pulmonary artery. b Prone CT chest on day 7 of admission, revealing persistent intra-alveolar opacities with associated mediastinal lymphadenopathy
Additional diagnostic evaluation demonstrated marked elevation of CRP (80 mg/L) and ESR (67 mm/hr). Pheochromocytoma screening with serum catecholamines and metanephrines was negative. An echocardiogram revealed an ejection fraction of 40%, moderate concentric left ventricular hypertrophy, and trivial pericardial effusion without evidence of tamponade or pulmonary artery hypertension. Despite continuation of antibiotics for pneumonia and adjunctive heart failure management, the patient’s clinical status failed to improve. In the setting of an unremarkable infectious workup and concern for an autoimmune etiology, the patient was started on oral prednisone 60 mg daily. The patient remained symptomatic, experiencing episodic chest pain and shortness of breath, with blood pressure lability. Repeat chest X-ray showed worsening bilateral infiltrates. Subsequently, ANA resulted weakly positive (1:160) with a homogenous pattern and rheumatoid factor (RF) returned negative.
On the fifth day of admission, antibiotics were discontinued in light of negative cultures and lack of significant clinical improvement. The patient’s blood pressure was noted to be slightly improved with addition of prednisone however remained poorly controlled on multiple medications (Fig. 2). Autoimmune panel including ANCA (MPO/p-ANCA, and PR3/c-ANCA), anti-double-stranded DNA antibody, anti-Smith antibody, C3 and C4 complements, anti-histone antibody, as well as other autoimmune related factors and infectious serologies returned negative or within normal limits (Table 1). Renal ultrasound and renal artery duplex were performed which did not reveal any evidence of hydronephrosis or renal artery stenosis, respectively. A repeat high-resolution chest CT scan was obtained, both in supine and prone positions, to help differentiate early interstitial lung disease from intra-alveolar processes, which showed persistent intra-alveolar opacities without any change on prone position (Fig. 1b). Over the course of the following days, the patient reported improvement in his symptomatology and his blood pressure improved, therefore he was taken off prednisone on the sixth day. Pulmonary function testing was performed in the setting of bilateral hilar adenopathy and fixed infiltrates, which revealed a mixed obstructive and restrictive pattern. He eventually underwent lung biopsy by video-assisted thoracoscopic surgery (VATS) with right medial lobe wedge resection and was subsequently discharged with instructions to follow up with rheumatology for planned initiation of rituximab. The histopathological results of his lung biopsy demonstrated extensive intra-alveolar hemorrhage with linear polymorphonuclear (PMN) cell collections in alveolar septa and capillaritis without any evidence of granulomatous changes, indicative of microscopic polyangiitis (Fig. 3). Immunohistochemistry on lung biopsy samples was not performed and renal biopsy was deferred to outpatient rheumatology.Fig. 2 Blood pressure and creatinine during first and second hospitalizations. SBP Systolic Blood Pressure, DBP Diastolic Blood Pressure
Table 1 Autoimmune and infectious workup results during first admission
Lab Results Lab Results Lab Results
WBC 9.3 Neutrophils 75.9% Potassium 2.9
Hgb 13.1 Lymphocytes 12.5% Sodium 138
Hct 37.8 Eosinophils 1.3% Creatinine 2.03
Platelet 343 Monocytes 10.1% GFR 52
Troponin 0.232 D-Dimer 1.3 TSH 1.65
CRP 80 GBM Ab Negative CMV IgM Negative
ESR 67 SS-A/Ro Negative Cox A & B Ab Negative
ANA 1:160 (Homogenous) SS-B/La Negative Cryptococcal Ag Negative
RF < 10 ACA (IgG, IgM) < 9 EBV DNA Negative
Anti-CCP 4 TTG (IgA, IgG) 1, 3 HBV DNA Negative
ANCA Negative Ribosome IgG 3 HCV RNA Negative
Anti ds-DNA Negative Endomysial IgG < 1:10 HIV 1&2 Ab Negative
Anti-Smith Ab Negative Anti Gliadin < 7 Parvovirus B19 Negative
Histone auto Ab Negative Anti Gliadin < 2 Syphilis (RPR/FTA) Negative
Scl-70 Ab Negative Free Kappa 1.73 HHV6 DNA Negative
C3 130 Free Lambda 1.49 Lyme ELISA Negative
C4 32.4 K/L Ratio 1.16 Histoplasma Ag Negative
IgA 250 IgG 1160 IgM 1110
WBC White Blood Cell, Hgb Hemoglobin, Hct Hematocrit, GFR Glomerular Filtration Rate, TSH Thyroid Stimulating Hormone, Ab Antibody, Ig Immunoglobulin, ESR Erythrocyte Sedimentation Rate, CRP C-Reactive Protein, ANA Anti-Neutrophil Antibody, ANCA Anti-Neutrophil Cytoplasmic Antibody, Scl Scleroderma, C3 Complement 3, C4 Complement 4, ds-DNA Double-Stranded DNA, RF Rheumatoid Factor, CCP Cyclic Citrullinated Peptide, SS-A Sjӧgren-Syndrome-related-antigen A, SS-B Sjӧgren-syndrome-related-antigen B, ACA Anti Cardiolipin Ab, TTG Tissue trans-glutaminase, HIV Human Immunodeficiency Virus, HCV Hepatitis C Virus, HBV Hepatitis B Virus, CMV Cytomegalovirus, EBV Epstein-Barr Virus, Cox A & B Coxsackievirus A & B, HHV Human Herpes Virus, RPR: Rapid Plasma Reagin, FTA Fluorescent Treponemal Antibody
Fig. 3 Lung Biopsy. a Intra-alveolar hemorrhage (100×) b Polymorphonuclear cells in alveolar septa; capillaritis (Arrow) (400x)
Unfortunately, the patient was lost to follow up, failing to attend any of the scheduled appointments. He was subsequently readmitted six months later with similar symptoms, and once again found to be in hypertensive emergency, complicated by acute decompensated heart failure. Repeat echocardiogram revealed a further decline in his ejection fraction to 25% and a trivial pericardial effusion. Rheumatology was consulted and recommended pulse steroid therapy with methylprednisolone 250 mg four times a day for three days, which led to significant improvement in symptoms and blood pressure. Repeat ANCA and autoimmune serological workup remained negative. Following initiation of pulse steroid therapy, he underwent renal biopsy. The biopsy contained forty glomeruli, six of which were globally sclerotic. One glomerulus had segmental sclerosis. There were changes suggestive of microangiopathic injury in some arteries and glomeruli, such as bloodless glomeruli and mild intimal myxoid changes in arteries, with associated acute tubular injury. Focal tubular atrophy and interstitial fibrosis were estimated to involve approximately 10% of the cortex. No evidence of crescents or granulomatous changes were observed. Immunofluorescence was unremarkable, with only non-specific linear glomerular and tubular basement membrane staining for IgG, kappa, lambda, and albumin, indicative of pauci-immunity. Electron microscopy demonstrated segmental effacement of podocyte foot processes (40%) with vacuolation and microvillous transformation of the podocyte cytoplasm, ischemic-type capillary wall wrinkling, and subendothelial electron lucent widening (Fig. 4). He was subsequently discharged on a steroid taper with plans for outpatient rituximab. Despite extensive education about his condition he was once again lost to follow up and missed appropriate treatment.Fig. 4 Kidney Biopsy. a Glomerulus with segmental sclerosis of the right half of the tuft, Periodic Acid-Methenamine Silver (PASM, 200×) b One glomerulus (left) with an ischemic appearance including capillary wall wrinkling and tuft retraction, other glomerulus (right) has mild hypercellularity including a few neutrophils (H&E, 100×) c A glomerulus with a bloodless appearance, obliteration of capillary lumens and thickening of capillary walls with segmental duplication (Periodic Acid-Schiff (PAS), 200×) d Tubules show cytoplasmic vacuolation, apical blebbing, thinning, and focal simplification. The interstitium contains a sparse lymphocytic infiltrate (PAS, 100×) e Electron micrograph of glomerular tuft showing ischemic-type capillary wall wrinkling (asterisk) and diffuse subendothelial electron lucent widening (arrow) f Electron micrograph showing podocyte foot process effacement (arrow) and mild subendothelial electron-lucent widening (asterisk)
Over the course of the next year, he was readmitted on multiple occasions and eventually progressed to dialysis-dependent end-stage renal disease. His two most recent admissions were characterized by pancreatitis with pancreatic pseudoaneurysm complicated by retroperitoneal hematoma and cardiac tamponade, respectively. With respect to his pancreatitis, he presented in the context of acute onset abdominal pain with associated nausea and vomiting. Laboratory diagnostics demonstrated an elevated lipase (3400), normal triglycerides, and a negative IgG4 serology. Abdominal CT was significant for peripancreatic fat stranding and inflammatory changes without evidence of gallstones or biliary ductal dilation. He denied recent alcohol use. Pancreatitis course was further complicated by retroperitoneal hematoma, which was found to be secondary to a 7 mm pancreatic pseudoaneurysm rupture, as revealed on repeat abdominal CT angiography (Fig. 5). He was managed conservatively and subsequently discharged. One month later he presented with dyspnea, chest pain and nausea, and was found to have large pericardial effusion with an acute decrease in ejection fraction to 10% (Fig. 6). He underwent pericardiocentesis with removal of one liter of serosanguineous fluid. Fluid analysis was indicative of hemorrhagic etiology and negative for malignancy. On review of most recent outpatient records, the patient has been maintained on high-dose suppressive steroid therapy with plans for initiation of Rituximab or Cyclophosphamide.Fig. 5 CT angiography of the Abdomen. A 7 mm arterially enhancing focus in the tail of the pancreas that follows the blood flow (Arrow), consistent with a pseudoaneurysm, with an associated large left upper quadrant hematoma and small amount of hemorrhage in the right paracolic gutter
Fig. 6 Echocardiogram. Four chamber views in diastole a and systole (c). Short axis views in Diastole b and systole (d). Echocardiography demonstrating a large circumferential pericardial effusion (Asterisks) without hemodynamic compromise, mildly dilated left ventricle (LV) with normal wall thickness, and severe globally depressed systolic function with left ventricular ejection fraction of 10%, normal right ventricle (RV) size and mildly reduced right ventricular systolic function
Discussion
Since the sentinel publications on ANCA in early 1980s and the landmark article by van der Woude et al. [5], our understanding of ANCA has significantly expanded. ANCA is currently recognized as having a central role in the pathogenesis of necrotizing vasculitis and glomerulonephritis particularly AAV, however the exact mechanism, and if a direct pathogenic role exists for ANCA, remains to be elucidated [8]. Recently an association between ANCA-induced neutrophil activation, regulated necrosis (necroptosis), neutrophil endothelial trap (NET) generation, complement activation, and endothelial cell damage leading to vasculitis and necrotizing glomerulonephritis has been identified in AAV by Schreiber et al. [9]. Nonetheless, detection of ANCA has become an essential part of the routine workup for vasculitis and many other autoimmune disorders. Currently only two ANCA antigens, PR3/ c-ANCA and MPO/ p-ANCA, critical components for neutrophil-mediated innate immunity, have been recognized to be clinically significant for AAV amongst a diverse array of ANCA antigens [9]. While indirect immunofluorescence testing on ethanol-fixed neutrophils is the reference method for ANCA detection and screening, positive results prompt specific testing for PR3 and MPO. As new ANCA detection methods have developed, the most recent revised international consensus recommends high-quality antigen-specific assays for PR3-ANCA and MPO-ANCA should be used as the primary screening method for ANCA, and if results for both are negative with strong clinical suspicion for small-vessel vasculitis, other immunoassays, indirect immunofluorescence, or referral to an experienced lab is recommended [10].
ANCA is detected in 80–90% of cases of MPA out of which 70% are positive for MPO-ANCA [3–6, 11–14]. Seronegative ANCA, also known as pauci-immune vasculitis, is similar to seronegative lupus or seronegative rheumatoid arthritis and the absence of specific markers may lead not only to a delay in diagnosis, but also misdiagnosis [1, 2]. Furthermore, ANCA, though initially negative, may become positive later in the course of disease or may not be detectable with currently available methods [3–5]. On the other hand, antibodies to antigens other than PR3 and MPO have been detected and are referred to as minor ANCA antigens [15]. Interestingly these antibodies are frequently detected in sera of MPO- and PR3-ANCA negative patients, and while they can mimic c-ANCA or p-ANCA patterns, they are detected in other types of small vessel vasculitis such as cocaine-induced vasculitis mimicking GPA as well as other autoimmune diseases such as Sjӧgren, rheumatoid arthritis, and ulcerative colitis [9, 15]. It is noteworthy to mention that ethnic differences between MPO and PR3 ANCA subtypes have also been observed with PR3 predominance in Japanese and Chinese ethnicity and MPO predominance in Northern Europeans and Middle-Eastern/Turkish groups [7].
Classically MPA presents with acute onset of rapidly progressive glomerulonephritis, however presentation is often atypical. Most commonly, patients present with constitutional symptoms—fever, weight loss, fatigue—over an acute or chronic course over weeks to months [3–5]. The most common age of presentation is in 5–6th decades of life with a slight male predominance [3, 4]. Multiple organs can be involved with the most common organs being kidneys and lungs, followed by skin, gastrointestinal, cardiac and nervous systems [5, 6, 11]. Renal involvement is reported in 80–100% of MPA cases and is classically characterized by rapidly progressive glomerulonephritis (GN), however renal involvement on initial presentation may range from minimal proteinuria to end-stage renal disease requiring dialysis [5]. Pauci-immune necrotizing and crescentic GN is the classic finding on biopsy in systemic AAV [12]. Crescentic involvement of the glomeruli is the most common form of glomerular involvement in MPA and is visualized in up to 90% of cases, however interstitial nephritis and tubular atrophy, as observed in this case, are reported on biopsies as well [1–5]. Berden et al. proposed a classification criteria for AAV GN, based on the pathologic features of the glomerulus, into four major groups of focal, crescentic, mixed and sclerotic [12]. Considering the Berden’s classification, our patient would fall into the focal subgroup with more than 50% normal glomeruli, which have a relatively preserved kidney function and an overall more favorable outcome compared to other pathologic subgroups [12]. In another study of ANCA-negative patients with pauci-immune renal vasculitis, 29% of renal biopsies revealed normal glomeruli and only 50% had crescents on histology [14].
Pulmonary involvement can occur in up to 55% of cases of MPA and mostly present as dyspnea, cough, and hemoptysis. Classically MPA is associated with diffuse alveolar hemorrhage and a pauci-immune, hemorrhagic necrotizing alveolar capillaritis characterized by an absence of granulomatous changes on lung and renal biopsy [5, 6], similar to what was observed in our patient (Fig. 3). Diffuse alveolar hemorrhage, caused by pulmonary capillaritis, is considered a serious complication and if accompanied by glomerulonephritis (pulmonary-renal syndrome) portends a poor prognosis [5, 6]. Pulmonary function testing in patients with MPA can show either obstructive or restrictive pattern with reduced carbon monoxide diffusion capacity (DLCO) [5].
Gastrointestinal bleeding has been reported in up to 29% of MPA patients [5], however additional manifestations such as colonic ulceration, bowel ischemia, perforation, and arterial aneurysms have also been reported [5]. Pancreatic involvement in MPA is rare and may present as acute pancreatitis or pancreatic mass [16]. In a study of 62 patients with small-medium vessel vasculitis, Pagnoux et al. demonstrated that only 3 patients had pancreatitis as a complication, with only one having MPA [17]. Cardiac involvement in patients with MPA is reported to occur in 17–50% of cases with pathophysiology similar to that of other organ systems such as lung and kidney [18, 19]. Cardiac involvement may present as hypertension, heart failure, pericarditis, and less commonly myocardial infarction [10, 18].
Management of MPA and other AAV’s includes an induction phase followed by a maintenance phase. Classic induction strategies include oral corticosteroids (1 mg/kg daily) and cyclophosphamide (2 mg/kg daily). Rituximab and cyclophosphamide are considered the drug of choice for both induction and maintenance of remission. Rituximab has been shown to be non-inferior to cyclophosphamide by the RAVE and RITUXVAS trials [3–6, 11–13]. The NORAM study revealed methotrexate was as effective as cyclophosphamide with regards to induction of remission in mild disease however relapse rates were higher for methotrexate [3–5]. Plasmapheresis has been used in cases of aggressive AAV and was shown to have better renal outcomes in MEPEX trial, however PEXIVAS trial (Plasma exchange and glucocorticoids for treatment of AAV), the largest trial in AAV so far, failed to show a significant difference in all-cause mortality or end-stage renal disease, and plasmapheresis use remains controversial [3, 4, 20]. Maintenance therapy is generally achieved by less toxic agents such as rituximab, azathioprine, and methotrexate, with rituximab becoming more and more favored in recent years. Other immunosuppressive agents like leflunomide, mycophenolate mofetil, and trimethoprim-sulfamethoxazole have been used and studied as maintenance therapy strategies as well [3–6, 11].
This case was differentiated from other potential autoimmune disorders such as systemic lupus erythematosus, Sjӧgren syndrome, sarcoidosis, and other small to medium sized vessel vasculitis such as granulomatosis with polyangiitis, polyarteritis nodosa, IgA vasculitis and cryoglobulinemic vasculitis based on presentation, laboratory and imaging findings and biopsy of the lung revealing capillaritis without granulomatous changes. Absence of pathognomic noncaseating granulomas on lung biopsy, ruled out sarcoidosis. In the light of absence of certain characteristics such as palpable purpura, as well as absence of immune complexes on tissue biopsy, immune complex vasculitides such as anti-glomerular basement membrane disease, IgA and cryoglobulinemic vasculitis were ruled out. While differentiation of GPA from MPA is difficult and they tend to share characteristics of AAV disease spectrum, the absence of granulomatous lesions on both biopsies and lack of certain classical features of GPA made it less likely in this case. EGPA was also deemed less likely considering lack of peripheral eosinophilia and tissue eosinophilic infiltration. We also believe the kidney biopsy results were affected by pulse steroids and possible steroid consumption in between admissions, however pauci-immunity and absence of granulomatous changes, and immune complex deposition favors MPA over other vasculitides.
Conclusion
MPA is differentiated not only by the presence of anti-MPO (p-ANCA) but also histopathologically by non-granulomatous lesions and capillaritis. ANCA serologies, however, may be negative in AAV specifically MPA in as many as 10-20% of cases. This case underscores the importance of identifying pulmonary-renal syndrome and its association with AAV, the need to maintain a high index of suspicion in cases of negative ANCA serologies, and to pursue tissue biopsy despite negative serologies in such circumstances. This case further serves to demonstrate the rapid clinical deterioration and high morbidity in those cases of AAV with delayed diagnosis or inadequate treatment.
Abbreviations
MPAMicroscopic Polyangiitis
ANCAAnti-neutrophil cytoplasmic antibody
AAVANCA-associated Vasculitis
GPAGranulomatosis with polyangiitis
EGPAEosinophilic granulomatosis with angiitis
G6PDGlucose 6 Phosphate Dehydrogenase
CTComputed Tomography
IVIntravenous
CRPC-reactive Protein
ESRErythrocyte sedimentation Rate
CAPCommunity Acquired Pneumonia
ANAAnti-Neutrophil Antibody
RFRheumatoid Factor
FVCForced Vital Capacity
FEVForced Expiratory Volume
VCVital Capacity
FRCForced Residual Capacity
RVResidual Capacity
TLCTotal Lung Capacity
DLCODiffusing Capacity of Lung for Carbon Monoxide
VATSVideo-Assisted Thoracoscopic Surgery
PMNPolymorphonuclear
FSGSFocal Segmental Glomerulonephritis
IgGImmunoglobulin G
NETNeutrophil Endothelial Trap
Publisher's Note
Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
Authors’ contributions
AM designed the study, gathered data and resources, drafted, edited and finalized the entire manuscript. NNC and RA gathered data and resources. JSI provided and interpreted lung biopsy. LJA provided and interpreted kidney biopsy. SHFS assisted and edited discussion section. CJH edited, critically revised and helped finalize the entire manuscript. All authors read and approved the final manuscript.
Funding
No financial support or grant was provided for the preparation of this manuscript.
Consent for publication
A written informed consent has been signed and obtained from the patient and is available upon request.
Competing interests
Authors hereby declare no personal or financial conflict of interest. | AZITHROMYCIN, CEFTRIAXONE, UNSPECIFIED INGREDIENT | DrugsGivenReaction | CC BY | 33407881 | 19,165,871 | 2021-01-06 |
Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Ejection fraction decreased'. | ANCA-negative microscopic polyangiitis with diffuse alveolar hemorrhage masquerading as congestive heart failure.
BACKGROUND
Microscopic polyangiitis (MPA) is a subtype of anti-neutrophil cytoplasmic antibody-associated vasculitis (AAV), involving small and medium sized vessels, often affecting the kidneys and lungs. Anti-neutrophil cytoplasmic antibody (ANCA) is detected in up to 90% of cases of MPA and its detection helps guide diagnosis, however cases of ANCA-negative MPA have been reported, hence definitive diagnosis relies on tissue biopsy.
METHODS
A 23-year-old man was evaluated for dyspnea and pleuritic chest pain, and found to have bilateral intra-alveolar opacities and hilar adenopathy. Diagnostic work up revealed positive anti-nuclear antibodies (ANA) and negative ANCA, which in the setting of a non-classical presentation, delayed diagnosis and appropriate treatment. Due to persistent symptoms and a high suspicion for autoimmune disease with pulmonary-renal syndrome, he underwent lung biopsy which revealed intra-alveolar hemorrhage and capillaritis indicative of microscopic polyangiitis (MPA). Surprisingly, kidney biopsy was not typical of classic MPA, but revealed less common features. Due to therapeutic noncompliance he was readmitted multiple times thereafter with rare complications of MPA such as acute pancreatitis and hemorrhagic pericardial effusion with tamponade.
CONCLUSIONS
This case serves as an important clinical reminder to consider AAV even in those with negative ANCA serologies and a high suspicion for pulmonary-renal syndrome. It also demonstrates the high morbidity in cases of diagnostic delay and inadequate treatment.
Background
The 2012 Chapel Hill Consensus guideline recognizes microscopic polyangiitis (MPA) as a subset of ANCA-associated vasculitis (AAV), a group of necrotizing pauci-immune vasculitides that predominantly affects small vessels—capillaries, venules, and arterioles—with few or no immune deposits [1]. AAV commonly affects the renal and pulmonary parenchyma to varying degrees, and is characterized by the presence of antibodies against neutrophilic cytoplasmic components, Proteinase-3 (PR3, c-ANCA) and Myeloperoxidase (MPO, p-ANCA). AAV include Microscopic Polyangiitis (MPA), Granulomatosis with polyangiitis (GPA; Wegener’s) and Eosinophilic granulomatosis with angiitis (EGPA; Churg-Strauss), as well as a variety of additional AAV-associated syndromes (drug-induced vasculitis, renal-limited vasculitis (RLV)), each characterized by the presence of distinct clinical presentation, ANCA subtypes, histopathological findings, and associated laboratory findings [1–4].
MPA is characterized by the presence of anti-MPO (p-ANCA) antibodies, renal and pulmonary involvement, and the absence of granulomatous inflammation on histopathology, a defining feature when compared to GPA and EGPA which, while demonstrating both renal and pulmonary involvement, are characterized by the presence of anti-PR3 (c-ANCA) and granulomatous disease. Though a widely accepted marker for AAV, the presence of ANCA is variable and not detected in all cases. ANCA is detected in 80–90% of cases of MPA and its detection has become integral in the diagnostic workup as well as classification and prognostication of all AAV [3, 4]. While current evidence indicates that ANCA plays a role in pathogenesis of MPA and other AAV, cases of ANCA-negative vasculitis, including cases of ANCA-negative MPA, GPA, and EGPA have been reported [1–7]. We present a case of ANCA-negative MPA in a young man who presented with hemoptysis and was found to have diffuse bilateral lung infiltrates, acute kidney injury, and heart failure. Following a circuitous diagnostic course masked by symptoms of heart failure, he was eventually diagnosed with MPA, however the course of his disease was further complicated by medication non-compliance as well as rare complications of AAV, including acute pancreatitis, pancreatic pseudoaneurysm, and cardiac tamponade.
Case report
A 23-year-old African-American man with past medical history of G6PD-deficiency and obesity presented with dyspnea and pleuritic chest pain that improved upon leaning forward and scant hemoptysis of two weeks duration. He was notably hypertensive to the 220/110 s mmHg and tachycardic to the 120 s, but had a preserved respiratory rate and oxygen saturation. Physical exam was remarkable for bilateral diffuse wheezing throughout all lung fields. Other parts of the exam including cardiovascular, nasopharynx, skin and musculoskeletal systems were unremarkable. Additional pertinent history was remarkable only for marijuana smoking. Electrocardiogram was unremarkable except for left atrial enlargement. Chest X-ray revealed bilateral pulmonary infiltrates, cardiomegaly, and mediastinal enlargement suggestive of bulky hilar adenopathy. Computed tomography (CT) scan of the chest with contrast was performed which was negative for pulmonary embolism, but revealed bilateral centrilobular opacities, hilar/mediastinal lymphadenopathy, and a trivial pericardial effusion (Fig. 1a). Initial laboratory diagnostics were significant for acute kidney injury with a serum creatinine of 2.03 (mg/dL), trace proteinuria, troponin elevation to 0.232 (ng/mL), and a D-Dimer of 1.3 (mcg/mL). Complete blood count revealed no leukocytosis, but concomitant eosinophilia, with no evidence of anemia. The patient was subsequently admitted to the medicine wards and a therapeutic regimen of antihypertensive agents as well as intravenous ceftriaxone and azithromycin for presumed community acquired pneumonia was initiated.Fig. 1 CT scans of the chest. a CT Scan of the chest on first day of presentation demonstrating bilateral centrilobular opacities, hilar/mediastinal lymphadenopathy, moderate cardiomegaly, a trivial pericardial effusion and enlargement of the main pulmonary artery. b Prone CT chest on day 7 of admission, revealing persistent intra-alveolar opacities with associated mediastinal lymphadenopathy
Additional diagnostic evaluation demonstrated marked elevation of CRP (80 mg/L) and ESR (67 mm/hr). Pheochromocytoma screening with serum catecholamines and metanephrines was negative. An echocardiogram revealed an ejection fraction of 40%, moderate concentric left ventricular hypertrophy, and trivial pericardial effusion without evidence of tamponade or pulmonary artery hypertension. Despite continuation of antibiotics for pneumonia and adjunctive heart failure management, the patient’s clinical status failed to improve. In the setting of an unremarkable infectious workup and concern for an autoimmune etiology, the patient was started on oral prednisone 60 mg daily. The patient remained symptomatic, experiencing episodic chest pain and shortness of breath, with blood pressure lability. Repeat chest X-ray showed worsening bilateral infiltrates. Subsequently, ANA resulted weakly positive (1:160) with a homogenous pattern and rheumatoid factor (RF) returned negative.
On the fifth day of admission, antibiotics were discontinued in light of negative cultures and lack of significant clinical improvement. The patient’s blood pressure was noted to be slightly improved with addition of prednisone however remained poorly controlled on multiple medications (Fig. 2). Autoimmune panel including ANCA (MPO/p-ANCA, and PR3/c-ANCA), anti-double-stranded DNA antibody, anti-Smith antibody, C3 and C4 complements, anti-histone antibody, as well as other autoimmune related factors and infectious serologies returned negative or within normal limits (Table 1). Renal ultrasound and renal artery duplex were performed which did not reveal any evidence of hydronephrosis or renal artery stenosis, respectively. A repeat high-resolution chest CT scan was obtained, both in supine and prone positions, to help differentiate early interstitial lung disease from intra-alveolar processes, which showed persistent intra-alveolar opacities without any change on prone position (Fig. 1b). Over the course of the following days, the patient reported improvement in his symptomatology and his blood pressure improved, therefore he was taken off prednisone on the sixth day. Pulmonary function testing was performed in the setting of bilateral hilar adenopathy and fixed infiltrates, which revealed a mixed obstructive and restrictive pattern. He eventually underwent lung biopsy by video-assisted thoracoscopic surgery (VATS) with right medial lobe wedge resection and was subsequently discharged with instructions to follow up with rheumatology for planned initiation of rituximab. The histopathological results of his lung biopsy demonstrated extensive intra-alveolar hemorrhage with linear polymorphonuclear (PMN) cell collections in alveolar septa and capillaritis without any evidence of granulomatous changes, indicative of microscopic polyangiitis (Fig. 3). Immunohistochemistry on lung biopsy samples was not performed and renal biopsy was deferred to outpatient rheumatology.Fig. 2 Blood pressure and creatinine during first and second hospitalizations. SBP Systolic Blood Pressure, DBP Diastolic Blood Pressure
Table 1 Autoimmune and infectious workup results during first admission
Lab Results Lab Results Lab Results
WBC 9.3 Neutrophils 75.9% Potassium 2.9
Hgb 13.1 Lymphocytes 12.5% Sodium 138
Hct 37.8 Eosinophils 1.3% Creatinine 2.03
Platelet 343 Monocytes 10.1% GFR 52
Troponin 0.232 D-Dimer 1.3 TSH 1.65
CRP 80 GBM Ab Negative CMV IgM Negative
ESR 67 SS-A/Ro Negative Cox A & B Ab Negative
ANA 1:160 (Homogenous) SS-B/La Negative Cryptococcal Ag Negative
RF < 10 ACA (IgG, IgM) < 9 EBV DNA Negative
Anti-CCP 4 TTG (IgA, IgG) 1, 3 HBV DNA Negative
ANCA Negative Ribosome IgG 3 HCV RNA Negative
Anti ds-DNA Negative Endomysial IgG < 1:10 HIV 1&2 Ab Negative
Anti-Smith Ab Negative Anti Gliadin < 7 Parvovirus B19 Negative
Histone auto Ab Negative Anti Gliadin < 2 Syphilis (RPR/FTA) Negative
Scl-70 Ab Negative Free Kappa 1.73 HHV6 DNA Negative
C3 130 Free Lambda 1.49 Lyme ELISA Negative
C4 32.4 K/L Ratio 1.16 Histoplasma Ag Negative
IgA 250 IgG 1160 IgM 1110
WBC White Blood Cell, Hgb Hemoglobin, Hct Hematocrit, GFR Glomerular Filtration Rate, TSH Thyroid Stimulating Hormone, Ab Antibody, Ig Immunoglobulin, ESR Erythrocyte Sedimentation Rate, CRP C-Reactive Protein, ANA Anti-Neutrophil Antibody, ANCA Anti-Neutrophil Cytoplasmic Antibody, Scl Scleroderma, C3 Complement 3, C4 Complement 4, ds-DNA Double-Stranded DNA, RF Rheumatoid Factor, CCP Cyclic Citrullinated Peptide, SS-A Sjӧgren-Syndrome-related-antigen A, SS-B Sjӧgren-syndrome-related-antigen B, ACA Anti Cardiolipin Ab, TTG Tissue trans-glutaminase, HIV Human Immunodeficiency Virus, HCV Hepatitis C Virus, HBV Hepatitis B Virus, CMV Cytomegalovirus, EBV Epstein-Barr Virus, Cox A & B Coxsackievirus A & B, HHV Human Herpes Virus, RPR: Rapid Plasma Reagin, FTA Fluorescent Treponemal Antibody
Fig. 3 Lung Biopsy. a Intra-alveolar hemorrhage (100×) b Polymorphonuclear cells in alveolar septa; capillaritis (Arrow) (400x)
Unfortunately, the patient was lost to follow up, failing to attend any of the scheduled appointments. He was subsequently readmitted six months later with similar symptoms, and once again found to be in hypertensive emergency, complicated by acute decompensated heart failure. Repeat echocardiogram revealed a further decline in his ejection fraction to 25% and a trivial pericardial effusion. Rheumatology was consulted and recommended pulse steroid therapy with methylprednisolone 250 mg four times a day for three days, which led to significant improvement in symptoms and blood pressure. Repeat ANCA and autoimmune serological workup remained negative. Following initiation of pulse steroid therapy, he underwent renal biopsy. The biopsy contained forty glomeruli, six of which were globally sclerotic. One glomerulus had segmental sclerosis. There were changes suggestive of microangiopathic injury in some arteries and glomeruli, such as bloodless glomeruli and mild intimal myxoid changes in arteries, with associated acute tubular injury. Focal tubular atrophy and interstitial fibrosis were estimated to involve approximately 10% of the cortex. No evidence of crescents or granulomatous changes were observed. Immunofluorescence was unremarkable, with only non-specific linear glomerular and tubular basement membrane staining for IgG, kappa, lambda, and albumin, indicative of pauci-immunity. Electron microscopy demonstrated segmental effacement of podocyte foot processes (40%) with vacuolation and microvillous transformation of the podocyte cytoplasm, ischemic-type capillary wall wrinkling, and subendothelial electron lucent widening (Fig. 4). He was subsequently discharged on a steroid taper with plans for outpatient rituximab. Despite extensive education about his condition he was once again lost to follow up and missed appropriate treatment.Fig. 4 Kidney Biopsy. a Glomerulus with segmental sclerosis of the right half of the tuft, Periodic Acid-Methenamine Silver (PASM, 200×) b One glomerulus (left) with an ischemic appearance including capillary wall wrinkling and tuft retraction, other glomerulus (right) has mild hypercellularity including a few neutrophils (H&E, 100×) c A glomerulus with a bloodless appearance, obliteration of capillary lumens and thickening of capillary walls with segmental duplication (Periodic Acid-Schiff (PAS), 200×) d Tubules show cytoplasmic vacuolation, apical blebbing, thinning, and focal simplification. The interstitium contains a sparse lymphocytic infiltrate (PAS, 100×) e Electron micrograph of glomerular tuft showing ischemic-type capillary wall wrinkling (asterisk) and diffuse subendothelial electron lucent widening (arrow) f Electron micrograph showing podocyte foot process effacement (arrow) and mild subendothelial electron-lucent widening (asterisk)
Over the course of the next year, he was readmitted on multiple occasions and eventually progressed to dialysis-dependent end-stage renal disease. His two most recent admissions were characterized by pancreatitis with pancreatic pseudoaneurysm complicated by retroperitoneal hematoma and cardiac tamponade, respectively. With respect to his pancreatitis, he presented in the context of acute onset abdominal pain with associated nausea and vomiting. Laboratory diagnostics demonstrated an elevated lipase (3400), normal triglycerides, and a negative IgG4 serology. Abdominal CT was significant for peripancreatic fat stranding and inflammatory changes without evidence of gallstones or biliary ductal dilation. He denied recent alcohol use. Pancreatitis course was further complicated by retroperitoneal hematoma, which was found to be secondary to a 7 mm pancreatic pseudoaneurysm rupture, as revealed on repeat abdominal CT angiography (Fig. 5). He was managed conservatively and subsequently discharged. One month later he presented with dyspnea, chest pain and nausea, and was found to have large pericardial effusion with an acute decrease in ejection fraction to 10% (Fig. 6). He underwent pericardiocentesis with removal of one liter of serosanguineous fluid. Fluid analysis was indicative of hemorrhagic etiology and negative for malignancy. On review of most recent outpatient records, the patient has been maintained on high-dose suppressive steroid therapy with plans for initiation of Rituximab or Cyclophosphamide.Fig. 5 CT angiography of the Abdomen. A 7 mm arterially enhancing focus in the tail of the pancreas that follows the blood flow (Arrow), consistent with a pseudoaneurysm, with an associated large left upper quadrant hematoma and small amount of hemorrhage in the right paracolic gutter
Fig. 6 Echocardiogram. Four chamber views in diastole a and systole (c). Short axis views in Diastole b and systole (d). Echocardiography demonstrating a large circumferential pericardial effusion (Asterisks) without hemodynamic compromise, mildly dilated left ventricle (LV) with normal wall thickness, and severe globally depressed systolic function with left ventricular ejection fraction of 10%, normal right ventricle (RV) size and mildly reduced right ventricular systolic function
Discussion
Since the sentinel publications on ANCA in early 1980s and the landmark article by van der Woude et al. [5], our understanding of ANCA has significantly expanded. ANCA is currently recognized as having a central role in the pathogenesis of necrotizing vasculitis and glomerulonephritis particularly AAV, however the exact mechanism, and if a direct pathogenic role exists for ANCA, remains to be elucidated [8]. Recently an association between ANCA-induced neutrophil activation, regulated necrosis (necroptosis), neutrophil endothelial trap (NET) generation, complement activation, and endothelial cell damage leading to vasculitis and necrotizing glomerulonephritis has been identified in AAV by Schreiber et al. [9]. Nonetheless, detection of ANCA has become an essential part of the routine workup for vasculitis and many other autoimmune disorders. Currently only two ANCA antigens, PR3/ c-ANCA and MPO/ p-ANCA, critical components for neutrophil-mediated innate immunity, have been recognized to be clinically significant for AAV amongst a diverse array of ANCA antigens [9]. While indirect immunofluorescence testing on ethanol-fixed neutrophils is the reference method for ANCA detection and screening, positive results prompt specific testing for PR3 and MPO. As new ANCA detection methods have developed, the most recent revised international consensus recommends high-quality antigen-specific assays for PR3-ANCA and MPO-ANCA should be used as the primary screening method for ANCA, and if results for both are negative with strong clinical suspicion for small-vessel vasculitis, other immunoassays, indirect immunofluorescence, or referral to an experienced lab is recommended [10].
ANCA is detected in 80–90% of cases of MPA out of which 70% are positive for MPO-ANCA [3–6, 11–14]. Seronegative ANCA, also known as pauci-immune vasculitis, is similar to seronegative lupus or seronegative rheumatoid arthritis and the absence of specific markers may lead not only to a delay in diagnosis, but also misdiagnosis [1, 2]. Furthermore, ANCA, though initially negative, may become positive later in the course of disease or may not be detectable with currently available methods [3–5]. On the other hand, antibodies to antigens other than PR3 and MPO have been detected and are referred to as minor ANCA antigens [15]. Interestingly these antibodies are frequently detected in sera of MPO- and PR3-ANCA negative patients, and while they can mimic c-ANCA or p-ANCA patterns, they are detected in other types of small vessel vasculitis such as cocaine-induced vasculitis mimicking GPA as well as other autoimmune diseases such as Sjӧgren, rheumatoid arthritis, and ulcerative colitis [9, 15]. It is noteworthy to mention that ethnic differences between MPO and PR3 ANCA subtypes have also been observed with PR3 predominance in Japanese and Chinese ethnicity and MPO predominance in Northern Europeans and Middle-Eastern/Turkish groups [7].
Classically MPA presents with acute onset of rapidly progressive glomerulonephritis, however presentation is often atypical. Most commonly, patients present with constitutional symptoms—fever, weight loss, fatigue—over an acute or chronic course over weeks to months [3–5]. The most common age of presentation is in 5–6th decades of life with a slight male predominance [3, 4]. Multiple organs can be involved with the most common organs being kidneys and lungs, followed by skin, gastrointestinal, cardiac and nervous systems [5, 6, 11]. Renal involvement is reported in 80–100% of MPA cases and is classically characterized by rapidly progressive glomerulonephritis (GN), however renal involvement on initial presentation may range from minimal proteinuria to end-stage renal disease requiring dialysis [5]. Pauci-immune necrotizing and crescentic GN is the classic finding on biopsy in systemic AAV [12]. Crescentic involvement of the glomeruli is the most common form of glomerular involvement in MPA and is visualized in up to 90% of cases, however interstitial nephritis and tubular atrophy, as observed in this case, are reported on biopsies as well [1–5]. Berden et al. proposed a classification criteria for AAV GN, based on the pathologic features of the glomerulus, into four major groups of focal, crescentic, mixed and sclerotic [12]. Considering the Berden’s classification, our patient would fall into the focal subgroup with more than 50% normal glomeruli, which have a relatively preserved kidney function and an overall more favorable outcome compared to other pathologic subgroups [12]. In another study of ANCA-negative patients with pauci-immune renal vasculitis, 29% of renal biopsies revealed normal glomeruli and only 50% had crescents on histology [14].
Pulmonary involvement can occur in up to 55% of cases of MPA and mostly present as dyspnea, cough, and hemoptysis. Classically MPA is associated with diffuse alveolar hemorrhage and a pauci-immune, hemorrhagic necrotizing alveolar capillaritis characterized by an absence of granulomatous changes on lung and renal biopsy [5, 6], similar to what was observed in our patient (Fig. 3). Diffuse alveolar hemorrhage, caused by pulmonary capillaritis, is considered a serious complication and if accompanied by glomerulonephritis (pulmonary-renal syndrome) portends a poor prognosis [5, 6]. Pulmonary function testing in patients with MPA can show either obstructive or restrictive pattern with reduced carbon monoxide diffusion capacity (DLCO) [5].
Gastrointestinal bleeding has been reported in up to 29% of MPA patients [5], however additional manifestations such as colonic ulceration, bowel ischemia, perforation, and arterial aneurysms have also been reported [5]. Pancreatic involvement in MPA is rare and may present as acute pancreatitis or pancreatic mass [16]. In a study of 62 patients with small-medium vessel vasculitis, Pagnoux et al. demonstrated that only 3 patients had pancreatitis as a complication, with only one having MPA [17]. Cardiac involvement in patients with MPA is reported to occur in 17–50% of cases with pathophysiology similar to that of other organ systems such as lung and kidney [18, 19]. Cardiac involvement may present as hypertension, heart failure, pericarditis, and less commonly myocardial infarction [10, 18].
Management of MPA and other AAV’s includes an induction phase followed by a maintenance phase. Classic induction strategies include oral corticosteroids (1 mg/kg daily) and cyclophosphamide (2 mg/kg daily). Rituximab and cyclophosphamide are considered the drug of choice for both induction and maintenance of remission. Rituximab has been shown to be non-inferior to cyclophosphamide by the RAVE and RITUXVAS trials [3–6, 11–13]. The NORAM study revealed methotrexate was as effective as cyclophosphamide with regards to induction of remission in mild disease however relapse rates were higher for methotrexate [3–5]. Plasmapheresis has been used in cases of aggressive AAV and was shown to have better renal outcomes in MEPEX trial, however PEXIVAS trial (Plasma exchange and glucocorticoids for treatment of AAV), the largest trial in AAV so far, failed to show a significant difference in all-cause mortality or end-stage renal disease, and plasmapheresis use remains controversial [3, 4, 20]. Maintenance therapy is generally achieved by less toxic agents such as rituximab, azathioprine, and methotrexate, with rituximab becoming more and more favored in recent years. Other immunosuppressive agents like leflunomide, mycophenolate mofetil, and trimethoprim-sulfamethoxazole have been used and studied as maintenance therapy strategies as well [3–6, 11].
This case was differentiated from other potential autoimmune disorders such as systemic lupus erythematosus, Sjӧgren syndrome, sarcoidosis, and other small to medium sized vessel vasculitis such as granulomatosis with polyangiitis, polyarteritis nodosa, IgA vasculitis and cryoglobulinemic vasculitis based on presentation, laboratory and imaging findings and biopsy of the lung revealing capillaritis without granulomatous changes. Absence of pathognomic noncaseating granulomas on lung biopsy, ruled out sarcoidosis. In the light of absence of certain characteristics such as palpable purpura, as well as absence of immune complexes on tissue biopsy, immune complex vasculitides such as anti-glomerular basement membrane disease, IgA and cryoglobulinemic vasculitis were ruled out. While differentiation of GPA from MPA is difficult and they tend to share characteristics of AAV disease spectrum, the absence of granulomatous lesions on both biopsies and lack of certain classical features of GPA made it less likely in this case. EGPA was also deemed less likely considering lack of peripheral eosinophilia and tissue eosinophilic infiltration. We also believe the kidney biopsy results were affected by pulse steroids and possible steroid consumption in between admissions, however pauci-immunity and absence of granulomatous changes, and immune complex deposition favors MPA over other vasculitides.
Conclusion
MPA is differentiated not only by the presence of anti-MPO (p-ANCA) but also histopathologically by non-granulomatous lesions and capillaritis. ANCA serologies, however, may be negative in AAV specifically MPA in as many as 10-20% of cases. This case underscores the importance of identifying pulmonary-renal syndrome and its association with AAV, the need to maintain a high index of suspicion in cases of negative ANCA serologies, and to pursue tissue biopsy despite negative serologies in such circumstances. This case further serves to demonstrate the rapid clinical deterioration and high morbidity in those cases of AAV with delayed diagnosis or inadequate treatment.
Abbreviations
MPAMicroscopic Polyangiitis
ANCAAnti-neutrophil cytoplasmic antibody
AAVANCA-associated Vasculitis
GPAGranulomatosis with polyangiitis
EGPAEosinophilic granulomatosis with angiitis
G6PDGlucose 6 Phosphate Dehydrogenase
CTComputed Tomography
IVIntravenous
CRPC-reactive Protein
ESRErythrocyte sedimentation Rate
CAPCommunity Acquired Pneumonia
ANAAnti-Neutrophil Antibody
RFRheumatoid Factor
FVCForced Vital Capacity
FEVForced Expiratory Volume
VCVital Capacity
FRCForced Residual Capacity
RVResidual Capacity
TLCTotal Lung Capacity
DLCODiffusing Capacity of Lung for Carbon Monoxide
VATSVideo-Assisted Thoracoscopic Surgery
PMNPolymorphonuclear
FSGSFocal Segmental Glomerulonephritis
IgGImmunoglobulin G
NETNeutrophil Endothelial Trap
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Authors’ contributions
AM designed the study, gathered data and resources, drafted, edited and finalized the entire manuscript. NNC and RA gathered data and resources. JSI provided and interpreted lung biopsy. LJA provided and interpreted kidney biopsy. SHFS assisted and edited discussion section. CJH edited, critically revised and helped finalize the entire manuscript. All authors read and approved the final manuscript.
Funding
No financial support or grant was provided for the preparation of this manuscript.
Consent for publication
A written informed consent has been signed and obtained from the patient and is available upon request.
Competing interests
Authors hereby declare no personal or financial conflict of interest. | AZITHROMYCIN, CEFTRIAXONE, UNSPECIFIED INGREDIENT | DrugsGivenReaction | CC BY | 33407881 | 19,165,871 | 2021-01-06 |
Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Left ventricular hypertrophy'. | ANCA-negative microscopic polyangiitis with diffuse alveolar hemorrhage masquerading as congestive heart failure.
BACKGROUND
Microscopic polyangiitis (MPA) is a subtype of anti-neutrophil cytoplasmic antibody-associated vasculitis (AAV), involving small and medium sized vessels, often affecting the kidneys and lungs. Anti-neutrophil cytoplasmic antibody (ANCA) is detected in up to 90% of cases of MPA and its detection helps guide diagnosis, however cases of ANCA-negative MPA have been reported, hence definitive diagnosis relies on tissue biopsy.
METHODS
A 23-year-old man was evaluated for dyspnea and pleuritic chest pain, and found to have bilateral intra-alveolar opacities and hilar adenopathy. Diagnostic work up revealed positive anti-nuclear antibodies (ANA) and negative ANCA, which in the setting of a non-classical presentation, delayed diagnosis and appropriate treatment. Due to persistent symptoms and a high suspicion for autoimmune disease with pulmonary-renal syndrome, he underwent lung biopsy which revealed intra-alveolar hemorrhage and capillaritis indicative of microscopic polyangiitis (MPA). Surprisingly, kidney biopsy was not typical of classic MPA, but revealed less common features. Due to therapeutic noncompliance he was readmitted multiple times thereafter with rare complications of MPA such as acute pancreatitis and hemorrhagic pericardial effusion with tamponade.
CONCLUSIONS
This case serves as an important clinical reminder to consider AAV even in those with negative ANCA serologies and a high suspicion for pulmonary-renal syndrome. It also demonstrates the high morbidity in cases of diagnostic delay and inadequate treatment.
Background
The 2012 Chapel Hill Consensus guideline recognizes microscopic polyangiitis (MPA) as a subset of ANCA-associated vasculitis (AAV), a group of necrotizing pauci-immune vasculitides that predominantly affects small vessels—capillaries, venules, and arterioles—with few or no immune deposits [1]. AAV commonly affects the renal and pulmonary parenchyma to varying degrees, and is characterized by the presence of antibodies against neutrophilic cytoplasmic components, Proteinase-3 (PR3, c-ANCA) and Myeloperoxidase (MPO, p-ANCA). AAV include Microscopic Polyangiitis (MPA), Granulomatosis with polyangiitis (GPA; Wegener’s) and Eosinophilic granulomatosis with angiitis (EGPA; Churg-Strauss), as well as a variety of additional AAV-associated syndromes (drug-induced vasculitis, renal-limited vasculitis (RLV)), each characterized by the presence of distinct clinical presentation, ANCA subtypes, histopathological findings, and associated laboratory findings [1–4].
MPA is characterized by the presence of anti-MPO (p-ANCA) antibodies, renal and pulmonary involvement, and the absence of granulomatous inflammation on histopathology, a defining feature when compared to GPA and EGPA which, while demonstrating both renal and pulmonary involvement, are characterized by the presence of anti-PR3 (c-ANCA) and granulomatous disease. Though a widely accepted marker for AAV, the presence of ANCA is variable and not detected in all cases. ANCA is detected in 80–90% of cases of MPA and its detection has become integral in the diagnostic workup as well as classification and prognostication of all AAV [3, 4]. While current evidence indicates that ANCA plays a role in pathogenesis of MPA and other AAV, cases of ANCA-negative vasculitis, including cases of ANCA-negative MPA, GPA, and EGPA have been reported [1–7]. We present a case of ANCA-negative MPA in a young man who presented with hemoptysis and was found to have diffuse bilateral lung infiltrates, acute kidney injury, and heart failure. Following a circuitous diagnostic course masked by symptoms of heart failure, he was eventually diagnosed with MPA, however the course of his disease was further complicated by medication non-compliance as well as rare complications of AAV, including acute pancreatitis, pancreatic pseudoaneurysm, and cardiac tamponade.
Case report
A 23-year-old African-American man with past medical history of G6PD-deficiency and obesity presented with dyspnea and pleuritic chest pain that improved upon leaning forward and scant hemoptysis of two weeks duration. He was notably hypertensive to the 220/110 s mmHg and tachycardic to the 120 s, but had a preserved respiratory rate and oxygen saturation. Physical exam was remarkable for bilateral diffuse wheezing throughout all lung fields. Other parts of the exam including cardiovascular, nasopharynx, skin and musculoskeletal systems were unremarkable. Additional pertinent history was remarkable only for marijuana smoking. Electrocardiogram was unremarkable except for left atrial enlargement. Chest X-ray revealed bilateral pulmonary infiltrates, cardiomegaly, and mediastinal enlargement suggestive of bulky hilar adenopathy. Computed tomography (CT) scan of the chest with contrast was performed which was negative for pulmonary embolism, but revealed bilateral centrilobular opacities, hilar/mediastinal lymphadenopathy, and a trivial pericardial effusion (Fig. 1a). Initial laboratory diagnostics were significant for acute kidney injury with a serum creatinine of 2.03 (mg/dL), trace proteinuria, troponin elevation to 0.232 (ng/mL), and a D-Dimer of 1.3 (mcg/mL). Complete blood count revealed no leukocytosis, but concomitant eosinophilia, with no evidence of anemia. The patient was subsequently admitted to the medicine wards and a therapeutic regimen of antihypertensive agents as well as intravenous ceftriaxone and azithromycin for presumed community acquired pneumonia was initiated.Fig. 1 CT scans of the chest. a CT Scan of the chest on first day of presentation demonstrating bilateral centrilobular opacities, hilar/mediastinal lymphadenopathy, moderate cardiomegaly, a trivial pericardial effusion and enlargement of the main pulmonary artery. b Prone CT chest on day 7 of admission, revealing persistent intra-alveolar opacities with associated mediastinal lymphadenopathy
Additional diagnostic evaluation demonstrated marked elevation of CRP (80 mg/L) and ESR (67 mm/hr). Pheochromocytoma screening with serum catecholamines and metanephrines was negative. An echocardiogram revealed an ejection fraction of 40%, moderate concentric left ventricular hypertrophy, and trivial pericardial effusion without evidence of tamponade or pulmonary artery hypertension. Despite continuation of antibiotics for pneumonia and adjunctive heart failure management, the patient’s clinical status failed to improve. In the setting of an unremarkable infectious workup and concern for an autoimmune etiology, the patient was started on oral prednisone 60 mg daily. The patient remained symptomatic, experiencing episodic chest pain and shortness of breath, with blood pressure lability. Repeat chest X-ray showed worsening bilateral infiltrates. Subsequently, ANA resulted weakly positive (1:160) with a homogenous pattern and rheumatoid factor (RF) returned negative.
On the fifth day of admission, antibiotics were discontinued in light of negative cultures and lack of significant clinical improvement. The patient’s blood pressure was noted to be slightly improved with addition of prednisone however remained poorly controlled on multiple medications (Fig. 2). Autoimmune panel including ANCA (MPO/p-ANCA, and PR3/c-ANCA), anti-double-stranded DNA antibody, anti-Smith antibody, C3 and C4 complements, anti-histone antibody, as well as other autoimmune related factors and infectious serologies returned negative or within normal limits (Table 1). Renal ultrasound and renal artery duplex were performed which did not reveal any evidence of hydronephrosis or renal artery stenosis, respectively. A repeat high-resolution chest CT scan was obtained, both in supine and prone positions, to help differentiate early interstitial lung disease from intra-alveolar processes, which showed persistent intra-alveolar opacities without any change on prone position (Fig. 1b). Over the course of the following days, the patient reported improvement in his symptomatology and his blood pressure improved, therefore he was taken off prednisone on the sixth day. Pulmonary function testing was performed in the setting of bilateral hilar adenopathy and fixed infiltrates, which revealed a mixed obstructive and restrictive pattern. He eventually underwent lung biopsy by video-assisted thoracoscopic surgery (VATS) with right medial lobe wedge resection and was subsequently discharged with instructions to follow up with rheumatology for planned initiation of rituximab. The histopathological results of his lung biopsy demonstrated extensive intra-alveolar hemorrhage with linear polymorphonuclear (PMN) cell collections in alveolar septa and capillaritis without any evidence of granulomatous changes, indicative of microscopic polyangiitis (Fig. 3). Immunohistochemistry on lung biopsy samples was not performed and renal biopsy was deferred to outpatient rheumatology.Fig. 2 Blood pressure and creatinine during first and second hospitalizations. SBP Systolic Blood Pressure, DBP Diastolic Blood Pressure
Table 1 Autoimmune and infectious workup results during first admission
Lab Results Lab Results Lab Results
WBC 9.3 Neutrophils 75.9% Potassium 2.9
Hgb 13.1 Lymphocytes 12.5% Sodium 138
Hct 37.8 Eosinophils 1.3% Creatinine 2.03
Platelet 343 Monocytes 10.1% GFR 52
Troponin 0.232 D-Dimer 1.3 TSH 1.65
CRP 80 GBM Ab Negative CMV IgM Negative
ESR 67 SS-A/Ro Negative Cox A & B Ab Negative
ANA 1:160 (Homogenous) SS-B/La Negative Cryptococcal Ag Negative
RF < 10 ACA (IgG, IgM) < 9 EBV DNA Negative
Anti-CCP 4 TTG (IgA, IgG) 1, 3 HBV DNA Negative
ANCA Negative Ribosome IgG 3 HCV RNA Negative
Anti ds-DNA Negative Endomysial IgG < 1:10 HIV 1&2 Ab Negative
Anti-Smith Ab Negative Anti Gliadin < 7 Parvovirus B19 Negative
Histone auto Ab Negative Anti Gliadin < 2 Syphilis (RPR/FTA) Negative
Scl-70 Ab Negative Free Kappa 1.73 HHV6 DNA Negative
C3 130 Free Lambda 1.49 Lyme ELISA Negative
C4 32.4 K/L Ratio 1.16 Histoplasma Ag Negative
IgA 250 IgG 1160 IgM 1110
WBC White Blood Cell, Hgb Hemoglobin, Hct Hematocrit, GFR Glomerular Filtration Rate, TSH Thyroid Stimulating Hormone, Ab Antibody, Ig Immunoglobulin, ESR Erythrocyte Sedimentation Rate, CRP C-Reactive Protein, ANA Anti-Neutrophil Antibody, ANCA Anti-Neutrophil Cytoplasmic Antibody, Scl Scleroderma, C3 Complement 3, C4 Complement 4, ds-DNA Double-Stranded DNA, RF Rheumatoid Factor, CCP Cyclic Citrullinated Peptide, SS-A Sjӧgren-Syndrome-related-antigen A, SS-B Sjӧgren-syndrome-related-antigen B, ACA Anti Cardiolipin Ab, TTG Tissue trans-glutaminase, HIV Human Immunodeficiency Virus, HCV Hepatitis C Virus, HBV Hepatitis B Virus, CMV Cytomegalovirus, EBV Epstein-Barr Virus, Cox A & B Coxsackievirus A & B, HHV Human Herpes Virus, RPR: Rapid Plasma Reagin, FTA Fluorescent Treponemal Antibody
Fig. 3 Lung Biopsy. a Intra-alveolar hemorrhage (100×) b Polymorphonuclear cells in alveolar septa; capillaritis (Arrow) (400x)
Unfortunately, the patient was lost to follow up, failing to attend any of the scheduled appointments. He was subsequently readmitted six months later with similar symptoms, and once again found to be in hypertensive emergency, complicated by acute decompensated heart failure. Repeat echocardiogram revealed a further decline in his ejection fraction to 25% and a trivial pericardial effusion. Rheumatology was consulted and recommended pulse steroid therapy with methylprednisolone 250 mg four times a day for three days, which led to significant improvement in symptoms and blood pressure. Repeat ANCA and autoimmune serological workup remained negative. Following initiation of pulse steroid therapy, he underwent renal biopsy. The biopsy contained forty glomeruli, six of which were globally sclerotic. One glomerulus had segmental sclerosis. There were changes suggestive of microangiopathic injury in some arteries and glomeruli, such as bloodless glomeruli and mild intimal myxoid changes in arteries, with associated acute tubular injury. Focal tubular atrophy and interstitial fibrosis were estimated to involve approximately 10% of the cortex. No evidence of crescents or granulomatous changes were observed. Immunofluorescence was unremarkable, with only non-specific linear glomerular and tubular basement membrane staining for IgG, kappa, lambda, and albumin, indicative of pauci-immunity. Electron microscopy demonstrated segmental effacement of podocyte foot processes (40%) with vacuolation and microvillous transformation of the podocyte cytoplasm, ischemic-type capillary wall wrinkling, and subendothelial electron lucent widening (Fig. 4). He was subsequently discharged on a steroid taper with plans for outpatient rituximab. Despite extensive education about his condition he was once again lost to follow up and missed appropriate treatment.Fig. 4 Kidney Biopsy. a Glomerulus with segmental sclerosis of the right half of the tuft, Periodic Acid-Methenamine Silver (PASM, 200×) b One glomerulus (left) with an ischemic appearance including capillary wall wrinkling and tuft retraction, other glomerulus (right) has mild hypercellularity including a few neutrophils (H&E, 100×) c A glomerulus with a bloodless appearance, obliteration of capillary lumens and thickening of capillary walls with segmental duplication (Periodic Acid-Schiff (PAS), 200×) d Tubules show cytoplasmic vacuolation, apical blebbing, thinning, and focal simplification. The interstitium contains a sparse lymphocytic infiltrate (PAS, 100×) e Electron micrograph of glomerular tuft showing ischemic-type capillary wall wrinkling (asterisk) and diffuse subendothelial electron lucent widening (arrow) f Electron micrograph showing podocyte foot process effacement (arrow) and mild subendothelial electron-lucent widening (asterisk)
Over the course of the next year, he was readmitted on multiple occasions and eventually progressed to dialysis-dependent end-stage renal disease. His two most recent admissions were characterized by pancreatitis with pancreatic pseudoaneurysm complicated by retroperitoneal hematoma and cardiac tamponade, respectively. With respect to his pancreatitis, he presented in the context of acute onset abdominal pain with associated nausea and vomiting. Laboratory diagnostics demonstrated an elevated lipase (3400), normal triglycerides, and a negative IgG4 serology. Abdominal CT was significant for peripancreatic fat stranding and inflammatory changes without evidence of gallstones or biliary ductal dilation. He denied recent alcohol use. Pancreatitis course was further complicated by retroperitoneal hematoma, which was found to be secondary to a 7 mm pancreatic pseudoaneurysm rupture, as revealed on repeat abdominal CT angiography (Fig. 5). He was managed conservatively and subsequently discharged. One month later he presented with dyspnea, chest pain and nausea, and was found to have large pericardial effusion with an acute decrease in ejection fraction to 10% (Fig. 6). He underwent pericardiocentesis with removal of one liter of serosanguineous fluid. Fluid analysis was indicative of hemorrhagic etiology and negative for malignancy. On review of most recent outpatient records, the patient has been maintained on high-dose suppressive steroid therapy with plans for initiation of Rituximab or Cyclophosphamide.Fig. 5 CT angiography of the Abdomen. A 7 mm arterially enhancing focus in the tail of the pancreas that follows the blood flow (Arrow), consistent with a pseudoaneurysm, with an associated large left upper quadrant hematoma and small amount of hemorrhage in the right paracolic gutter
Fig. 6 Echocardiogram. Four chamber views in diastole a and systole (c). Short axis views in Diastole b and systole (d). Echocardiography demonstrating a large circumferential pericardial effusion (Asterisks) without hemodynamic compromise, mildly dilated left ventricle (LV) with normal wall thickness, and severe globally depressed systolic function with left ventricular ejection fraction of 10%, normal right ventricle (RV) size and mildly reduced right ventricular systolic function
Discussion
Since the sentinel publications on ANCA in early 1980s and the landmark article by van der Woude et al. [5], our understanding of ANCA has significantly expanded. ANCA is currently recognized as having a central role in the pathogenesis of necrotizing vasculitis and glomerulonephritis particularly AAV, however the exact mechanism, and if a direct pathogenic role exists for ANCA, remains to be elucidated [8]. Recently an association between ANCA-induced neutrophil activation, regulated necrosis (necroptosis), neutrophil endothelial trap (NET) generation, complement activation, and endothelial cell damage leading to vasculitis and necrotizing glomerulonephritis has been identified in AAV by Schreiber et al. [9]. Nonetheless, detection of ANCA has become an essential part of the routine workup for vasculitis and many other autoimmune disorders. Currently only two ANCA antigens, PR3/ c-ANCA and MPO/ p-ANCA, critical components for neutrophil-mediated innate immunity, have been recognized to be clinically significant for AAV amongst a diverse array of ANCA antigens [9]. While indirect immunofluorescence testing on ethanol-fixed neutrophils is the reference method for ANCA detection and screening, positive results prompt specific testing for PR3 and MPO. As new ANCA detection methods have developed, the most recent revised international consensus recommends high-quality antigen-specific assays for PR3-ANCA and MPO-ANCA should be used as the primary screening method for ANCA, and if results for both are negative with strong clinical suspicion for small-vessel vasculitis, other immunoassays, indirect immunofluorescence, or referral to an experienced lab is recommended [10].
ANCA is detected in 80–90% of cases of MPA out of which 70% are positive for MPO-ANCA [3–6, 11–14]. Seronegative ANCA, also known as pauci-immune vasculitis, is similar to seronegative lupus or seronegative rheumatoid arthritis and the absence of specific markers may lead not only to a delay in diagnosis, but also misdiagnosis [1, 2]. Furthermore, ANCA, though initially negative, may become positive later in the course of disease or may not be detectable with currently available methods [3–5]. On the other hand, antibodies to antigens other than PR3 and MPO have been detected and are referred to as minor ANCA antigens [15]. Interestingly these antibodies are frequently detected in sera of MPO- and PR3-ANCA negative patients, and while they can mimic c-ANCA or p-ANCA patterns, they are detected in other types of small vessel vasculitis such as cocaine-induced vasculitis mimicking GPA as well as other autoimmune diseases such as Sjӧgren, rheumatoid arthritis, and ulcerative colitis [9, 15]. It is noteworthy to mention that ethnic differences between MPO and PR3 ANCA subtypes have also been observed with PR3 predominance in Japanese and Chinese ethnicity and MPO predominance in Northern Europeans and Middle-Eastern/Turkish groups [7].
Classically MPA presents with acute onset of rapidly progressive glomerulonephritis, however presentation is often atypical. Most commonly, patients present with constitutional symptoms—fever, weight loss, fatigue—over an acute or chronic course over weeks to months [3–5]. The most common age of presentation is in 5–6th decades of life with a slight male predominance [3, 4]. Multiple organs can be involved with the most common organs being kidneys and lungs, followed by skin, gastrointestinal, cardiac and nervous systems [5, 6, 11]. Renal involvement is reported in 80–100% of MPA cases and is classically characterized by rapidly progressive glomerulonephritis (GN), however renal involvement on initial presentation may range from minimal proteinuria to end-stage renal disease requiring dialysis [5]. Pauci-immune necrotizing and crescentic GN is the classic finding on biopsy in systemic AAV [12]. Crescentic involvement of the glomeruli is the most common form of glomerular involvement in MPA and is visualized in up to 90% of cases, however interstitial nephritis and tubular atrophy, as observed in this case, are reported on biopsies as well [1–5]. Berden et al. proposed a classification criteria for AAV GN, based on the pathologic features of the glomerulus, into four major groups of focal, crescentic, mixed and sclerotic [12]. Considering the Berden’s classification, our patient would fall into the focal subgroup with more than 50% normal glomeruli, which have a relatively preserved kidney function and an overall more favorable outcome compared to other pathologic subgroups [12]. In another study of ANCA-negative patients with pauci-immune renal vasculitis, 29% of renal biopsies revealed normal glomeruli and only 50% had crescents on histology [14].
Pulmonary involvement can occur in up to 55% of cases of MPA and mostly present as dyspnea, cough, and hemoptysis. Classically MPA is associated with diffuse alveolar hemorrhage and a pauci-immune, hemorrhagic necrotizing alveolar capillaritis characterized by an absence of granulomatous changes on lung and renal biopsy [5, 6], similar to what was observed in our patient (Fig. 3). Diffuse alveolar hemorrhage, caused by pulmonary capillaritis, is considered a serious complication and if accompanied by glomerulonephritis (pulmonary-renal syndrome) portends a poor prognosis [5, 6]. Pulmonary function testing in patients with MPA can show either obstructive or restrictive pattern with reduced carbon monoxide diffusion capacity (DLCO) [5].
Gastrointestinal bleeding has been reported in up to 29% of MPA patients [5], however additional manifestations such as colonic ulceration, bowel ischemia, perforation, and arterial aneurysms have also been reported [5]. Pancreatic involvement in MPA is rare and may present as acute pancreatitis or pancreatic mass [16]. In a study of 62 patients with small-medium vessel vasculitis, Pagnoux et al. demonstrated that only 3 patients had pancreatitis as a complication, with only one having MPA [17]. Cardiac involvement in patients with MPA is reported to occur in 17–50% of cases with pathophysiology similar to that of other organ systems such as lung and kidney [18, 19]. Cardiac involvement may present as hypertension, heart failure, pericarditis, and less commonly myocardial infarction [10, 18].
Management of MPA and other AAV’s includes an induction phase followed by a maintenance phase. Classic induction strategies include oral corticosteroids (1 mg/kg daily) and cyclophosphamide (2 mg/kg daily). Rituximab and cyclophosphamide are considered the drug of choice for both induction and maintenance of remission. Rituximab has been shown to be non-inferior to cyclophosphamide by the RAVE and RITUXVAS trials [3–6, 11–13]. The NORAM study revealed methotrexate was as effective as cyclophosphamide with regards to induction of remission in mild disease however relapse rates were higher for methotrexate [3–5]. Plasmapheresis has been used in cases of aggressive AAV and was shown to have better renal outcomes in MEPEX trial, however PEXIVAS trial (Plasma exchange and glucocorticoids for treatment of AAV), the largest trial in AAV so far, failed to show a significant difference in all-cause mortality or end-stage renal disease, and plasmapheresis use remains controversial [3, 4, 20]. Maintenance therapy is generally achieved by less toxic agents such as rituximab, azathioprine, and methotrexate, with rituximab becoming more and more favored in recent years. Other immunosuppressive agents like leflunomide, mycophenolate mofetil, and trimethoprim-sulfamethoxazole have been used and studied as maintenance therapy strategies as well [3–6, 11].
This case was differentiated from other potential autoimmune disorders such as systemic lupus erythematosus, Sjӧgren syndrome, sarcoidosis, and other small to medium sized vessel vasculitis such as granulomatosis with polyangiitis, polyarteritis nodosa, IgA vasculitis and cryoglobulinemic vasculitis based on presentation, laboratory and imaging findings and biopsy of the lung revealing capillaritis without granulomatous changes. Absence of pathognomic noncaseating granulomas on lung biopsy, ruled out sarcoidosis. In the light of absence of certain characteristics such as palpable purpura, as well as absence of immune complexes on tissue biopsy, immune complex vasculitides such as anti-glomerular basement membrane disease, IgA and cryoglobulinemic vasculitis were ruled out. While differentiation of GPA from MPA is difficult and they tend to share characteristics of AAV disease spectrum, the absence of granulomatous lesions on both biopsies and lack of certain classical features of GPA made it less likely in this case. EGPA was also deemed less likely considering lack of peripheral eosinophilia and tissue eosinophilic infiltration. We also believe the kidney biopsy results were affected by pulse steroids and possible steroid consumption in between admissions, however pauci-immunity and absence of granulomatous changes, and immune complex deposition favors MPA over other vasculitides.
Conclusion
MPA is differentiated not only by the presence of anti-MPO (p-ANCA) but also histopathologically by non-granulomatous lesions and capillaritis. ANCA serologies, however, may be negative in AAV specifically MPA in as many as 10-20% of cases. This case underscores the importance of identifying pulmonary-renal syndrome and its association with AAV, the need to maintain a high index of suspicion in cases of negative ANCA serologies, and to pursue tissue biopsy despite negative serologies in such circumstances. This case further serves to demonstrate the rapid clinical deterioration and high morbidity in those cases of AAV with delayed diagnosis or inadequate treatment.
Abbreviations
MPAMicroscopic Polyangiitis
ANCAAnti-neutrophil cytoplasmic antibody
AAVANCA-associated Vasculitis
GPAGranulomatosis with polyangiitis
EGPAEosinophilic granulomatosis with angiitis
G6PDGlucose 6 Phosphate Dehydrogenase
CTComputed Tomography
IVIntravenous
CRPC-reactive Protein
ESRErythrocyte sedimentation Rate
CAPCommunity Acquired Pneumonia
ANAAnti-Neutrophil Antibody
RFRheumatoid Factor
FVCForced Vital Capacity
FEVForced Expiratory Volume
VCVital Capacity
FRCForced Residual Capacity
RVResidual Capacity
TLCTotal Lung Capacity
DLCODiffusing Capacity of Lung for Carbon Monoxide
VATSVideo-Assisted Thoracoscopic Surgery
PMNPolymorphonuclear
FSGSFocal Segmental Glomerulonephritis
IgGImmunoglobulin G
NETNeutrophil Endothelial Trap
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Authors’ contributions
AM designed the study, gathered data and resources, drafted, edited and finalized the entire manuscript. NNC and RA gathered data and resources. JSI provided and interpreted lung biopsy. LJA provided and interpreted kidney biopsy. SHFS assisted and edited discussion section. CJH edited, critically revised and helped finalize the entire manuscript. All authors read and approved the final manuscript.
Funding
No financial support or grant was provided for the preparation of this manuscript.
Consent for publication
A written informed consent has been signed and obtained from the patient and is available upon request.
Competing interests
Authors hereby declare no personal or financial conflict of interest. | AZITHROMYCIN, CEFTRIAXONE, UNSPECIFIED INGREDIENT | DrugsGivenReaction | CC BY | 33407881 | 19,165,871 | 2021-01-06 |
Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Lung infiltration'. | ANCA-negative microscopic polyangiitis with diffuse alveolar hemorrhage masquerading as congestive heart failure.
BACKGROUND
Microscopic polyangiitis (MPA) is a subtype of anti-neutrophil cytoplasmic antibody-associated vasculitis (AAV), involving small and medium sized vessels, often affecting the kidneys and lungs. Anti-neutrophil cytoplasmic antibody (ANCA) is detected in up to 90% of cases of MPA and its detection helps guide diagnosis, however cases of ANCA-negative MPA have been reported, hence definitive diagnosis relies on tissue biopsy.
METHODS
A 23-year-old man was evaluated for dyspnea and pleuritic chest pain, and found to have bilateral intra-alveolar opacities and hilar adenopathy. Diagnostic work up revealed positive anti-nuclear antibodies (ANA) and negative ANCA, which in the setting of a non-classical presentation, delayed diagnosis and appropriate treatment. Due to persistent symptoms and a high suspicion for autoimmune disease with pulmonary-renal syndrome, he underwent lung biopsy which revealed intra-alveolar hemorrhage and capillaritis indicative of microscopic polyangiitis (MPA). Surprisingly, kidney biopsy was not typical of classic MPA, but revealed less common features. Due to therapeutic noncompliance he was readmitted multiple times thereafter with rare complications of MPA such as acute pancreatitis and hemorrhagic pericardial effusion with tamponade.
CONCLUSIONS
This case serves as an important clinical reminder to consider AAV even in those with negative ANCA serologies and a high suspicion for pulmonary-renal syndrome. It also demonstrates the high morbidity in cases of diagnostic delay and inadequate treatment.
Background
The 2012 Chapel Hill Consensus guideline recognizes microscopic polyangiitis (MPA) as a subset of ANCA-associated vasculitis (AAV), a group of necrotizing pauci-immune vasculitides that predominantly affects small vessels—capillaries, venules, and arterioles—with few or no immune deposits [1]. AAV commonly affects the renal and pulmonary parenchyma to varying degrees, and is characterized by the presence of antibodies against neutrophilic cytoplasmic components, Proteinase-3 (PR3, c-ANCA) and Myeloperoxidase (MPO, p-ANCA). AAV include Microscopic Polyangiitis (MPA), Granulomatosis with polyangiitis (GPA; Wegener’s) and Eosinophilic granulomatosis with angiitis (EGPA; Churg-Strauss), as well as a variety of additional AAV-associated syndromes (drug-induced vasculitis, renal-limited vasculitis (RLV)), each characterized by the presence of distinct clinical presentation, ANCA subtypes, histopathological findings, and associated laboratory findings [1–4].
MPA is characterized by the presence of anti-MPO (p-ANCA) antibodies, renal and pulmonary involvement, and the absence of granulomatous inflammation on histopathology, a defining feature when compared to GPA and EGPA which, while demonstrating both renal and pulmonary involvement, are characterized by the presence of anti-PR3 (c-ANCA) and granulomatous disease. Though a widely accepted marker for AAV, the presence of ANCA is variable and not detected in all cases. ANCA is detected in 80–90% of cases of MPA and its detection has become integral in the diagnostic workup as well as classification and prognostication of all AAV [3, 4]. While current evidence indicates that ANCA plays a role in pathogenesis of MPA and other AAV, cases of ANCA-negative vasculitis, including cases of ANCA-negative MPA, GPA, and EGPA have been reported [1–7]. We present a case of ANCA-negative MPA in a young man who presented with hemoptysis and was found to have diffuse bilateral lung infiltrates, acute kidney injury, and heart failure. Following a circuitous diagnostic course masked by symptoms of heart failure, he was eventually diagnosed with MPA, however the course of his disease was further complicated by medication non-compliance as well as rare complications of AAV, including acute pancreatitis, pancreatic pseudoaneurysm, and cardiac tamponade.
Case report
A 23-year-old African-American man with past medical history of G6PD-deficiency and obesity presented with dyspnea and pleuritic chest pain that improved upon leaning forward and scant hemoptysis of two weeks duration. He was notably hypertensive to the 220/110 s mmHg and tachycardic to the 120 s, but had a preserved respiratory rate and oxygen saturation. Physical exam was remarkable for bilateral diffuse wheezing throughout all lung fields. Other parts of the exam including cardiovascular, nasopharynx, skin and musculoskeletal systems were unremarkable. Additional pertinent history was remarkable only for marijuana smoking. Electrocardiogram was unremarkable except for left atrial enlargement. Chest X-ray revealed bilateral pulmonary infiltrates, cardiomegaly, and mediastinal enlargement suggestive of bulky hilar adenopathy. Computed tomography (CT) scan of the chest with contrast was performed which was negative for pulmonary embolism, but revealed bilateral centrilobular opacities, hilar/mediastinal lymphadenopathy, and a trivial pericardial effusion (Fig. 1a). Initial laboratory diagnostics were significant for acute kidney injury with a serum creatinine of 2.03 (mg/dL), trace proteinuria, troponin elevation to 0.232 (ng/mL), and a D-Dimer of 1.3 (mcg/mL). Complete blood count revealed no leukocytosis, but concomitant eosinophilia, with no evidence of anemia. The patient was subsequently admitted to the medicine wards and a therapeutic regimen of antihypertensive agents as well as intravenous ceftriaxone and azithromycin for presumed community acquired pneumonia was initiated.Fig. 1 CT scans of the chest. a CT Scan of the chest on first day of presentation demonstrating bilateral centrilobular opacities, hilar/mediastinal lymphadenopathy, moderate cardiomegaly, a trivial pericardial effusion and enlargement of the main pulmonary artery. b Prone CT chest on day 7 of admission, revealing persistent intra-alveolar opacities with associated mediastinal lymphadenopathy
Additional diagnostic evaluation demonstrated marked elevation of CRP (80 mg/L) and ESR (67 mm/hr). Pheochromocytoma screening with serum catecholamines and metanephrines was negative. An echocardiogram revealed an ejection fraction of 40%, moderate concentric left ventricular hypertrophy, and trivial pericardial effusion without evidence of tamponade or pulmonary artery hypertension. Despite continuation of antibiotics for pneumonia and adjunctive heart failure management, the patient’s clinical status failed to improve. In the setting of an unremarkable infectious workup and concern for an autoimmune etiology, the patient was started on oral prednisone 60 mg daily. The patient remained symptomatic, experiencing episodic chest pain and shortness of breath, with blood pressure lability. Repeat chest X-ray showed worsening bilateral infiltrates. Subsequently, ANA resulted weakly positive (1:160) with a homogenous pattern and rheumatoid factor (RF) returned negative.
On the fifth day of admission, antibiotics were discontinued in light of negative cultures and lack of significant clinical improvement. The patient’s blood pressure was noted to be slightly improved with addition of prednisone however remained poorly controlled on multiple medications (Fig. 2). Autoimmune panel including ANCA (MPO/p-ANCA, and PR3/c-ANCA), anti-double-stranded DNA antibody, anti-Smith antibody, C3 and C4 complements, anti-histone antibody, as well as other autoimmune related factors and infectious serologies returned negative or within normal limits (Table 1). Renal ultrasound and renal artery duplex were performed which did not reveal any evidence of hydronephrosis or renal artery stenosis, respectively. A repeat high-resolution chest CT scan was obtained, both in supine and prone positions, to help differentiate early interstitial lung disease from intra-alveolar processes, which showed persistent intra-alveolar opacities without any change on prone position (Fig. 1b). Over the course of the following days, the patient reported improvement in his symptomatology and his blood pressure improved, therefore he was taken off prednisone on the sixth day. Pulmonary function testing was performed in the setting of bilateral hilar adenopathy and fixed infiltrates, which revealed a mixed obstructive and restrictive pattern. He eventually underwent lung biopsy by video-assisted thoracoscopic surgery (VATS) with right medial lobe wedge resection and was subsequently discharged with instructions to follow up with rheumatology for planned initiation of rituximab. The histopathological results of his lung biopsy demonstrated extensive intra-alveolar hemorrhage with linear polymorphonuclear (PMN) cell collections in alveolar septa and capillaritis without any evidence of granulomatous changes, indicative of microscopic polyangiitis (Fig. 3). Immunohistochemistry on lung biopsy samples was not performed and renal biopsy was deferred to outpatient rheumatology.Fig. 2 Blood pressure and creatinine during first and second hospitalizations. SBP Systolic Blood Pressure, DBP Diastolic Blood Pressure
Table 1 Autoimmune and infectious workup results during first admission
Lab Results Lab Results Lab Results
WBC 9.3 Neutrophils 75.9% Potassium 2.9
Hgb 13.1 Lymphocytes 12.5% Sodium 138
Hct 37.8 Eosinophils 1.3% Creatinine 2.03
Platelet 343 Monocytes 10.1% GFR 52
Troponin 0.232 D-Dimer 1.3 TSH 1.65
CRP 80 GBM Ab Negative CMV IgM Negative
ESR 67 SS-A/Ro Negative Cox A & B Ab Negative
ANA 1:160 (Homogenous) SS-B/La Negative Cryptococcal Ag Negative
RF < 10 ACA (IgG, IgM) < 9 EBV DNA Negative
Anti-CCP 4 TTG (IgA, IgG) 1, 3 HBV DNA Negative
ANCA Negative Ribosome IgG 3 HCV RNA Negative
Anti ds-DNA Negative Endomysial IgG < 1:10 HIV 1&2 Ab Negative
Anti-Smith Ab Negative Anti Gliadin < 7 Parvovirus B19 Negative
Histone auto Ab Negative Anti Gliadin < 2 Syphilis (RPR/FTA) Negative
Scl-70 Ab Negative Free Kappa 1.73 HHV6 DNA Negative
C3 130 Free Lambda 1.49 Lyme ELISA Negative
C4 32.4 K/L Ratio 1.16 Histoplasma Ag Negative
IgA 250 IgG 1160 IgM 1110
WBC White Blood Cell, Hgb Hemoglobin, Hct Hematocrit, GFR Glomerular Filtration Rate, TSH Thyroid Stimulating Hormone, Ab Antibody, Ig Immunoglobulin, ESR Erythrocyte Sedimentation Rate, CRP C-Reactive Protein, ANA Anti-Neutrophil Antibody, ANCA Anti-Neutrophil Cytoplasmic Antibody, Scl Scleroderma, C3 Complement 3, C4 Complement 4, ds-DNA Double-Stranded DNA, RF Rheumatoid Factor, CCP Cyclic Citrullinated Peptide, SS-A Sjӧgren-Syndrome-related-antigen A, SS-B Sjӧgren-syndrome-related-antigen B, ACA Anti Cardiolipin Ab, TTG Tissue trans-glutaminase, HIV Human Immunodeficiency Virus, HCV Hepatitis C Virus, HBV Hepatitis B Virus, CMV Cytomegalovirus, EBV Epstein-Barr Virus, Cox A & B Coxsackievirus A & B, HHV Human Herpes Virus, RPR: Rapid Plasma Reagin, FTA Fluorescent Treponemal Antibody
Fig. 3 Lung Biopsy. a Intra-alveolar hemorrhage (100×) b Polymorphonuclear cells in alveolar septa; capillaritis (Arrow) (400x)
Unfortunately, the patient was lost to follow up, failing to attend any of the scheduled appointments. He was subsequently readmitted six months later with similar symptoms, and once again found to be in hypertensive emergency, complicated by acute decompensated heart failure. Repeat echocardiogram revealed a further decline in his ejection fraction to 25% and a trivial pericardial effusion. Rheumatology was consulted and recommended pulse steroid therapy with methylprednisolone 250 mg four times a day for three days, which led to significant improvement in symptoms and blood pressure. Repeat ANCA and autoimmune serological workup remained negative. Following initiation of pulse steroid therapy, he underwent renal biopsy. The biopsy contained forty glomeruli, six of which were globally sclerotic. One glomerulus had segmental sclerosis. There were changes suggestive of microangiopathic injury in some arteries and glomeruli, such as bloodless glomeruli and mild intimal myxoid changes in arteries, with associated acute tubular injury. Focal tubular atrophy and interstitial fibrosis were estimated to involve approximately 10% of the cortex. No evidence of crescents or granulomatous changes were observed. Immunofluorescence was unremarkable, with only non-specific linear glomerular and tubular basement membrane staining for IgG, kappa, lambda, and albumin, indicative of pauci-immunity. Electron microscopy demonstrated segmental effacement of podocyte foot processes (40%) with vacuolation and microvillous transformation of the podocyte cytoplasm, ischemic-type capillary wall wrinkling, and subendothelial electron lucent widening (Fig. 4). He was subsequently discharged on a steroid taper with plans for outpatient rituximab. Despite extensive education about his condition he was once again lost to follow up and missed appropriate treatment.Fig. 4 Kidney Biopsy. a Glomerulus with segmental sclerosis of the right half of the tuft, Periodic Acid-Methenamine Silver (PASM, 200×) b One glomerulus (left) with an ischemic appearance including capillary wall wrinkling and tuft retraction, other glomerulus (right) has mild hypercellularity including a few neutrophils (H&E, 100×) c A glomerulus with a bloodless appearance, obliteration of capillary lumens and thickening of capillary walls with segmental duplication (Periodic Acid-Schiff (PAS), 200×) d Tubules show cytoplasmic vacuolation, apical blebbing, thinning, and focal simplification. The interstitium contains a sparse lymphocytic infiltrate (PAS, 100×) e Electron micrograph of glomerular tuft showing ischemic-type capillary wall wrinkling (asterisk) and diffuse subendothelial electron lucent widening (arrow) f Electron micrograph showing podocyte foot process effacement (arrow) and mild subendothelial electron-lucent widening (asterisk)
Over the course of the next year, he was readmitted on multiple occasions and eventually progressed to dialysis-dependent end-stage renal disease. His two most recent admissions were characterized by pancreatitis with pancreatic pseudoaneurysm complicated by retroperitoneal hematoma and cardiac tamponade, respectively. With respect to his pancreatitis, he presented in the context of acute onset abdominal pain with associated nausea and vomiting. Laboratory diagnostics demonstrated an elevated lipase (3400), normal triglycerides, and a negative IgG4 serology. Abdominal CT was significant for peripancreatic fat stranding and inflammatory changes without evidence of gallstones or biliary ductal dilation. He denied recent alcohol use. Pancreatitis course was further complicated by retroperitoneal hematoma, which was found to be secondary to a 7 mm pancreatic pseudoaneurysm rupture, as revealed on repeat abdominal CT angiography (Fig. 5). He was managed conservatively and subsequently discharged. One month later he presented with dyspnea, chest pain and nausea, and was found to have large pericardial effusion with an acute decrease in ejection fraction to 10% (Fig. 6). He underwent pericardiocentesis with removal of one liter of serosanguineous fluid. Fluid analysis was indicative of hemorrhagic etiology and negative for malignancy. On review of most recent outpatient records, the patient has been maintained on high-dose suppressive steroid therapy with plans for initiation of Rituximab or Cyclophosphamide.Fig. 5 CT angiography of the Abdomen. A 7 mm arterially enhancing focus in the tail of the pancreas that follows the blood flow (Arrow), consistent with a pseudoaneurysm, with an associated large left upper quadrant hematoma and small amount of hemorrhage in the right paracolic gutter
Fig. 6 Echocardiogram. Four chamber views in diastole a and systole (c). Short axis views in Diastole b and systole (d). Echocardiography demonstrating a large circumferential pericardial effusion (Asterisks) without hemodynamic compromise, mildly dilated left ventricle (LV) with normal wall thickness, and severe globally depressed systolic function with left ventricular ejection fraction of 10%, normal right ventricle (RV) size and mildly reduced right ventricular systolic function
Discussion
Since the sentinel publications on ANCA in early 1980s and the landmark article by van der Woude et al. [5], our understanding of ANCA has significantly expanded. ANCA is currently recognized as having a central role in the pathogenesis of necrotizing vasculitis and glomerulonephritis particularly AAV, however the exact mechanism, and if a direct pathogenic role exists for ANCA, remains to be elucidated [8]. Recently an association between ANCA-induced neutrophil activation, regulated necrosis (necroptosis), neutrophil endothelial trap (NET) generation, complement activation, and endothelial cell damage leading to vasculitis and necrotizing glomerulonephritis has been identified in AAV by Schreiber et al. [9]. Nonetheless, detection of ANCA has become an essential part of the routine workup for vasculitis and many other autoimmune disorders. Currently only two ANCA antigens, PR3/ c-ANCA and MPO/ p-ANCA, critical components for neutrophil-mediated innate immunity, have been recognized to be clinically significant for AAV amongst a diverse array of ANCA antigens [9]. While indirect immunofluorescence testing on ethanol-fixed neutrophils is the reference method for ANCA detection and screening, positive results prompt specific testing for PR3 and MPO. As new ANCA detection methods have developed, the most recent revised international consensus recommends high-quality antigen-specific assays for PR3-ANCA and MPO-ANCA should be used as the primary screening method for ANCA, and if results for both are negative with strong clinical suspicion for small-vessel vasculitis, other immunoassays, indirect immunofluorescence, or referral to an experienced lab is recommended [10].
ANCA is detected in 80–90% of cases of MPA out of which 70% are positive for MPO-ANCA [3–6, 11–14]. Seronegative ANCA, also known as pauci-immune vasculitis, is similar to seronegative lupus or seronegative rheumatoid arthritis and the absence of specific markers may lead not only to a delay in diagnosis, but also misdiagnosis [1, 2]. Furthermore, ANCA, though initially negative, may become positive later in the course of disease or may not be detectable with currently available methods [3–5]. On the other hand, antibodies to antigens other than PR3 and MPO have been detected and are referred to as minor ANCA antigens [15]. Interestingly these antibodies are frequently detected in sera of MPO- and PR3-ANCA negative patients, and while they can mimic c-ANCA or p-ANCA patterns, they are detected in other types of small vessel vasculitis such as cocaine-induced vasculitis mimicking GPA as well as other autoimmune diseases such as Sjӧgren, rheumatoid arthritis, and ulcerative colitis [9, 15]. It is noteworthy to mention that ethnic differences between MPO and PR3 ANCA subtypes have also been observed with PR3 predominance in Japanese and Chinese ethnicity and MPO predominance in Northern Europeans and Middle-Eastern/Turkish groups [7].
Classically MPA presents with acute onset of rapidly progressive glomerulonephritis, however presentation is often atypical. Most commonly, patients present with constitutional symptoms—fever, weight loss, fatigue—over an acute or chronic course over weeks to months [3–5]. The most common age of presentation is in 5–6th decades of life with a slight male predominance [3, 4]. Multiple organs can be involved with the most common organs being kidneys and lungs, followed by skin, gastrointestinal, cardiac and nervous systems [5, 6, 11]. Renal involvement is reported in 80–100% of MPA cases and is classically characterized by rapidly progressive glomerulonephritis (GN), however renal involvement on initial presentation may range from minimal proteinuria to end-stage renal disease requiring dialysis [5]. Pauci-immune necrotizing and crescentic GN is the classic finding on biopsy in systemic AAV [12]. Crescentic involvement of the glomeruli is the most common form of glomerular involvement in MPA and is visualized in up to 90% of cases, however interstitial nephritis and tubular atrophy, as observed in this case, are reported on biopsies as well [1–5]. Berden et al. proposed a classification criteria for AAV GN, based on the pathologic features of the glomerulus, into four major groups of focal, crescentic, mixed and sclerotic [12]. Considering the Berden’s classification, our patient would fall into the focal subgroup with more than 50% normal glomeruli, which have a relatively preserved kidney function and an overall more favorable outcome compared to other pathologic subgroups [12]. In another study of ANCA-negative patients with pauci-immune renal vasculitis, 29% of renal biopsies revealed normal glomeruli and only 50% had crescents on histology [14].
Pulmonary involvement can occur in up to 55% of cases of MPA and mostly present as dyspnea, cough, and hemoptysis. Classically MPA is associated with diffuse alveolar hemorrhage and a pauci-immune, hemorrhagic necrotizing alveolar capillaritis characterized by an absence of granulomatous changes on lung and renal biopsy [5, 6], similar to what was observed in our patient (Fig. 3). Diffuse alveolar hemorrhage, caused by pulmonary capillaritis, is considered a serious complication and if accompanied by glomerulonephritis (pulmonary-renal syndrome) portends a poor prognosis [5, 6]. Pulmonary function testing in patients with MPA can show either obstructive or restrictive pattern with reduced carbon monoxide diffusion capacity (DLCO) [5].
Gastrointestinal bleeding has been reported in up to 29% of MPA patients [5], however additional manifestations such as colonic ulceration, bowel ischemia, perforation, and arterial aneurysms have also been reported [5]. Pancreatic involvement in MPA is rare and may present as acute pancreatitis or pancreatic mass [16]. In a study of 62 patients with small-medium vessel vasculitis, Pagnoux et al. demonstrated that only 3 patients had pancreatitis as a complication, with only one having MPA [17]. Cardiac involvement in patients with MPA is reported to occur in 17–50% of cases with pathophysiology similar to that of other organ systems such as lung and kidney [18, 19]. Cardiac involvement may present as hypertension, heart failure, pericarditis, and less commonly myocardial infarction [10, 18].
Management of MPA and other AAV’s includes an induction phase followed by a maintenance phase. Classic induction strategies include oral corticosteroids (1 mg/kg daily) and cyclophosphamide (2 mg/kg daily). Rituximab and cyclophosphamide are considered the drug of choice for both induction and maintenance of remission. Rituximab has been shown to be non-inferior to cyclophosphamide by the RAVE and RITUXVAS trials [3–6, 11–13]. The NORAM study revealed methotrexate was as effective as cyclophosphamide with regards to induction of remission in mild disease however relapse rates were higher for methotrexate [3–5]. Plasmapheresis has been used in cases of aggressive AAV and was shown to have better renal outcomes in MEPEX trial, however PEXIVAS trial (Plasma exchange and glucocorticoids for treatment of AAV), the largest trial in AAV so far, failed to show a significant difference in all-cause mortality or end-stage renal disease, and plasmapheresis use remains controversial [3, 4, 20]. Maintenance therapy is generally achieved by less toxic agents such as rituximab, azathioprine, and methotrexate, with rituximab becoming more and more favored in recent years. Other immunosuppressive agents like leflunomide, mycophenolate mofetil, and trimethoprim-sulfamethoxazole have been used and studied as maintenance therapy strategies as well [3–6, 11].
This case was differentiated from other potential autoimmune disorders such as systemic lupus erythematosus, Sjӧgren syndrome, sarcoidosis, and other small to medium sized vessel vasculitis such as granulomatosis with polyangiitis, polyarteritis nodosa, IgA vasculitis and cryoglobulinemic vasculitis based on presentation, laboratory and imaging findings and biopsy of the lung revealing capillaritis without granulomatous changes. Absence of pathognomic noncaseating granulomas on lung biopsy, ruled out sarcoidosis. In the light of absence of certain characteristics such as palpable purpura, as well as absence of immune complexes on tissue biopsy, immune complex vasculitides such as anti-glomerular basement membrane disease, IgA and cryoglobulinemic vasculitis were ruled out. While differentiation of GPA from MPA is difficult and they tend to share characteristics of AAV disease spectrum, the absence of granulomatous lesions on both biopsies and lack of certain classical features of GPA made it less likely in this case. EGPA was also deemed less likely considering lack of peripheral eosinophilia and tissue eosinophilic infiltration. We also believe the kidney biopsy results were affected by pulse steroids and possible steroid consumption in between admissions, however pauci-immunity and absence of granulomatous changes, and immune complex deposition favors MPA over other vasculitides.
Conclusion
MPA is differentiated not only by the presence of anti-MPO (p-ANCA) but also histopathologically by non-granulomatous lesions and capillaritis. ANCA serologies, however, may be negative in AAV specifically MPA in as many as 10-20% of cases. This case underscores the importance of identifying pulmonary-renal syndrome and its association with AAV, the need to maintain a high index of suspicion in cases of negative ANCA serologies, and to pursue tissue biopsy despite negative serologies in such circumstances. This case further serves to demonstrate the rapid clinical deterioration and high morbidity in those cases of AAV with delayed diagnosis or inadequate treatment.
Abbreviations
MPAMicroscopic Polyangiitis
ANCAAnti-neutrophil cytoplasmic antibody
AAVANCA-associated Vasculitis
GPAGranulomatosis with polyangiitis
EGPAEosinophilic granulomatosis with angiitis
G6PDGlucose 6 Phosphate Dehydrogenase
CTComputed Tomography
IVIntravenous
CRPC-reactive Protein
ESRErythrocyte sedimentation Rate
CAPCommunity Acquired Pneumonia
ANAAnti-Neutrophil Antibody
RFRheumatoid Factor
FVCForced Vital Capacity
FEVForced Expiratory Volume
VCVital Capacity
FRCForced Residual Capacity
RVResidual Capacity
TLCTotal Lung Capacity
DLCODiffusing Capacity of Lung for Carbon Monoxide
VATSVideo-Assisted Thoracoscopic Surgery
PMNPolymorphonuclear
FSGSFocal Segmental Glomerulonephritis
IgGImmunoglobulin G
NETNeutrophil Endothelial Trap
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Authors’ contributions
AM designed the study, gathered data and resources, drafted, edited and finalized the entire manuscript. NNC and RA gathered data and resources. JSI provided and interpreted lung biopsy. LJA provided and interpreted kidney biopsy. SHFS assisted and edited discussion section. CJH edited, critically revised and helped finalize the entire manuscript. All authors read and approved the final manuscript.
Funding
No financial support or grant was provided for the preparation of this manuscript.
Consent for publication
A written informed consent has been signed and obtained from the patient and is available upon request.
Competing interests
Authors hereby declare no personal or financial conflict of interest. | AZITHROMYCIN, CEFTRIAXONE, UNSPECIFIED INGREDIENT | DrugsGivenReaction | CC BY | 33407881 | 19,165,871 | 2021-01-06 |
Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Microscopic polyangiitis'. | ANCA-negative microscopic polyangiitis with diffuse alveolar hemorrhage masquerading as congestive heart failure.
BACKGROUND
Microscopic polyangiitis (MPA) is a subtype of anti-neutrophil cytoplasmic antibody-associated vasculitis (AAV), involving small and medium sized vessels, often affecting the kidneys and lungs. Anti-neutrophil cytoplasmic antibody (ANCA) is detected in up to 90% of cases of MPA and its detection helps guide diagnosis, however cases of ANCA-negative MPA have been reported, hence definitive diagnosis relies on tissue biopsy.
METHODS
A 23-year-old man was evaluated for dyspnea and pleuritic chest pain, and found to have bilateral intra-alveolar opacities and hilar adenopathy. Diagnostic work up revealed positive anti-nuclear antibodies (ANA) and negative ANCA, which in the setting of a non-classical presentation, delayed diagnosis and appropriate treatment. Due to persistent symptoms and a high suspicion for autoimmune disease with pulmonary-renal syndrome, he underwent lung biopsy which revealed intra-alveolar hemorrhage and capillaritis indicative of microscopic polyangiitis (MPA). Surprisingly, kidney biopsy was not typical of classic MPA, but revealed less common features. Due to therapeutic noncompliance he was readmitted multiple times thereafter with rare complications of MPA such as acute pancreatitis and hemorrhagic pericardial effusion with tamponade.
CONCLUSIONS
This case serves as an important clinical reminder to consider AAV even in those with negative ANCA serologies and a high suspicion for pulmonary-renal syndrome. It also demonstrates the high morbidity in cases of diagnostic delay and inadequate treatment.
Background
The 2012 Chapel Hill Consensus guideline recognizes microscopic polyangiitis (MPA) as a subset of ANCA-associated vasculitis (AAV), a group of necrotizing pauci-immune vasculitides that predominantly affects small vessels—capillaries, venules, and arterioles—with few or no immune deposits [1]. AAV commonly affects the renal and pulmonary parenchyma to varying degrees, and is characterized by the presence of antibodies against neutrophilic cytoplasmic components, Proteinase-3 (PR3, c-ANCA) and Myeloperoxidase (MPO, p-ANCA). AAV include Microscopic Polyangiitis (MPA), Granulomatosis with polyangiitis (GPA; Wegener’s) and Eosinophilic granulomatosis with angiitis (EGPA; Churg-Strauss), as well as a variety of additional AAV-associated syndromes (drug-induced vasculitis, renal-limited vasculitis (RLV)), each characterized by the presence of distinct clinical presentation, ANCA subtypes, histopathological findings, and associated laboratory findings [1–4].
MPA is characterized by the presence of anti-MPO (p-ANCA) antibodies, renal and pulmonary involvement, and the absence of granulomatous inflammation on histopathology, a defining feature when compared to GPA and EGPA which, while demonstrating both renal and pulmonary involvement, are characterized by the presence of anti-PR3 (c-ANCA) and granulomatous disease. Though a widely accepted marker for AAV, the presence of ANCA is variable and not detected in all cases. ANCA is detected in 80–90% of cases of MPA and its detection has become integral in the diagnostic workup as well as classification and prognostication of all AAV [3, 4]. While current evidence indicates that ANCA plays a role in pathogenesis of MPA and other AAV, cases of ANCA-negative vasculitis, including cases of ANCA-negative MPA, GPA, and EGPA have been reported [1–7]. We present a case of ANCA-negative MPA in a young man who presented with hemoptysis and was found to have diffuse bilateral lung infiltrates, acute kidney injury, and heart failure. Following a circuitous diagnostic course masked by symptoms of heart failure, he was eventually diagnosed with MPA, however the course of his disease was further complicated by medication non-compliance as well as rare complications of AAV, including acute pancreatitis, pancreatic pseudoaneurysm, and cardiac tamponade.
Case report
A 23-year-old African-American man with past medical history of G6PD-deficiency and obesity presented with dyspnea and pleuritic chest pain that improved upon leaning forward and scant hemoptysis of two weeks duration. He was notably hypertensive to the 220/110 s mmHg and tachycardic to the 120 s, but had a preserved respiratory rate and oxygen saturation. Physical exam was remarkable for bilateral diffuse wheezing throughout all lung fields. Other parts of the exam including cardiovascular, nasopharynx, skin and musculoskeletal systems were unremarkable. Additional pertinent history was remarkable only for marijuana smoking. Electrocardiogram was unremarkable except for left atrial enlargement. Chest X-ray revealed bilateral pulmonary infiltrates, cardiomegaly, and mediastinal enlargement suggestive of bulky hilar adenopathy. Computed tomography (CT) scan of the chest with contrast was performed which was negative for pulmonary embolism, but revealed bilateral centrilobular opacities, hilar/mediastinal lymphadenopathy, and a trivial pericardial effusion (Fig. 1a). Initial laboratory diagnostics were significant for acute kidney injury with a serum creatinine of 2.03 (mg/dL), trace proteinuria, troponin elevation to 0.232 (ng/mL), and a D-Dimer of 1.3 (mcg/mL). Complete blood count revealed no leukocytosis, but concomitant eosinophilia, with no evidence of anemia. The patient was subsequently admitted to the medicine wards and a therapeutic regimen of antihypertensive agents as well as intravenous ceftriaxone and azithromycin for presumed community acquired pneumonia was initiated.Fig. 1 CT scans of the chest. a CT Scan of the chest on first day of presentation demonstrating bilateral centrilobular opacities, hilar/mediastinal lymphadenopathy, moderate cardiomegaly, a trivial pericardial effusion and enlargement of the main pulmonary artery. b Prone CT chest on day 7 of admission, revealing persistent intra-alveolar opacities with associated mediastinal lymphadenopathy
Additional diagnostic evaluation demonstrated marked elevation of CRP (80 mg/L) and ESR (67 mm/hr). Pheochromocytoma screening with serum catecholamines and metanephrines was negative. An echocardiogram revealed an ejection fraction of 40%, moderate concentric left ventricular hypertrophy, and trivial pericardial effusion without evidence of tamponade or pulmonary artery hypertension. Despite continuation of antibiotics for pneumonia and adjunctive heart failure management, the patient’s clinical status failed to improve. In the setting of an unremarkable infectious workup and concern for an autoimmune etiology, the patient was started on oral prednisone 60 mg daily. The patient remained symptomatic, experiencing episodic chest pain and shortness of breath, with blood pressure lability. Repeat chest X-ray showed worsening bilateral infiltrates. Subsequently, ANA resulted weakly positive (1:160) with a homogenous pattern and rheumatoid factor (RF) returned negative.
On the fifth day of admission, antibiotics were discontinued in light of negative cultures and lack of significant clinical improvement. The patient’s blood pressure was noted to be slightly improved with addition of prednisone however remained poorly controlled on multiple medications (Fig. 2). Autoimmune panel including ANCA (MPO/p-ANCA, and PR3/c-ANCA), anti-double-stranded DNA antibody, anti-Smith antibody, C3 and C4 complements, anti-histone antibody, as well as other autoimmune related factors and infectious serologies returned negative or within normal limits (Table 1). Renal ultrasound and renal artery duplex were performed which did not reveal any evidence of hydronephrosis or renal artery stenosis, respectively. A repeat high-resolution chest CT scan was obtained, both in supine and prone positions, to help differentiate early interstitial lung disease from intra-alveolar processes, which showed persistent intra-alveolar opacities without any change on prone position (Fig. 1b). Over the course of the following days, the patient reported improvement in his symptomatology and his blood pressure improved, therefore he was taken off prednisone on the sixth day. Pulmonary function testing was performed in the setting of bilateral hilar adenopathy and fixed infiltrates, which revealed a mixed obstructive and restrictive pattern. He eventually underwent lung biopsy by video-assisted thoracoscopic surgery (VATS) with right medial lobe wedge resection and was subsequently discharged with instructions to follow up with rheumatology for planned initiation of rituximab. The histopathological results of his lung biopsy demonstrated extensive intra-alveolar hemorrhage with linear polymorphonuclear (PMN) cell collections in alveolar septa and capillaritis without any evidence of granulomatous changes, indicative of microscopic polyangiitis (Fig. 3). Immunohistochemistry on lung biopsy samples was not performed and renal biopsy was deferred to outpatient rheumatology.Fig. 2 Blood pressure and creatinine during first and second hospitalizations. SBP Systolic Blood Pressure, DBP Diastolic Blood Pressure
Table 1 Autoimmune and infectious workup results during first admission
Lab Results Lab Results Lab Results
WBC 9.3 Neutrophils 75.9% Potassium 2.9
Hgb 13.1 Lymphocytes 12.5% Sodium 138
Hct 37.8 Eosinophils 1.3% Creatinine 2.03
Platelet 343 Monocytes 10.1% GFR 52
Troponin 0.232 D-Dimer 1.3 TSH 1.65
CRP 80 GBM Ab Negative CMV IgM Negative
ESR 67 SS-A/Ro Negative Cox A & B Ab Negative
ANA 1:160 (Homogenous) SS-B/La Negative Cryptococcal Ag Negative
RF < 10 ACA (IgG, IgM) < 9 EBV DNA Negative
Anti-CCP 4 TTG (IgA, IgG) 1, 3 HBV DNA Negative
ANCA Negative Ribosome IgG 3 HCV RNA Negative
Anti ds-DNA Negative Endomysial IgG < 1:10 HIV 1&2 Ab Negative
Anti-Smith Ab Negative Anti Gliadin < 7 Parvovirus B19 Negative
Histone auto Ab Negative Anti Gliadin < 2 Syphilis (RPR/FTA) Negative
Scl-70 Ab Negative Free Kappa 1.73 HHV6 DNA Negative
C3 130 Free Lambda 1.49 Lyme ELISA Negative
C4 32.4 K/L Ratio 1.16 Histoplasma Ag Negative
IgA 250 IgG 1160 IgM 1110
WBC White Blood Cell, Hgb Hemoglobin, Hct Hematocrit, GFR Glomerular Filtration Rate, TSH Thyroid Stimulating Hormone, Ab Antibody, Ig Immunoglobulin, ESR Erythrocyte Sedimentation Rate, CRP C-Reactive Protein, ANA Anti-Neutrophil Antibody, ANCA Anti-Neutrophil Cytoplasmic Antibody, Scl Scleroderma, C3 Complement 3, C4 Complement 4, ds-DNA Double-Stranded DNA, RF Rheumatoid Factor, CCP Cyclic Citrullinated Peptide, SS-A Sjӧgren-Syndrome-related-antigen A, SS-B Sjӧgren-syndrome-related-antigen B, ACA Anti Cardiolipin Ab, TTG Tissue trans-glutaminase, HIV Human Immunodeficiency Virus, HCV Hepatitis C Virus, HBV Hepatitis B Virus, CMV Cytomegalovirus, EBV Epstein-Barr Virus, Cox A & B Coxsackievirus A & B, HHV Human Herpes Virus, RPR: Rapid Plasma Reagin, FTA Fluorescent Treponemal Antibody
Fig. 3 Lung Biopsy. a Intra-alveolar hemorrhage (100×) b Polymorphonuclear cells in alveolar septa; capillaritis (Arrow) (400x)
Unfortunately, the patient was lost to follow up, failing to attend any of the scheduled appointments. He was subsequently readmitted six months later with similar symptoms, and once again found to be in hypertensive emergency, complicated by acute decompensated heart failure. Repeat echocardiogram revealed a further decline in his ejection fraction to 25% and a trivial pericardial effusion. Rheumatology was consulted and recommended pulse steroid therapy with methylprednisolone 250 mg four times a day for three days, which led to significant improvement in symptoms and blood pressure. Repeat ANCA and autoimmune serological workup remained negative. Following initiation of pulse steroid therapy, he underwent renal biopsy. The biopsy contained forty glomeruli, six of which were globally sclerotic. One glomerulus had segmental sclerosis. There were changes suggestive of microangiopathic injury in some arteries and glomeruli, such as bloodless glomeruli and mild intimal myxoid changes in arteries, with associated acute tubular injury. Focal tubular atrophy and interstitial fibrosis were estimated to involve approximately 10% of the cortex. No evidence of crescents or granulomatous changes were observed. Immunofluorescence was unremarkable, with only non-specific linear glomerular and tubular basement membrane staining for IgG, kappa, lambda, and albumin, indicative of pauci-immunity. Electron microscopy demonstrated segmental effacement of podocyte foot processes (40%) with vacuolation and microvillous transformation of the podocyte cytoplasm, ischemic-type capillary wall wrinkling, and subendothelial electron lucent widening (Fig. 4). He was subsequently discharged on a steroid taper with plans for outpatient rituximab. Despite extensive education about his condition he was once again lost to follow up and missed appropriate treatment.Fig. 4 Kidney Biopsy. a Glomerulus with segmental sclerosis of the right half of the tuft, Periodic Acid-Methenamine Silver (PASM, 200×) b One glomerulus (left) with an ischemic appearance including capillary wall wrinkling and tuft retraction, other glomerulus (right) has mild hypercellularity including a few neutrophils (H&E, 100×) c A glomerulus with a bloodless appearance, obliteration of capillary lumens and thickening of capillary walls with segmental duplication (Periodic Acid-Schiff (PAS), 200×) d Tubules show cytoplasmic vacuolation, apical blebbing, thinning, and focal simplification. The interstitium contains a sparse lymphocytic infiltrate (PAS, 100×) e Electron micrograph of glomerular tuft showing ischemic-type capillary wall wrinkling (asterisk) and diffuse subendothelial electron lucent widening (arrow) f Electron micrograph showing podocyte foot process effacement (arrow) and mild subendothelial electron-lucent widening (asterisk)
Over the course of the next year, he was readmitted on multiple occasions and eventually progressed to dialysis-dependent end-stage renal disease. His two most recent admissions were characterized by pancreatitis with pancreatic pseudoaneurysm complicated by retroperitoneal hematoma and cardiac tamponade, respectively. With respect to his pancreatitis, he presented in the context of acute onset abdominal pain with associated nausea and vomiting. Laboratory diagnostics demonstrated an elevated lipase (3400), normal triglycerides, and a negative IgG4 serology. Abdominal CT was significant for peripancreatic fat stranding and inflammatory changes without evidence of gallstones or biliary ductal dilation. He denied recent alcohol use. Pancreatitis course was further complicated by retroperitoneal hematoma, which was found to be secondary to a 7 mm pancreatic pseudoaneurysm rupture, as revealed on repeat abdominal CT angiography (Fig. 5). He was managed conservatively and subsequently discharged. One month later he presented with dyspnea, chest pain and nausea, and was found to have large pericardial effusion with an acute decrease in ejection fraction to 10% (Fig. 6). He underwent pericardiocentesis with removal of one liter of serosanguineous fluid. Fluid analysis was indicative of hemorrhagic etiology and negative for malignancy. On review of most recent outpatient records, the patient has been maintained on high-dose suppressive steroid therapy with plans for initiation of Rituximab or Cyclophosphamide.Fig. 5 CT angiography of the Abdomen. A 7 mm arterially enhancing focus in the tail of the pancreas that follows the blood flow (Arrow), consistent with a pseudoaneurysm, with an associated large left upper quadrant hematoma and small amount of hemorrhage in the right paracolic gutter
Fig. 6 Echocardiogram. Four chamber views in diastole a and systole (c). Short axis views in Diastole b and systole (d). Echocardiography demonstrating a large circumferential pericardial effusion (Asterisks) without hemodynamic compromise, mildly dilated left ventricle (LV) with normal wall thickness, and severe globally depressed systolic function with left ventricular ejection fraction of 10%, normal right ventricle (RV) size and mildly reduced right ventricular systolic function
Discussion
Since the sentinel publications on ANCA in early 1980s and the landmark article by van der Woude et al. [5], our understanding of ANCA has significantly expanded. ANCA is currently recognized as having a central role in the pathogenesis of necrotizing vasculitis and glomerulonephritis particularly AAV, however the exact mechanism, and if a direct pathogenic role exists for ANCA, remains to be elucidated [8]. Recently an association between ANCA-induced neutrophil activation, regulated necrosis (necroptosis), neutrophil endothelial trap (NET) generation, complement activation, and endothelial cell damage leading to vasculitis and necrotizing glomerulonephritis has been identified in AAV by Schreiber et al. [9]. Nonetheless, detection of ANCA has become an essential part of the routine workup for vasculitis and many other autoimmune disorders. Currently only two ANCA antigens, PR3/ c-ANCA and MPO/ p-ANCA, critical components for neutrophil-mediated innate immunity, have been recognized to be clinically significant for AAV amongst a diverse array of ANCA antigens [9]. While indirect immunofluorescence testing on ethanol-fixed neutrophils is the reference method for ANCA detection and screening, positive results prompt specific testing for PR3 and MPO. As new ANCA detection methods have developed, the most recent revised international consensus recommends high-quality antigen-specific assays for PR3-ANCA and MPO-ANCA should be used as the primary screening method for ANCA, and if results for both are negative with strong clinical suspicion for small-vessel vasculitis, other immunoassays, indirect immunofluorescence, or referral to an experienced lab is recommended [10].
ANCA is detected in 80–90% of cases of MPA out of which 70% are positive for MPO-ANCA [3–6, 11–14]. Seronegative ANCA, also known as pauci-immune vasculitis, is similar to seronegative lupus or seronegative rheumatoid arthritis and the absence of specific markers may lead not only to a delay in diagnosis, but also misdiagnosis [1, 2]. Furthermore, ANCA, though initially negative, may become positive later in the course of disease or may not be detectable with currently available methods [3–5]. On the other hand, antibodies to antigens other than PR3 and MPO have been detected and are referred to as minor ANCA antigens [15]. Interestingly these antibodies are frequently detected in sera of MPO- and PR3-ANCA negative patients, and while they can mimic c-ANCA or p-ANCA patterns, they are detected in other types of small vessel vasculitis such as cocaine-induced vasculitis mimicking GPA as well as other autoimmune diseases such as Sjӧgren, rheumatoid arthritis, and ulcerative colitis [9, 15]. It is noteworthy to mention that ethnic differences between MPO and PR3 ANCA subtypes have also been observed with PR3 predominance in Japanese and Chinese ethnicity and MPO predominance in Northern Europeans and Middle-Eastern/Turkish groups [7].
Classically MPA presents with acute onset of rapidly progressive glomerulonephritis, however presentation is often atypical. Most commonly, patients present with constitutional symptoms—fever, weight loss, fatigue—over an acute or chronic course over weeks to months [3–5]. The most common age of presentation is in 5–6th decades of life with a slight male predominance [3, 4]. Multiple organs can be involved with the most common organs being kidneys and lungs, followed by skin, gastrointestinal, cardiac and nervous systems [5, 6, 11]. Renal involvement is reported in 80–100% of MPA cases and is classically characterized by rapidly progressive glomerulonephritis (GN), however renal involvement on initial presentation may range from minimal proteinuria to end-stage renal disease requiring dialysis [5]. Pauci-immune necrotizing and crescentic GN is the classic finding on biopsy in systemic AAV [12]. Crescentic involvement of the glomeruli is the most common form of glomerular involvement in MPA and is visualized in up to 90% of cases, however interstitial nephritis and tubular atrophy, as observed in this case, are reported on biopsies as well [1–5]. Berden et al. proposed a classification criteria for AAV GN, based on the pathologic features of the glomerulus, into four major groups of focal, crescentic, mixed and sclerotic [12]. Considering the Berden’s classification, our patient would fall into the focal subgroup with more than 50% normal glomeruli, which have a relatively preserved kidney function and an overall more favorable outcome compared to other pathologic subgroups [12]. In another study of ANCA-negative patients with pauci-immune renal vasculitis, 29% of renal biopsies revealed normal glomeruli and only 50% had crescents on histology [14].
Pulmonary involvement can occur in up to 55% of cases of MPA and mostly present as dyspnea, cough, and hemoptysis. Classically MPA is associated with diffuse alveolar hemorrhage and a pauci-immune, hemorrhagic necrotizing alveolar capillaritis characterized by an absence of granulomatous changes on lung and renal biopsy [5, 6], similar to what was observed in our patient (Fig. 3). Diffuse alveolar hemorrhage, caused by pulmonary capillaritis, is considered a serious complication and if accompanied by glomerulonephritis (pulmonary-renal syndrome) portends a poor prognosis [5, 6]. Pulmonary function testing in patients with MPA can show either obstructive or restrictive pattern with reduced carbon monoxide diffusion capacity (DLCO) [5].
Gastrointestinal bleeding has been reported in up to 29% of MPA patients [5], however additional manifestations such as colonic ulceration, bowel ischemia, perforation, and arterial aneurysms have also been reported [5]. Pancreatic involvement in MPA is rare and may present as acute pancreatitis or pancreatic mass [16]. In a study of 62 patients with small-medium vessel vasculitis, Pagnoux et al. demonstrated that only 3 patients had pancreatitis as a complication, with only one having MPA [17]. Cardiac involvement in patients with MPA is reported to occur in 17–50% of cases with pathophysiology similar to that of other organ systems such as lung and kidney [18, 19]. Cardiac involvement may present as hypertension, heart failure, pericarditis, and less commonly myocardial infarction [10, 18].
Management of MPA and other AAV’s includes an induction phase followed by a maintenance phase. Classic induction strategies include oral corticosteroids (1 mg/kg daily) and cyclophosphamide (2 mg/kg daily). Rituximab and cyclophosphamide are considered the drug of choice for both induction and maintenance of remission. Rituximab has been shown to be non-inferior to cyclophosphamide by the RAVE and RITUXVAS trials [3–6, 11–13]. The NORAM study revealed methotrexate was as effective as cyclophosphamide with regards to induction of remission in mild disease however relapse rates were higher for methotrexate [3–5]. Plasmapheresis has been used in cases of aggressive AAV and was shown to have better renal outcomes in MEPEX trial, however PEXIVAS trial (Plasma exchange and glucocorticoids for treatment of AAV), the largest trial in AAV so far, failed to show a significant difference in all-cause mortality or end-stage renal disease, and plasmapheresis use remains controversial [3, 4, 20]. Maintenance therapy is generally achieved by less toxic agents such as rituximab, azathioprine, and methotrexate, with rituximab becoming more and more favored in recent years. Other immunosuppressive agents like leflunomide, mycophenolate mofetil, and trimethoprim-sulfamethoxazole have been used and studied as maintenance therapy strategies as well [3–6, 11].
This case was differentiated from other potential autoimmune disorders such as systemic lupus erythematosus, Sjӧgren syndrome, sarcoidosis, and other small to medium sized vessel vasculitis such as granulomatosis with polyangiitis, polyarteritis nodosa, IgA vasculitis and cryoglobulinemic vasculitis based on presentation, laboratory and imaging findings and biopsy of the lung revealing capillaritis without granulomatous changes. Absence of pathognomic noncaseating granulomas on lung biopsy, ruled out sarcoidosis. In the light of absence of certain characteristics such as palpable purpura, as well as absence of immune complexes on tissue biopsy, immune complex vasculitides such as anti-glomerular basement membrane disease, IgA and cryoglobulinemic vasculitis were ruled out. While differentiation of GPA from MPA is difficult and they tend to share characteristics of AAV disease spectrum, the absence of granulomatous lesions on both biopsies and lack of certain classical features of GPA made it less likely in this case. EGPA was also deemed less likely considering lack of peripheral eosinophilia and tissue eosinophilic infiltration. We also believe the kidney biopsy results were affected by pulse steroids and possible steroid consumption in between admissions, however pauci-immunity and absence of granulomatous changes, and immune complex deposition favors MPA over other vasculitides.
Conclusion
MPA is differentiated not only by the presence of anti-MPO (p-ANCA) but also histopathologically by non-granulomatous lesions and capillaritis. ANCA serologies, however, may be negative in AAV specifically MPA in as many as 10-20% of cases. This case underscores the importance of identifying pulmonary-renal syndrome and its association with AAV, the need to maintain a high index of suspicion in cases of negative ANCA serologies, and to pursue tissue biopsy despite negative serologies in such circumstances. This case further serves to demonstrate the rapid clinical deterioration and high morbidity in those cases of AAV with delayed diagnosis or inadequate treatment.
Abbreviations
MPAMicroscopic Polyangiitis
ANCAAnti-neutrophil cytoplasmic antibody
AAVANCA-associated Vasculitis
GPAGranulomatosis with polyangiitis
EGPAEosinophilic granulomatosis with angiitis
G6PDGlucose 6 Phosphate Dehydrogenase
CTComputed Tomography
IVIntravenous
CRPC-reactive Protein
ESRErythrocyte sedimentation Rate
CAPCommunity Acquired Pneumonia
ANAAnti-Neutrophil Antibody
RFRheumatoid Factor
FVCForced Vital Capacity
FEVForced Expiratory Volume
VCVital Capacity
FRCForced Residual Capacity
RVResidual Capacity
TLCTotal Lung Capacity
DLCODiffusing Capacity of Lung for Carbon Monoxide
VATSVideo-Assisted Thoracoscopic Surgery
PMNPolymorphonuclear
FSGSFocal Segmental Glomerulonephritis
IgGImmunoglobulin G
NETNeutrophil Endothelial Trap
Publisher's Note
Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
Authors’ contributions
AM designed the study, gathered data and resources, drafted, edited and finalized the entire manuscript. NNC and RA gathered data and resources. JSI provided and interpreted lung biopsy. LJA provided and interpreted kidney biopsy. SHFS assisted and edited discussion section. CJH edited, critically revised and helped finalize the entire manuscript. All authors read and approved the final manuscript.
Funding
No financial support or grant was provided for the preparation of this manuscript.
Consent for publication
A written informed consent has been signed and obtained from the patient and is available upon request.
Competing interests
Authors hereby declare no personal or financial conflict of interest. | AZITHROMYCIN, CEFTRIAXONE, UNSPECIFIED INGREDIENT | DrugsGivenReaction | CC BY | 33407881 | 19,165,871 | 2021-01-06 |
Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Pericardial effusion'. | ANCA-negative microscopic polyangiitis with diffuse alveolar hemorrhage masquerading as congestive heart failure.
BACKGROUND
Microscopic polyangiitis (MPA) is a subtype of anti-neutrophil cytoplasmic antibody-associated vasculitis (AAV), involving small and medium sized vessels, often affecting the kidneys and lungs. Anti-neutrophil cytoplasmic antibody (ANCA) is detected in up to 90% of cases of MPA and its detection helps guide diagnosis, however cases of ANCA-negative MPA have been reported, hence definitive diagnosis relies on tissue biopsy.
METHODS
A 23-year-old man was evaluated for dyspnea and pleuritic chest pain, and found to have bilateral intra-alveolar opacities and hilar adenopathy. Diagnostic work up revealed positive anti-nuclear antibodies (ANA) and negative ANCA, which in the setting of a non-classical presentation, delayed diagnosis and appropriate treatment. Due to persistent symptoms and a high suspicion for autoimmune disease with pulmonary-renal syndrome, he underwent lung biopsy which revealed intra-alveolar hemorrhage and capillaritis indicative of microscopic polyangiitis (MPA). Surprisingly, kidney biopsy was not typical of classic MPA, but revealed less common features. Due to therapeutic noncompliance he was readmitted multiple times thereafter with rare complications of MPA such as acute pancreatitis and hemorrhagic pericardial effusion with tamponade.
CONCLUSIONS
This case serves as an important clinical reminder to consider AAV even in those with negative ANCA serologies and a high suspicion for pulmonary-renal syndrome. It also demonstrates the high morbidity in cases of diagnostic delay and inadequate treatment.
Background
The 2012 Chapel Hill Consensus guideline recognizes microscopic polyangiitis (MPA) as a subset of ANCA-associated vasculitis (AAV), a group of necrotizing pauci-immune vasculitides that predominantly affects small vessels—capillaries, venules, and arterioles—with few or no immune deposits [1]. AAV commonly affects the renal and pulmonary parenchyma to varying degrees, and is characterized by the presence of antibodies against neutrophilic cytoplasmic components, Proteinase-3 (PR3, c-ANCA) and Myeloperoxidase (MPO, p-ANCA). AAV include Microscopic Polyangiitis (MPA), Granulomatosis with polyangiitis (GPA; Wegener’s) and Eosinophilic granulomatosis with angiitis (EGPA; Churg-Strauss), as well as a variety of additional AAV-associated syndromes (drug-induced vasculitis, renal-limited vasculitis (RLV)), each characterized by the presence of distinct clinical presentation, ANCA subtypes, histopathological findings, and associated laboratory findings [1–4].
MPA is characterized by the presence of anti-MPO (p-ANCA) antibodies, renal and pulmonary involvement, and the absence of granulomatous inflammation on histopathology, a defining feature when compared to GPA and EGPA which, while demonstrating both renal and pulmonary involvement, are characterized by the presence of anti-PR3 (c-ANCA) and granulomatous disease. Though a widely accepted marker for AAV, the presence of ANCA is variable and not detected in all cases. ANCA is detected in 80–90% of cases of MPA and its detection has become integral in the diagnostic workup as well as classification and prognostication of all AAV [3, 4]. While current evidence indicates that ANCA plays a role in pathogenesis of MPA and other AAV, cases of ANCA-negative vasculitis, including cases of ANCA-negative MPA, GPA, and EGPA have been reported [1–7]. We present a case of ANCA-negative MPA in a young man who presented with hemoptysis and was found to have diffuse bilateral lung infiltrates, acute kidney injury, and heart failure. Following a circuitous diagnostic course masked by symptoms of heart failure, he was eventually diagnosed with MPA, however the course of his disease was further complicated by medication non-compliance as well as rare complications of AAV, including acute pancreatitis, pancreatic pseudoaneurysm, and cardiac tamponade.
Case report
A 23-year-old African-American man with past medical history of G6PD-deficiency and obesity presented with dyspnea and pleuritic chest pain that improved upon leaning forward and scant hemoptysis of two weeks duration. He was notably hypertensive to the 220/110 s mmHg and tachycardic to the 120 s, but had a preserved respiratory rate and oxygen saturation. Physical exam was remarkable for bilateral diffuse wheezing throughout all lung fields. Other parts of the exam including cardiovascular, nasopharynx, skin and musculoskeletal systems were unremarkable. Additional pertinent history was remarkable only for marijuana smoking. Electrocardiogram was unremarkable except for left atrial enlargement. Chest X-ray revealed bilateral pulmonary infiltrates, cardiomegaly, and mediastinal enlargement suggestive of bulky hilar adenopathy. Computed tomography (CT) scan of the chest with contrast was performed which was negative for pulmonary embolism, but revealed bilateral centrilobular opacities, hilar/mediastinal lymphadenopathy, and a trivial pericardial effusion (Fig. 1a). Initial laboratory diagnostics were significant for acute kidney injury with a serum creatinine of 2.03 (mg/dL), trace proteinuria, troponin elevation to 0.232 (ng/mL), and a D-Dimer of 1.3 (mcg/mL). Complete blood count revealed no leukocytosis, but concomitant eosinophilia, with no evidence of anemia. The patient was subsequently admitted to the medicine wards and a therapeutic regimen of antihypertensive agents as well as intravenous ceftriaxone and azithromycin for presumed community acquired pneumonia was initiated.Fig. 1 CT scans of the chest. a CT Scan of the chest on first day of presentation demonstrating bilateral centrilobular opacities, hilar/mediastinal lymphadenopathy, moderate cardiomegaly, a trivial pericardial effusion and enlargement of the main pulmonary artery. b Prone CT chest on day 7 of admission, revealing persistent intra-alveolar opacities with associated mediastinal lymphadenopathy
Additional diagnostic evaluation demonstrated marked elevation of CRP (80 mg/L) and ESR (67 mm/hr). Pheochromocytoma screening with serum catecholamines and metanephrines was negative. An echocardiogram revealed an ejection fraction of 40%, moderate concentric left ventricular hypertrophy, and trivial pericardial effusion without evidence of tamponade or pulmonary artery hypertension. Despite continuation of antibiotics for pneumonia and adjunctive heart failure management, the patient’s clinical status failed to improve. In the setting of an unremarkable infectious workup and concern for an autoimmune etiology, the patient was started on oral prednisone 60 mg daily. The patient remained symptomatic, experiencing episodic chest pain and shortness of breath, with blood pressure lability. Repeat chest X-ray showed worsening bilateral infiltrates. Subsequently, ANA resulted weakly positive (1:160) with a homogenous pattern and rheumatoid factor (RF) returned negative.
On the fifth day of admission, antibiotics were discontinued in light of negative cultures and lack of significant clinical improvement. The patient’s blood pressure was noted to be slightly improved with addition of prednisone however remained poorly controlled on multiple medications (Fig. 2). Autoimmune panel including ANCA (MPO/p-ANCA, and PR3/c-ANCA), anti-double-stranded DNA antibody, anti-Smith antibody, C3 and C4 complements, anti-histone antibody, as well as other autoimmune related factors and infectious serologies returned negative or within normal limits (Table 1). Renal ultrasound and renal artery duplex were performed which did not reveal any evidence of hydronephrosis or renal artery stenosis, respectively. A repeat high-resolution chest CT scan was obtained, both in supine and prone positions, to help differentiate early interstitial lung disease from intra-alveolar processes, which showed persistent intra-alveolar opacities without any change on prone position (Fig. 1b). Over the course of the following days, the patient reported improvement in his symptomatology and his blood pressure improved, therefore he was taken off prednisone on the sixth day. Pulmonary function testing was performed in the setting of bilateral hilar adenopathy and fixed infiltrates, which revealed a mixed obstructive and restrictive pattern. He eventually underwent lung biopsy by video-assisted thoracoscopic surgery (VATS) with right medial lobe wedge resection and was subsequently discharged with instructions to follow up with rheumatology for planned initiation of rituximab. The histopathological results of his lung biopsy demonstrated extensive intra-alveolar hemorrhage with linear polymorphonuclear (PMN) cell collections in alveolar septa and capillaritis without any evidence of granulomatous changes, indicative of microscopic polyangiitis (Fig. 3). Immunohistochemistry on lung biopsy samples was not performed and renal biopsy was deferred to outpatient rheumatology.Fig. 2 Blood pressure and creatinine during first and second hospitalizations. SBP Systolic Blood Pressure, DBP Diastolic Blood Pressure
Table 1 Autoimmune and infectious workup results during first admission
Lab Results Lab Results Lab Results
WBC 9.3 Neutrophils 75.9% Potassium 2.9
Hgb 13.1 Lymphocytes 12.5% Sodium 138
Hct 37.8 Eosinophils 1.3% Creatinine 2.03
Platelet 343 Monocytes 10.1% GFR 52
Troponin 0.232 D-Dimer 1.3 TSH 1.65
CRP 80 GBM Ab Negative CMV IgM Negative
ESR 67 SS-A/Ro Negative Cox A & B Ab Negative
ANA 1:160 (Homogenous) SS-B/La Negative Cryptococcal Ag Negative
RF < 10 ACA (IgG, IgM) < 9 EBV DNA Negative
Anti-CCP 4 TTG (IgA, IgG) 1, 3 HBV DNA Negative
ANCA Negative Ribosome IgG 3 HCV RNA Negative
Anti ds-DNA Negative Endomysial IgG < 1:10 HIV 1&2 Ab Negative
Anti-Smith Ab Negative Anti Gliadin < 7 Parvovirus B19 Negative
Histone auto Ab Negative Anti Gliadin < 2 Syphilis (RPR/FTA) Negative
Scl-70 Ab Negative Free Kappa 1.73 HHV6 DNA Negative
C3 130 Free Lambda 1.49 Lyme ELISA Negative
C4 32.4 K/L Ratio 1.16 Histoplasma Ag Negative
IgA 250 IgG 1160 IgM 1110
WBC White Blood Cell, Hgb Hemoglobin, Hct Hematocrit, GFR Glomerular Filtration Rate, TSH Thyroid Stimulating Hormone, Ab Antibody, Ig Immunoglobulin, ESR Erythrocyte Sedimentation Rate, CRP C-Reactive Protein, ANA Anti-Neutrophil Antibody, ANCA Anti-Neutrophil Cytoplasmic Antibody, Scl Scleroderma, C3 Complement 3, C4 Complement 4, ds-DNA Double-Stranded DNA, RF Rheumatoid Factor, CCP Cyclic Citrullinated Peptide, SS-A Sjӧgren-Syndrome-related-antigen A, SS-B Sjӧgren-syndrome-related-antigen B, ACA Anti Cardiolipin Ab, TTG Tissue trans-glutaminase, HIV Human Immunodeficiency Virus, HCV Hepatitis C Virus, HBV Hepatitis B Virus, CMV Cytomegalovirus, EBV Epstein-Barr Virus, Cox A & B Coxsackievirus A & B, HHV Human Herpes Virus, RPR: Rapid Plasma Reagin, FTA Fluorescent Treponemal Antibody
Fig. 3 Lung Biopsy. a Intra-alveolar hemorrhage (100×) b Polymorphonuclear cells in alveolar septa; capillaritis (Arrow) (400x)
Unfortunately, the patient was lost to follow up, failing to attend any of the scheduled appointments. He was subsequently readmitted six months later with similar symptoms, and once again found to be in hypertensive emergency, complicated by acute decompensated heart failure. Repeat echocardiogram revealed a further decline in his ejection fraction to 25% and a trivial pericardial effusion. Rheumatology was consulted and recommended pulse steroid therapy with methylprednisolone 250 mg four times a day for three days, which led to significant improvement in symptoms and blood pressure. Repeat ANCA and autoimmune serological workup remained negative. Following initiation of pulse steroid therapy, he underwent renal biopsy. The biopsy contained forty glomeruli, six of which were globally sclerotic. One glomerulus had segmental sclerosis. There were changes suggestive of microangiopathic injury in some arteries and glomeruli, such as bloodless glomeruli and mild intimal myxoid changes in arteries, with associated acute tubular injury. Focal tubular atrophy and interstitial fibrosis were estimated to involve approximately 10% of the cortex. No evidence of crescents or granulomatous changes were observed. Immunofluorescence was unremarkable, with only non-specific linear glomerular and tubular basement membrane staining for IgG, kappa, lambda, and albumin, indicative of pauci-immunity. Electron microscopy demonstrated segmental effacement of podocyte foot processes (40%) with vacuolation and microvillous transformation of the podocyte cytoplasm, ischemic-type capillary wall wrinkling, and subendothelial electron lucent widening (Fig. 4). He was subsequently discharged on a steroid taper with plans for outpatient rituximab. Despite extensive education about his condition he was once again lost to follow up and missed appropriate treatment.Fig. 4 Kidney Biopsy. a Glomerulus with segmental sclerosis of the right half of the tuft, Periodic Acid-Methenamine Silver (PASM, 200×) b One glomerulus (left) with an ischemic appearance including capillary wall wrinkling and tuft retraction, other glomerulus (right) has mild hypercellularity including a few neutrophils (H&E, 100×) c A glomerulus with a bloodless appearance, obliteration of capillary lumens and thickening of capillary walls with segmental duplication (Periodic Acid-Schiff (PAS), 200×) d Tubules show cytoplasmic vacuolation, apical blebbing, thinning, and focal simplification. The interstitium contains a sparse lymphocytic infiltrate (PAS, 100×) e Electron micrograph of glomerular tuft showing ischemic-type capillary wall wrinkling (asterisk) and diffuse subendothelial electron lucent widening (arrow) f Electron micrograph showing podocyte foot process effacement (arrow) and mild subendothelial electron-lucent widening (asterisk)
Over the course of the next year, he was readmitted on multiple occasions and eventually progressed to dialysis-dependent end-stage renal disease. His two most recent admissions were characterized by pancreatitis with pancreatic pseudoaneurysm complicated by retroperitoneal hematoma and cardiac tamponade, respectively. With respect to his pancreatitis, he presented in the context of acute onset abdominal pain with associated nausea and vomiting. Laboratory diagnostics demonstrated an elevated lipase (3400), normal triglycerides, and a negative IgG4 serology. Abdominal CT was significant for peripancreatic fat stranding and inflammatory changes without evidence of gallstones or biliary ductal dilation. He denied recent alcohol use. Pancreatitis course was further complicated by retroperitoneal hematoma, which was found to be secondary to a 7 mm pancreatic pseudoaneurysm rupture, as revealed on repeat abdominal CT angiography (Fig. 5). He was managed conservatively and subsequently discharged. One month later he presented with dyspnea, chest pain and nausea, and was found to have large pericardial effusion with an acute decrease in ejection fraction to 10% (Fig. 6). He underwent pericardiocentesis with removal of one liter of serosanguineous fluid. Fluid analysis was indicative of hemorrhagic etiology and negative for malignancy. On review of most recent outpatient records, the patient has been maintained on high-dose suppressive steroid therapy with plans for initiation of Rituximab or Cyclophosphamide.Fig. 5 CT angiography of the Abdomen. A 7 mm arterially enhancing focus in the tail of the pancreas that follows the blood flow (Arrow), consistent with a pseudoaneurysm, with an associated large left upper quadrant hematoma and small amount of hemorrhage in the right paracolic gutter
Fig. 6 Echocardiogram. Four chamber views in diastole a and systole (c). Short axis views in Diastole b and systole (d). Echocardiography demonstrating a large circumferential pericardial effusion (Asterisks) without hemodynamic compromise, mildly dilated left ventricle (LV) with normal wall thickness, and severe globally depressed systolic function with left ventricular ejection fraction of 10%, normal right ventricle (RV) size and mildly reduced right ventricular systolic function
Discussion
Since the sentinel publications on ANCA in early 1980s and the landmark article by van der Woude et al. [5], our understanding of ANCA has significantly expanded. ANCA is currently recognized as having a central role in the pathogenesis of necrotizing vasculitis and glomerulonephritis particularly AAV, however the exact mechanism, and if a direct pathogenic role exists for ANCA, remains to be elucidated [8]. Recently an association between ANCA-induced neutrophil activation, regulated necrosis (necroptosis), neutrophil endothelial trap (NET) generation, complement activation, and endothelial cell damage leading to vasculitis and necrotizing glomerulonephritis has been identified in AAV by Schreiber et al. [9]. Nonetheless, detection of ANCA has become an essential part of the routine workup for vasculitis and many other autoimmune disorders. Currently only two ANCA antigens, PR3/ c-ANCA and MPO/ p-ANCA, critical components for neutrophil-mediated innate immunity, have been recognized to be clinically significant for AAV amongst a diverse array of ANCA antigens [9]. While indirect immunofluorescence testing on ethanol-fixed neutrophils is the reference method for ANCA detection and screening, positive results prompt specific testing for PR3 and MPO. As new ANCA detection methods have developed, the most recent revised international consensus recommends high-quality antigen-specific assays for PR3-ANCA and MPO-ANCA should be used as the primary screening method for ANCA, and if results for both are negative with strong clinical suspicion for small-vessel vasculitis, other immunoassays, indirect immunofluorescence, or referral to an experienced lab is recommended [10].
ANCA is detected in 80–90% of cases of MPA out of which 70% are positive for MPO-ANCA [3–6, 11–14]. Seronegative ANCA, also known as pauci-immune vasculitis, is similar to seronegative lupus or seronegative rheumatoid arthritis and the absence of specific markers may lead not only to a delay in diagnosis, but also misdiagnosis [1, 2]. Furthermore, ANCA, though initially negative, may become positive later in the course of disease or may not be detectable with currently available methods [3–5]. On the other hand, antibodies to antigens other than PR3 and MPO have been detected and are referred to as minor ANCA antigens [15]. Interestingly these antibodies are frequently detected in sera of MPO- and PR3-ANCA negative patients, and while they can mimic c-ANCA or p-ANCA patterns, they are detected in other types of small vessel vasculitis such as cocaine-induced vasculitis mimicking GPA as well as other autoimmune diseases such as Sjӧgren, rheumatoid arthritis, and ulcerative colitis [9, 15]. It is noteworthy to mention that ethnic differences between MPO and PR3 ANCA subtypes have also been observed with PR3 predominance in Japanese and Chinese ethnicity and MPO predominance in Northern Europeans and Middle-Eastern/Turkish groups [7].
Classically MPA presents with acute onset of rapidly progressive glomerulonephritis, however presentation is often atypical. Most commonly, patients present with constitutional symptoms—fever, weight loss, fatigue—over an acute or chronic course over weeks to months [3–5]. The most common age of presentation is in 5–6th decades of life with a slight male predominance [3, 4]. Multiple organs can be involved with the most common organs being kidneys and lungs, followed by skin, gastrointestinal, cardiac and nervous systems [5, 6, 11]. Renal involvement is reported in 80–100% of MPA cases and is classically characterized by rapidly progressive glomerulonephritis (GN), however renal involvement on initial presentation may range from minimal proteinuria to end-stage renal disease requiring dialysis [5]. Pauci-immune necrotizing and crescentic GN is the classic finding on biopsy in systemic AAV [12]. Crescentic involvement of the glomeruli is the most common form of glomerular involvement in MPA and is visualized in up to 90% of cases, however interstitial nephritis and tubular atrophy, as observed in this case, are reported on biopsies as well [1–5]. Berden et al. proposed a classification criteria for AAV GN, based on the pathologic features of the glomerulus, into four major groups of focal, crescentic, mixed and sclerotic [12]. Considering the Berden’s classification, our patient would fall into the focal subgroup with more than 50% normal glomeruli, which have a relatively preserved kidney function and an overall more favorable outcome compared to other pathologic subgroups [12]. In another study of ANCA-negative patients with pauci-immune renal vasculitis, 29% of renal biopsies revealed normal glomeruli and only 50% had crescents on histology [14].
Pulmonary involvement can occur in up to 55% of cases of MPA and mostly present as dyspnea, cough, and hemoptysis. Classically MPA is associated with diffuse alveolar hemorrhage and a pauci-immune, hemorrhagic necrotizing alveolar capillaritis characterized by an absence of granulomatous changes on lung and renal biopsy [5, 6], similar to what was observed in our patient (Fig. 3). Diffuse alveolar hemorrhage, caused by pulmonary capillaritis, is considered a serious complication and if accompanied by glomerulonephritis (pulmonary-renal syndrome) portends a poor prognosis [5, 6]. Pulmonary function testing in patients with MPA can show either obstructive or restrictive pattern with reduced carbon monoxide diffusion capacity (DLCO) [5].
Gastrointestinal bleeding has been reported in up to 29% of MPA patients [5], however additional manifestations such as colonic ulceration, bowel ischemia, perforation, and arterial aneurysms have also been reported [5]. Pancreatic involvement in MPA is rare and may present as acute pancreatitis or pancreatic mass [16]. In a study of 62 patients with small-medium vessel vasculitis, Pagnoux et al. demonstrated that only 3 patients had pancreatitis as a complication, with only one having MPA [17]. Cardiac involvement in patients with MPA is reported to occur in 17–50% of cases with pathophysiology similar to that of other organ systems such as lung and kidney [18, 19]. Cardiac involvement may present as hypertension, heart failure, pericarditis, and less commonly myocardial infarction [10, 18].
Management of MPA and other AAV’s includes an induction phase followed by a maintenance phase. Classic induction strategies include oral corticosteroids (1 mg/kg daily) and cyclophosphamide (2 mg/kg daily). Rituximab and cyclophosphamide are considered the drug of choice for both induction and maintenance of remission. Rituximab has been shown to be non-inferior to cyclophosphamide by the RAVE and RITUXVAS trials [3–6, 11–13]. The NORAM study revealed methotrexate was as effective as cyclophosphamide with regards to induction of remission in mild disease however relapse rates were higher for methotrexate [3–5]. Plasmapheresis has been used in cases of aggressive AAV and was shown to have better renal outcomes in MEPEX trial, however PEXIVAS trial (Plasma exchange and glucocorticoids for treatment of AAV), the largest trial in AAV so far, failed to show a significant difference in all-cause mortality or end-stage renal disease, and plasmapheresis use remains controversial [3, 4, 20]. Maintenance therapy is generally achieved by less toxic agents such as rituximab, azathioprine, and methotrexate, with rituximab becoming more and more favored in recent years. Other immunosuppressive agents like leflunomide, mycophenolate mofetil, and trimethoprim-sulfamethoxazole have been used and studied as maintenance therapy strategies as well [3–6, 11].
This case was differentiated from other potential autoimmune disorders such as systemic lupus erythematosus, Sjӧgren syndrome, sarcoidosis, and other small to medium sized vessel vasculitis such as granulomatosis with polyangiitis, polyarteritis nodosa, IgA vasculitis and cryoglobulinemic vasculitis based on presentation, laboratory and imaging findings and biopsy of the lung revealing capillaritis without granulomatous changes. Absence of pathognomic noncaseating granulomas on lung biopsy, ruled out sarcoidosis. In the light of absence of certain characteristics such as palpable purpura, as well as absence of immune complexes on tissue biopsy, immune complex vasculitides such as anti-glomerular basement membrane disease, IgA and cryoglobulinemic vasculitis were ruled out. While differentiation of GPA from MPA is difficult and they tend to share characteristics of AAV disease spectrum, the absence of granulomatous lesions on both biopsies and lack of certain classical features of GPA made it less likely in this case. EGPA was also deemed less likely considering lack of peripheral eosinophilia and tissue eosinophilic infiltration. We also believe the kidney biopsy results were affected by pulse steroids and possible steroid consumption in between admissions, however pauci-immunity and absence of granulomatous changes, and immune complex deposition favors MPA over other vasculitides.
Conclusion
MPA is differentiated not only by the presence of anti-MPO (p-ANCA) but also histopathologically by non-granulomatous lesions and capillaritis. ANCA serologies, however, may be negative in AAV specifically MPA in as many as 10-20% of cases. This case underscores the importance of identifying pulmonary-renal syndrome and its association with AAV, the need to maintain a high index of suspicion in cases of negative ANCA serologies, and to pursue tissue biopsy despite negative serologies in such circumstances. This case further serves to demonstrate the rapid clinical deterioration and high morbidity in those cases of AAV with delayed diagnosis or inadequate treatment.
Abbreviations
MPAMicroscopic Polyangiitis
ANCAAnti-neutrophil cytoplasmic antibody
AAVANCA-associated Vasculitis
GPAGranulomatosis with polyangiitis
EGPAEosinophilic granulomatosis with angiitis
G6PDGlucose 6 Phosphate Dehydrogenase
CTComputed Tomography
IVIntravenous
CRPC-reactive Protein
ESRErythrocyte sedimentation Rate
CAPCommunity Acquired Pneumonia
ANAAnti-Neutrophil Antibody
RFRheumatoid Factor
FVCForced Vital Capacity
FEVForced Expiratory Volume
VCVital Capacity
FRCForced Residual Capacity
RVResidual Capacity
TLCTotal Lung Capacity
DLCODiffusing Capacity of Lung for Carbon Monoxide
VATSVideo-Assisted Thoracoscopic Surgery
PMNPolymorphonuclear
FSGSFocal Segmental Glomerulonephritis
IgGImmunoglobulin G
NETNeutrophil Endothelial Trap
Publisher's Note
Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
Authors’ contributions
AM designed the study, gathered data and resources, drafted, edited and finalized the entire manuscript. NNC and RA gathered data and resources. JSI provided and interpreted lung biopsy. LJA provided and interpreted kidney biopsy. SHFS assisted and edited discussion section. CJH edited, critically revised and helped finalize the entire manuscript. All authors read and approved the final manuscript.
Funding
No financial support or grant was provided for the preparation of this manuscript.
Consent for publication
A written informed consent has been signed and obtained from the patient and is available upon request.
Competing interests
Authors hereby declare no personal or financial conflict of interest. | AZITHROMYCIN, CEFTRIAXONE, UNSPECIFIED INGREDIENT | DrugsGivenReaction | CC BY | 33407881 | 19,165,871 | 2021-01-06 |
Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Treatment failure'. | ANCA-negative microscopic polyangiitis with diffuse alveolar hemorrhage masquerading as congestive heart failure.
BACKGROUND
Microscopic polyangiitis (MPA) is a subtype of anti-neutrophil cytoplasmic antibody-associated vasculitis (AAV), involving small and medium sized vessels, often affecting the kidneys and lungs. Anti-neutrophil cytoplasmic antibody (ANCA) is detected in up to 90% of cases of MPA and its detection helps guide diagnosis, however cases of ANCA-negative MPA have been reported, hence definitive diagnosis relies on tissue biopsy.
METHODS
A 23-year-old man was evaluated for dyspnea and pleuritic chest pain, and found to have bilateral intra-alveolar opacities and hilar adenopathy. Diagnostic work up revealed positive anti-nuclear antibodies (ANA) and negative ANCA, which in the setting of a non-classical presentation, delayed diagnosis and appropriate treatment. Due to persistent symptoms and a high suspicion for autoimmune disease with pulmonary-renal syndrome, he underwent lung biopsy which revealed intra-alveolar hemorrhage and capillaritis indicative of microscopic polyangiitis (MPA). Surprisingly, kidney biopsy was not typical of classic MPA, but revealed less common features. Due to therapeutic noncompliance he was readmitted multiple times thereafter with rare complications of MPA such as acute pancreatitis and hemorrhagic pericardial effusion with tamponade.
CONCLUSIONS
This case serves as an important clinical reminder to consider AAV even in those with negative ANCA serologies and a high suspicion for pulmonary-renal syndrome. It also demonstrates the high morbidity in cases of diagnostic delay and inadequate treatment.
Background
The 2012 Chapel Hill Consensus guideline recognizes microscopic polyangiitis (MPA) as a subset of ANCA-associated vasculitis (AAV), a group of necrotizing pauci-immune vasculitides that predominantly affects small vessels—capillaries, venules, and arterioles—with few or no immune deposits [1]. AAV commonly affects the renal and pulmonary parenchyma to varying degrees, and is characterized by the presence of antibodies against neutrophilic cytoplasmic components, Proteinase-3 (PR3, c-ANCA) and Myeloperoxidase (MPO, p-ANCA). AAV include Microscopic Polyangiitis (MPA), Granulomatosis with polyangiitis (GPA; Wegener’s) and Eosinophilic granulomatosis with angiitis (EGPA; Churg-Strauss), as well as a variety of additional AAV-associated syndromes (drug-induced vasculitis, renal-limited vasculitis (RLV)), each characterized by the presence of distinct clinical presentation, ANCA subtypes, histopathological findings, and associated laboratory findings [1–4].
MPA is characterized by the presence of anti-MPO (p-ANCA) antibodies, renal and pulmonary involvement, and the absence of granulomatous inflammation on histopathology, a defining feature when compared to GPA and EGPA which, while demonstrating both renal and pulmonary involvement, are characterized by the presence of anti-PR3 (c-ANCA) and granulomatous disease. Though a widely accepted marker for AAV, the presence of ANCA is variable and not detected in all cases. ANCA is detected in 80–90% of cases of MPA and its detection has become integral in the diagnostic workup as well as classification and prognostication of all AAV [3, 4]. While current evidence indicates that ANCA plays a role in pathogenesis of MPA and other AAV, cases of ANCA-negative vasculitis, including cases of ANCA-negative MPA, GPA, and EGPA have been reported [1–7]. We present a case of ANCA-negative MPA in a young man who presented with hemoptysis and was found to have diffuse bilateral lung infiltrates, acute kidney injury, and heart failure. Following a circuitous diagnostic course masked by symptoms of heart failure, he was eventually diagnosed with MPA, however the course of his disease was further complicated by medication non-compliance as well as rare complications of AAV, including acute pancreatitis, pancreatic pseudoaneurysm, and cardiac tamponade.
Case report
A 23-year-old African-American man with past medical history of G6PD-deficiency and obesity presented with dyspnea and pleuritic chest pain that improved upon leaning forward and scant hemoptysis of two weeks duration. He was notably hypertensive to the 220/110 s mmHg and tachycardic to the 120 s, but had a preserved respiratory rate and oxygen saturation. Physical exam was remarkable for bilateral diffuse wheezing throughout all lung fields. Other parts of the exam including cardiovascular, nasopharynx, skin and musculoskeletal systems were unremarkable. Additional pertinent history was remarkable only for marijuana smoking. Electrocardiogram was unremarkable except for left atrial enlargement. Chest X-ray revealed bilateral pulmonary infiltrates, cardiomegaly, and mediastinal enlargement suggestive of bulky hilar adenopathy. Computed tomography (CT) scan of the chest with contrast was performed which was negative for pulmonary embolism, but revealed bilateral centrilobular opacities, hilar/mediastinal lymphadenopathy, and a trivial pericardial effusion (Fig. 1a). Initial laboratory diagnostics were significant for acute kidney injury with a serum creatinine of 2.03 (mg/dL), trace proteinuria, troponin elevation to 0.232 (ng/mL), and a D-Dimer of 1.3 (mcg/mL). Complete blood count revealed no leukocytosis, but concomitant eosinophilia, with no evidence of anemia. The patient was subsequently admitted to the medicine wards and a therapeutic regimen of antihypertensive agents as well as intravenous ceftriaxone and azithromycin for presumed community acquired pneumonia was initiated.Fig. 1 CT scans of the chest. a CT Scan of the chest on first day of presentation demonstrating bilateral centrilobular opacities, hilar/mediastinal lymphadenopathy, moderate cardiomegaly, a trivial pericardial effusion and enlargement of the main pulmonary artery. b Prone CT chest on day 7 of admission, revealing persistent intra-alveolar opacities with associated mediastinal lymphadenopathy
Additional diagnostic evaluation demonstrated marked elevation of CRP (80 mg/L) and ESR (67 mm/hr). Pheochromocytoma screening with serum catecholamines and metanephrines was negative. An echocardiogram revealed an ejection fraction of 40%, moderate concentric left ventricular hypertrophy, and trivial pericardial effusion without evidence of tamponade or pulmonary artery hypertension. Despite continuation of antibiotics for pneumonia and adjunctive heart failure management, the patient’s clinical status failed to improve. In the setting of an unremarkable infectious workup and concern for an autoimmune etiology, the patient was started on oral prednisone 60 mg daily. The patient remained symptomatic, experiencing episodic chest pain and shortness of breath, with blood pressure lability. Repeat chest X-ray showed worsening bilateral infiltrates. Subsequently, ANA resulted weakly positive (1:160) with a homogenous pattern and rheumatoid factor (RF) returned negative.
On the fifth day of admission, antibiotics were discontinued in light of negative cultures and lack of significant clinical improvement. The patient’s blood pressure was noted to be slightly improved with addition of prednisone however remained poorly controlled on multiple medications (Fig. 2). Autoimmune panel including ANCA (MPO/p-ANCA, and PR3/c-ANCA), anti-double-stranded DNA antibody, anti-Smith antibody, C3 and C4 complements, anti-histone antibody, as well as other autoimmune related factors and infectious serologies returned negative or within normal limits (Table 1). Renal ultrasound and renal artery duplex were performed which did not reveal any evidence of hydronephrosis or renal artery stenosis, respectively. A repeat high-resolution chest CT scan was obtained, both in supine and prone positions, to help differentiate early interstitial lung disease from intra-alveolar processes, which showed persistent intra-alveolar opacities without any change on prone position (Fig. 1b). Over the course of the following days, the patient reported improvement in his symptomatology and his blood pressure improved, therefore he was taken off prednisone on the sixth day. Pulmonary function testing was performed in the setting of bilateral hilar adenopathy and fixed infiltrates, which revealed a mixed obstructive and restrictive pattern. He eventually underwent lung biopsy by video-assisted thoracoscopic surgery (VATS) with right medial lobe wedge resection and was subsequently discharged with instructions to follow up with rheumatology for planned initiation of rituximab. The histopathological results of his lung biopsy demonstrated extensive intra-alveolar hemorrhage with linear polymorphonuclear (PMN) cell collections in alveolar septa and capillaritis without any evidence of granulomatous changes, indicative of microscopic polyangiitis (Fig. 3). Immunohistochemistry on lung biopsy samples was not performed and renal biopsy was deferred to outpatient rheumatology.Fig. 2 Blood pressure and creatinine during first and second hospitalizations. SBP Systolic Blood Pressure, DBP Diastolic Blood Pressure
Table 1 Autoimmune and infectious workup results during first admission
Lab Results Lab Results Lab Results
WBC 9.3 Neutrophils 75.9% Potassium 2.9
Hgb 13.1 Lymphocytes 12.5% Sodium 138
Hct 37.8 Eosinophils 1.3% Creatinine 2.03
Platelet 343 Monocytes 10.1% GFR 52
Troponin 0.232 D-Dimer 1.3 TSH 1.65
CRP 80 GBM Ab Negative CMV IgM Negative
ESR 67 SS-A/Ro Negative Cox A & B Ab Negative
ANA 1:160 (Homogenous) SS-B/La Negative Cryptococcal Ag Negative
RF < 10 ACA (IgG, IgM) < 9 EBV DNA Negative
Anti-CCP 4 TTG (IgA, IgG) 1, 3 HBV DNA Negative
ANCA Negative Ribosome IgG 3 HCV RNA Negative
Anti ds-DNA Negative Endomysial IgG < 1:10 HIV 1&2 Ab Negative
Anti-Smith Ab Negative Anti Gliadin < 7 Parvovirus B19 Negative
Histone auto Ab Negative Anti Gliadin < 2 Syphilis (RPR/FTA) Negative
Scl-70 Ab Negative Free Kappa 1.73 HHV6 DNA Negative
C3 130 Free Lambda 1.49 Lyme ELISA Negative
C4 32.4 K/L Ratio 1.16 Histoplasma Ag Negative
IgA 250 IgG 1160 IgM 1110
WBC White Blood Cell, Hgb Hemoglobin, Hct Hematocrit, GFR Glomerular Filtration Rate, TSH Thyroid Stimulating Hormone, Ab Antibody, Ig Immunoglobulin, ESR Erythrocyte Sedimentation Rate, CRP C-Reactive Protein, ANA Anti-Neutrophil Antibody, ANCA Anti-Neutrophil Cytoplasmic Antibody, Scl Scleroderma, C3 Complement 3, C4 Complement 4, ds-DNA Double-Stranded DNA, RF Rheumatoid Factor, CCP Cyclic Citrullinated Peptide, SS-A Sjӧgren-Syndrome-related-antigen A, SS-B Sjӧgren-syndrome-related-antigen B, ACA Anti Cardiolipin Ab, TTG Tissue trans-glutaminase, HIV Human Immunodeficiency Virus, HCV Hepatitis C Virus, HBV Hepatitis B Virus, CMV Cytomegalovirus, EBV Epstein-Barr Virus, Cox A & B Coxsackievirus A & B, HHV Human Herpes Virus, RPR: Rapid Plasma Reagin, FTA Fluorescent Treponemal Antibody
Fig. 3 Lung Biopsy. a Intra-alveolar hemorrhage (100×) b Polymorphonuclear cells in alveolar septa; capillaritis (Arrow) (400x)
Unfortunately, the patient was lost to follow up, failing to attend any of the scheduled appointments. He was subsequently readmitted six months later with similar symptoms, and once again found to be in hypertensive emergency, complicated by acute decompensated heart failure. Repeat echocardiogram revealed a further decline in his ejection fraction to 25% and a trivial pericardial effusion. Rheumatology was consulted and recommended pulse steroid therapy with methylprednisolone 250 mg four times a day for three days, which led to significant improvement in symptoms and blood pressure. Repeat ANCA and autoimmune serological workup remained negative. Following initiation of pulse steroid therapy, he underwent renal biopsy. The biopsy contained forty glomeruli, six of which were globally sclerotic. One glomerulus had segmental sclerosis. There were changes suggestive of microangiopathic injury in some arteries and glomeruli, such as bloodless glomeruli and mild intimal myxoid changes in arteries, with associated acute tubular injury. Focal tubular atrophy and interstitial fibrosis were estimated to involve approximately 10% of the cortex. No evidence of crescents or granulomatous changes were observed. Immunofluorescence was unremarkable, with only non-specific linear glomerular and tubular basement membrane staining for IgG, kappa, lambda, and albumin, indicative of pauci-immunity. Electron microscopy demonstrated segmental effacement of podocyte foot processes (40%) with vacuolation and microvillous transformation of the podocyte cytoplasm, ischemic-type capillary wall wrinkling, and subendothelial electron lucent widening (Fig. 4). He was subsequently discharged on a steroid taper with plans for outpatient rituximab. Despite extensive education about his condition he was once again lost to follow up and missed appropriate treatment.Fig. 4 Kidney Biopsy. a Glomerulus with segmental sclerosis of the right half of the tuft, Periodic Acid-Methenamine Silver (PASM, 200×) b One glomerulus (left) with an ischemic appearance including capillary wall wrinkling and tuft retraction, other glomerulus (right) has mild hypercellularity including a few neutrophils (H&E, 100×) c A glomerulus with a bloodless appearance, obliteration of capillary lumens and thickening of capillary walls with segmental duplication (Periodic Acid-Schiff (PAS), 200×) d Tubules show cytoplasmic vacuolation, apical blebbing, thinning, and focal simplification. The interstitium contains a sparse lymphocytic infiltrate (PAS, 100×) e Electron micrograph of glomerular tuft showing ischemic-type capillary wall wrinkling (asterisk) and diffuse subendothelial electron lucent widening (arrow) f Electron micrograph showing podocyte foot process effacement (arrow) and mild subendothelial electron-lucent widening (asterisk)
Over the course of the next year, he was readmitted on multiple occasions and eventually progressed to dialysis-dependent end-stage renal disease. His two most recent admissions were characterized by pancreatitis with pancreatic pseudoaneurysm complicated by retroperitoneal hematoma and cardiac tamponade, respectively. With respect to his pancreatitis, he presented in the context of acute onset abdominal pain with associated nausea and vomiting. Laboratory diagnostics demonstrated an elevated lipase (3400), normal triglycerides, and a negative IgG4 serology. Abdominal CT was significant for peripancreatic fat stranding and inflammatory changes without evidence of gallstones or biliary ductal dilation. He denied recent alcohol use. Pancreatitis course was further complicated by retroperitoneal hematoma, which was found to be secondary to a 7 mm pancreatic pseudoaneurysm rupture, as revealed on repeat abdominal CT angiography (Fig. 5). He was managed conservatively and subsequently discharged. One month later he presented with dyspnea, chest pain and nausea, and was found to have large pericardial effusion with an acute decrease in ejection fraction to 10% (Fig. 6). He underwent pericardiocentesis with removal of one liter of serosanguineous fluid. Fluid analysis was indicative of hemorrhagic etiology and negative for malignancy. On review of most recent outpatient records, the patient has been maintained on high-dose suppressive steroid therapy with plans for initiation of Rituximab or Cyclophosphamide.Fig. 5 CT angiography of the Abdomen. A 7 mm arterially enhancing focus in the tail of the pancreas that follows the blood flow (Arrow), consistent with a pseudoaneurysm, with an associated large left upper quadrant hematoma and small amount of hemorrhage in the right paracolic gutter
Fig. 6 Echocardiogram. Four chamber views in diastole a and systole (c). Short axis views in Diastole b and systole (d). Echocardiography demonstrating a large circumferential pericardial effusion (Asterisks) without hemodynamic compromise, mildly dilated left ventricle (LV) with normal wall thickness, and severe globally depressed systolic function with left ventricular ejection fraction of 10%, normal right ventricle (RV) size and mildly reduced right ventricular systolic function
Discussion
Since the sentinel publications on ANCA in early 1980s and the landmark article by van der Woude et al. [5], our understanding of ANCA has significantly expanded. ANCA is currently recognized as having a central role in the pathogenesis of necrotizing vasculitis and glomerulonephritis particularly AAV, however the exact mechanism, and if a direct pathogenic role exists for ANCA, remains to be elucidated [8]. Recently an association between ANCA-induced neutrophil activation, regulated necrosis (necroptosis), neutrophil endothelial trap (NET) generation, complement activation, and endothelial cell damage leading to vasculitis and necrotizing glomerulonephritis has been identified in AAV by Schreiber et al. [9]. Nonetheless, detection of ANCA has become an essential part of the routine workup for vasculitis and many other autoimmune disorders. Currently only two ANCA antigens, PR3/ c-ANCA and MPO/ p-ANCA, critical components for neutrophil-mediated innate immunity, have been recognized to be clinically significant for AAV amongst a diverse array of ANCA antigens [9]. While indirect immunofluorescence testing on ethanol-fixed neutrophils is the reference method for ANCA detection and screening, positive results prompt specific testing for PR3 and MPO. As new ANCA detection methods have developed, the most recent revised international consensus recommends high-quality antigen-specific assays for PR3-ANCA and MPO-ANCA should be used as the primary screening method for ANCA, and if results for both are negative with strong clinical suspicion for small-vessel vasculitis, other immunoassays, indirect immunofluorescence, or referral to an experienced lab is recommended [10].
ANCA is detected in 80–90% of cases of MPA out of which 70% are positive for MPO-ANCA [3–6, 11–14]. Seronegative ANCA, also known as pauci-immune vasculitis, is similar to seronegative lupus or seronegative rheumatoid arthritis and the absence of specific markers may lead not only to a delay in diagnosis, but also misdiagnosis [1, 2]. Furthermore, ANCA, though initially negative, may become positive later in the course of disease or may not be detectable with currently available methods [3–5]. On the other hand, antibodies to antigens other than PR3 and MPO have been detected and are referred to as minor ANCA antigens [15]. Interestingly these antibodies are frequently detected in sera of MPO- and PR3-ANCA negative patients, and while they can mimic c-ANCA or p-ANCA patterns, they are detected in other types of small vessel vasculitis such as cocaine-induced vasculitis mimicking GPA as well as other autoimmune diseases such as Sjӧgren, rheumatoid arthritis, and ulcerative colitis [9, 15]. It is noteworthy to mention that ethnic differences between MPO and PR3 ANCA subtypes have also been observed with PR3 predominance in Japanese and Chinese ethnicity and MPO predominance in Northern Europeans and Middle-Eastern/Turkish groups [7].
Classically MPA presents with acute onset of rapidly progressive glomerulonephritis, however presentation is often atypical. Most commonly, patients present with constitutional symptoms—fever, weight loss, fatigue—over an acute or chronic course over weeks to months [3–5]. The most common age of presentation is in 5–6th decades of life with a slight male predominance [3, 4]. Multiple organs can be involved with the most common organs being kidneys and lungs, followed by skin, gastrointestinal, cardiac and nervous systems [5, 6, 11]. Renal involvement is reported in 80–100% of MPA cases and is classically characterized by rapidly progressive glomerulonephritis (GN), however renal involvement on initial presentation may range from minimal proteinuria to end-stage renal disease requiring dialysis [5]. Pauci-immune necrotizing and crescentic GN is the classic finding on biopsy in systemic AAV [12]. Crescentic involvement of the glomeruli is the most common form of glomerular involvement in MPA and is visualized in up to 90% of cases, however interstitial nephritis and tubular atrophy, as observed in this case, are reported on biopsies as well [1–5]. Berden et al. proposed a classification criteria for AAV GN, based on the pathologic features of the glomerulus, into four major groups of focal, crescentic, mixed and sclerotic [12]. Considering the Berden’s classification, our patient would fall into the focal subgroup with more than 50% normal glomeruli, which have a relatively preserved kidney function and an overall more favorable outcome compared to other pathologic subgroups [12]. In another study of ANCA-negative patients with pauci-immune renal vasculitis, 29% of renal biopsies revealed normal glomeruli and only 50% had crescents on histology [14].
Pulmonary involvement can occur in up to 55% of cases of MPA and mostly present as dyspnea, cough, and hemoptysis. Classically MPA is associated with diffuse alveolar hemorrhage and a pauci-immune, hemorrhagic necrotizing alveolar capillaritis characterized by an absence of granulomatous changes on lung and renal biopsy [5, 6], similar to what was observed in our patient (Fig. 3). Diffuse alveolar hemorrhage, caused by pulmonary capillaritis, is considered a serious complication and if accompanied by glomerulonephritis (pulmonary-renal syndrome) portends a poor prognosis [5, 6]. Pulmonary function testing in patients with MPA can show either obstructive or restrictive pattern with reduced carbon monoxide diffusion capacity (DLCO) [5].
Gastrointestinal bleeding has been reported in up to 29% of MPA patients [5], however additional manifestations such as colonic ulceration, bowel ischemia, perforation, and arterial aneurysms have also been reported [5]. Pancreatic involvement in MPA is rare and may present as acute pancreatitis or pancreatic mass [16]. In a study of 62 patients with small-medium vessel vasculitis, Pagnoux et al. demonstrated that only 3 patients had pancreatitis as a complication, with only one having MPA [17]. Cardiac involvement in patients with MPA is reported to occur in 17–50% of cases with pathophysiology similar to that of other organ systems such as lung and kidney [18, 19]. Cardiac involvement may present as hypertension, heart failure, pericarditis, and less commonly myocardial infarction [10, 18].
Management of MPA and other AAV’s includes an induction phase followed by a maintenance phase. Classic induction strategies include oral corticosteroids (1 mg/kg daily) and cyclophosphamide (2 mg/kg daily). Rituximab and cyclophosphamide are considered the drug of choice for both induction and maintenance of remission. Rituximab has been shown to be non-inferior to cyclophosphamide by the RAVE and RITUXVAS trials [3–6, 11–13]. The NORAM study revealed methotrexate was as effective as cyclophosphamide with regards to induction of remission in mild disease however relapse rates were higher for methotrexate [3–5]. Plasmapheresis has been used in cases of aggressive AAV and was shown to have better renal outcomes in MEPEX trial, however PEXIVAS trial (Plasma exchange and glucocorticoids for treatment of AAV), the largest trial in AAV so far, failed to show a significant difference in all-cause mortality or end-stage renal disease, and plasmapheresis use remains controversial [3, 4, 20]. Maintenance therapy is generally achieved by less toxic agents such as rituximab, azathioprine, and methotrexate, with rituximab becoming more and more favored in recent years. Other immunosuppressive agents like leflunomide, mycophenolate mofetil, and trimethoprim-sulfamethoxazole have been used and studied as maintenance therapy strategies as well [3–6, 11].
This case was differentiated from other potential autoimmune disorders such as systemic lupus erythematosus, Sjӧgren syndrome, sarcoidosis, and other small to medium sized vessel vasculitis such as granulomatosis with polyangiitis, polyarteritis nodosa, IgA vasculitis and cryoglobulinemic vasculitis based on presentation, laboratory and imaging findings and biopsy of the lung revealing capillaritis without granulomatous changes. Absence of pathognomic noncaseating granulomas on lung biopsy, ruled out sarcoidosis. In the light of absence of certain characteristics such as palpable purpura, as well as absence of immune complexes on tissue biopsy, immune complex vasculitides such as anti-glomerular basement membrane disease, IgA and cryoglobulinemic vasculitis were ruled out. While differentiation of GPA from MPA is difficult and they tend to share characteristics of AAV disease spectrum, the absence of granulomatous lesions on both biopsies and lack of certain classical features of GPA made it less likely in this case. EGPA was also deemed less likely considering lack of peripheral eosinophilia and tissue eosinophilic infiltration. We also believe the kidney biopsy results were affected by pulse steroids and possible steroid consumption in between admissions, however pauci-immunity and absence of granulomatous changes, and immune complex deposition favors MPA over other vasculitides.
Conclusion
MPA is differentiated not only by the presence of anti-MPO (p-ANCA) but also histopathologically by non-granulomatous lesions and capillaritis. ANCA serologies, however, may be negative in AAV specifically MPA in as many as 10-20% of cases. This case underscores the importance of identifying pulmonary-renal syndrome and its association with AAV, the need to maintain a high index of suspicion in cases of negative ANCA serologies, and to pursue tissue biopsy despite negative serologies in such circumstances. This case further serves to demonstrate the rapid clinical deterioration and high morbidity in those cases of AAV with delayed diagnosis or inadequate treatment.
Abbreviations
MPAMicroscopic Polyangiitis
ANCAAnti-neutrophil cytoplasmic antibody
AAVANCA-associated Vasculitis
GPAGranulomatosis with polyangiitis
EGPAEosinophilic granulomatosis with angiitis
G6PDGlucose 6 Phosphate Dehydrogenase
CTComputed Tomography
IVIntravenous
CRPC-reactive Protein
ESRErythrocyte sedimentation Rate
CAPCommunity Acquired Pneumonia
ANAAnti-Neutrophil Antibody
RFRheumatoid Factor
FVCForced Vital Capacity
FEVForced Expiratory Volume
VCVital Capacity
FRCForced Residual Capacity
RVResidual Capacity
TLCTotal Lung Capacity
DLCODiffusing Capacity of Lung for Carbon Monoxide
VATSVideo-Assisted Thoracoscopic Surgery
PMNPolymorphonuclear
FSGSFocal Segmental Glomerulonephritis
IgGImmunoglobulin G
NETNeutrophil Endothelial Trap
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Authors’ contributions
AM designed the study, gathered data and resources, drafted, edited and finalized the entire manuscript. NNC and RA gathered data and resources. JSI provided and interpreted lung biopsy. LJA provided and interpreted kidney biopsy. SHFS assisted and edited discussion section. CJH edited, critically revised and helped finalize the entire manuscript. All authors read and approved the final manuscript.
Funding
No financial support or grant was provided for the preparation of this manuscript.
Consent for publication
A written informed consent has been signed and obtained from the patient and is available upon request.
Competing interests
Authors hereby declare no personal or financial conflict of interest. | AZITHROMYCIN, CEFTRIAXONE, UNSPECIFIED INGREDIENT | DrugsGivenReaction | CC BY | 33407881 | 19,165,871 | 2021-01-06 |
What was the administration route of drug 'AZITHROMYCIN'? | ANCA-negative microscopic polyangiitis with diffuse alveolar hemorrhage masquerading as congestive heart failure.
BACKGROUND
Microscopic polyangiitis (MPA) is a subtype of anti-neutrophil cytoplasmic antibody-associated vasculitis (AAV), involving small and medium sized vessels, often affecting the kidneys and lungs. Anti-neutrophil cytoplasmic antibody (ANCA) is detected in up to 90% of cases of MPA and its detection helps guide diagnosis, however cases of ANCA-negative MPA have been reported, hence definitive diagnosis relies on tissue biopsy.
METHODS
A 23-year-old man was evaluated for dyspnea and pleuritic chest pain, and found to have bilateral intra-alveolar opacities and hilar adenopathy. Diagnostic work up revealed positive anti-nuclear antibodies (ANA) and negative ANCA, which in the setting of a non-classical presentation, delayed diagnosis and appropriate treatment. Due to persistent symptoms and a high suspicion for autoimmune disease with pulmonary-renal syndrome, he underwent lung biopsy which revealed intra-alveolar hemorrhage and capillaritis indicative of microscopic polyangiitis (MPA). Surprisingly, kidney biopsy was not typical of classic MPA, but revealed less common features. Due to therapeutic noncompliance he was readmitted multiple times thereafter with rare complications of MPA such as acute pancreatitis and hemorrhagic pericardial effusion with tamponade.
CONCLUSIONS
This case serves as an important clinical reminder to consider AAV even in those with negative ANCA serologies and a high suspicion for pulmonary-renal syndrome. It also demonstrates the high morbidity in cases of diagnostic delay and inadequate treatment.
Background
The 2012 Chapel Hill Consensus guideline recognizes microscopic polyangiitis (MPA) as a subset of ANCA-associated vasculitis (AAV), a group of necrotizing pauci-immune vasculitides that predominantly affects small vessels—capillaries, venules, and arterioles—with few or no immune deposits [1]. AAV commonly affects the renal and pulmonary parenchyma to varying degrees, and is characterized by the presence of antibodies against neutrophilic cytoplasmic components, Proteinase-3 (PR3, c-ANCA) and Myeloperoxidase (MPO, p-ANCA). AAV include Microscopic Polyangiitis (MPA), Granulomatosis with polyangiitis (GPA; Wegener’s) and Eosinophilic granulomatosis with angiitis (EGPA; Churg-Strauss), as well as a variety of additional AAV-associated syndromes (drug-induced vasculitis, renal-limited vasculitis (RLV)), each characterized by the presence of distinct clinical presentation, ANCA subtypes, histopathological findings, and associated laboratory findings [1–4].
MPA is characterized by the presence of anti-MPO (p-ANCA) antibodies, renal and pulmonary involvement, and the absence of granulomatous inflammation on histopathology, a defining feature when compared to GPA and EGPA which, while demonstrating both renal and pulmonary involvement, are characterized by the presence of anti-PR3 (c-ANCA) and granulomatous disease. Though a widely accepted marker for AAV, the presence of ANCA is variable and not detected in all cases. ANCA is detected in 80–90% of cases of MPA and its detection has become integral in the diagnostic workup as well as classification and prognostication of all AAV [3, 4]. While current evidence indicates that ANCA plays a role in pathogenesis of MPA and other AAV, cases of ANCA-negative vasculitis, including cases of ANCA-negative MPA, GPA, and EGPA have been reported [1–7]. We present a case of ANCA-negative MPA in a young man who presented with hemoptysis and was found to have diffuse bilateral lung infiltrates, acute kidney injury, and heart failure. Following a circuitous diagnostic course masked by symptoms of heart failure, he was eventually diagnosed with MPA, however the course of his disease was further complicated by medication non-compliance as well as rare complications of AAV, including acute pancreatitis, pancreatic pseudoaneurysm, and cardiac tamponade.
Case report
A 23-year-old African-American man with past medical history of G6PD-deficiency and obesity presented with dyspnea and pleuritic chest pain that improved upon leaning forward and scant hemoptysis of two weeks duration. He was notably hypertensive to the 220/110 s mmHg and tachycardic to the 120 s, but had a preserved respiratory rate and oxygen saturation. Physical exam was remarkable for bilateral diffuse wheezing throughout all lung fields. Other parts of the exam including cardiovascular, nasopharynx, skin and musculoskeletal systems were unremarkable. Additional pertinent history was remarkable only for marijuana smoking. Electrocardiogram was unremarkable except for left atrial enlargement. Chest X-ray revealed bilateral pulmonary infiltrates, cardiomegaly, and mediastinal enlargement suggestive of bulky hilar adenopathy. Computed tomography (CT) scan of the chest with contrast was performed which was negative for pulmonary embolism, but revealed bilateral centrilobular opacities, hilar/mediastinal lymphadenopathy, and a trivial pericardial effusion (Fig. 1a). Initial laboratory diagnostics were significant for acute kidney injury with a serum creatinine of 2.03 (mg/dL), trace proteinuria, troponin elevation to 0.232 (ng/mL), and a D-Dimer of 1.3 (mcg/mL). Complete blood count revealed no leukocytosis, but concomitant eosinophilia, with no evidence of anemia. The patient was subsequently admitted to the medicine wards and a therapeutic regimen of antihypertensive agents as well as intravenous ceftriaxone and azithromycin for presumed community acquired pneumonia was initiated.Fig. 1 CT scans of the chest. a CT Scan of the chest on first day of presentation demonstrating bilateral centrilobular opacities, hilar/mediastinal lymphadenopathy, moderate cardiomegaly, a trivial pericardial effusion and enlargement of the main pulmonary artery. b Prone CT chest on day 7 of admission, revealing persistent intra-alveolar opacities with associated mediastinal lymphadenopathy
Additional diagnostic evaluation demonstrated marked elevation of CRP (80 mg/L) and ESR (67 mm/hr). Pheochromocytoma screening with serum catecholamines and metanephrines was negative. An echocardiogram revealed an ejection fraction of 40%, moderate concentric left ventricular hypertrophy, and trivial pericardial effusion without evidence of tamponade or pulmonary artery hypertension. Despite continuation of antibiotics for pneumonia and adjunctive heart failure management, the patient’s clinical status failed to improve. In the setting of an unremarkable infectious workup and concern for an autoimmune etiology, the patient was started on oral prednisone 60 mg daily. The patient remained symptomatic, experiencing episodic chest pain and shortness of breath, with blood pressure lability. Repeat chest X-ray showed worsening bilateral infiltrates. Subsequently, ANA resulted weakly positive (1:160) with a homogenous pattern and rheumatoid factor (RF) returned negative.
On the fifth day of admission, antibiotics were discontinued in light of negative cultures and lack of significant clinical improvement. The patient’s blood pressure was noted to be slightly improved with addition of prednisone however remained poorly controlled on multiple medications (Fig. 2). Autoimmune panel including ANCA (MPO/p-ANCA, and PR3/c-ANCA), anti-double-stranded DNA antibody, anti-Smith antibody, C3 and C4 complements, anti-histone antibody, as well as other autoimmune related factors and infectious serologies returned negative or within normal limits (Table 1). Renal ultrasound and renal artery duplex were performed which did not reveal any evidence of hydronephrosis or renal artery stenosis, respectively. A repeat high-resolution chest CT scan was obtained, both in supine and prone positions, to help differentiate early interstitial lung disease from intra-alveolar processes, which showed persistent intra-alveolar opacities without any change on prone position (Fig. 1b). Over the course of the following days, the patient reported improvement in his symptomatology and his blood pressure improved, therefore he was taken off prednisone on the sixth day. Pulmonary function testing was performed in the setting of bilateral hilar adenopathy and fixed infiltrates, which revealed a mixed obstructive and restrictive pattern. He eventually underwent lung biopsy by video-assisted thoracoscopic surgery (VATS) with right medial lobe wedge resection and was subsequently discharged with instructions to follow up with rheumatology for planned initiation of rituximab. The histopathological results of his lung biopsy demonstrated extensive intra-alveolar hemorrhage with linear polymorphonuclear (PMN) cell collections in alveolar septa and capillaritis without any evidence of granulomatous changes, indicative of microscopic polyangiitis (Fig. 3). Immunohistochemistry on lung biopsy samples was not performed and renal biopsy was deferred to outpatient rheumatology.Fig. 2 Blood pressure and creatinine during first and second hospitalizations. SBP Systolic Blood Pressure, DBP Diastolic Blood Pressure
Table 1 Autoimmune and infectious workup results during first admission
Lab Results Lab Results Lab Results
WBC 9.3 Neutrophils 75.9% Potassium 2.9
Hgb 13.1 Lymphocytes 12.5% Sodium 138
Hct 37.8 Eosinophils 1.3% Creatinine 2.03
Platelet 343 Monocytes 10.1% GFR 52
Troponin 0.232 D-Dimer 1.3 TSH 1.65
CRP 80 GBM Ab Negative CMV IgM Negative
ESR 67 SS-A/Ro Negative Cox A & B Ab Negative
ANA 1:160 (Homogenous) SS-B/La Negative Cryptococcal Ag Negative
RF < 10 ACA (IgG, IgM) < 9 EBV DNA Negative
Anti-CCP 4 TTG (IgA, IgG) 1, 3 HBV DNA Negative
ANCA Negative Ribosome IgG 3 HCV RNA Negative
Anti ds-DNA Negative Endomysial IgG < 1:10 HIV 1&2 Ab Negative
Anti-Smith Ab Negative Anti Gliadin < 7 Parvovirus B19 Negative
Histone auto Ab Negative Anti Gliadin < 2 Syphilis (RPR/FTA) Negative
Scl-70 Ab Negative Free Kappa 1.73 HHV6 DNA Negative
C3 130 Free Lambda 1.49 Lyme ELISA Negative
C4 32.4 K/L Ratio 1.16 Histoplasma Ag Negative
IgA 250 IgG 1160 IgM 1110
WBC White Blood Cell, Hgb Hemoglobin, Hct Hematocrit, GFR Glomerular Filtration Rate, TSH Thyroid Stimulating Hormone, Ab Antibody, Ig Immunoglobulin, ESR Erythrocyte Sedimentation Rate, CRP C-Reactive Protein, ANA Anti-Neutrophil Antibody, ANCA Anti-Neutrophil Cytoplasmic Antibody, Scl Scleroderma, C3 Complement 3, C4 Complement 4, ds-DNA Double-Stranded DNA, RF Rheumatoid Factor, CCP Cyclic Citrullinated Peptide, SS-A Sjӧgren-Syndrome-related-antigen A, SS-B Sjӧgren-syndrome-related-antigen B, ACA Anti Cardiolipin Ab, TTG Tissue trans-glutaminase, HIV Human Immunodeficiency Virus, HCV Hepatitis C Virus, HBV Hepatitis B Virus, CMV Cytomegalovirus, EBV Epstein-Barr Virus, Cox A & B Coxsackievirus A & B, HHV Human Herpes Virus, RPR: Rapid Plasma Reagin, FTA Fluorescent Treponemal Antibody
Fig. 3 Lung Biopsy. a Intra-alveolar hemorrhage (100×) b Polymorphonuclear cells in alveolar septa; capillaritis (Arrow) (400x)
Unfortunately, the patient was lost to follow up, failing to attend any of the scheduled appointments. He was subsequently readmitted six months later with similar symptoms, and once again found to be in hypertensive emergency, complicated by acute decompensated heart failure. Repeat echocardiogram revealed a further decline in his ejection fraction to 25% and a trivial pericardial effusion. Rheumatology was consulted and recommended pulse steroid therapy with methylprednisolone 250 mg four times a day for three days, which led to significant improvement in symptoms and blood pressure. Repeat ANCA and autoimmune serological workup remained negative. Following initiation of pulse steroid therapy, he underwent renal biopsy. The biopsy contained forty glomeruli, six of which were globally sclerotic. One glomerulus had segmental sclerosis. There were changes suggestive of microangiopathic injury in some arteries and glomeruli, such as bloodless glomeruli and mild intimal myxoid changes in arteries, with associated acute tubular injury. Focal tubular atrophy and interstitial fibrosis were estimated to involve approximately 10% of the cortex. No evidence of crescents or granulomatous changes were observed. Immunofluorescence was unremarkable, with only non-specific linear glomerular and tubular basement membrane staining for IgG, kappa, lambda, and albumin, indicative of pauci-immunity. Electron microscopy demonstrated segmental effacement of podocyte foot processes (40%) with vacuolation and microvillous transformation of the podocyte cytoplasm, ischemic-type capillary wall wrinkling, and subendothelial electron lucent widening (Fig. 4). He was subsequently discharged on a steroid taper with plans for outpatient rituximab. Despite extensive education about his condition he was once again lost to follow up and missed appropriate treatment.Fig. 4 Kidney Biopsy. a Glomerulus with segmental sclerosis of the right half of the tuft, Periodic Acid-Methenamine Silver (PASM, 200×) b One glomerulus (left) with an ischemic appearance including capillary wall wrinkling and tuft retraction, other glomerulus (right) has mild hypercellularity including a few neutrophils (H&E, 100×) c A glomerulus with a bloodless appearance, obliteration of capillary lumens and thickening of capillary walls with segmental duplication (Periodic Acid-Schiff (PAS), 200×) d Tubules show cytoplasmic vacuolation, apical blebbing, thinning, and focal simplification. The interstitium contains a sparse lymphocytic infiltrate (PAS, 100×) e Electron micrograph of glomerular tuft showing ischemic-type capillary wall wrinkling (asterisk) and diffuse subendothelial electron lucent widening (arrow) f Electron micrograph showing podocyte foot process effacement (arrow) and mild subendothelial electron-lucent widening (asterisk)
Over the course of the next year, he was readmitted on multiple occasions and eventually progressed to dialysis-dependent end-stage renal disease. His two most recent admissions were characterized by pancreatitis with pancreatic pseudoaneurysm complicated by retroperitoneal hematoma and cardiac tamponade, respectively. With respect to his pancreatitis, he presented in the context of acute onset abdominal pain with associated nausea and vomiting. Laboratory diagnostics demonstrated an elevated lipase (3400), normal triglycerides, and a negative IgG4 serology. Abdominal CT was significant for peripancreatic fat stranding and inflammatory changes without evidence of gallstones or biliary ductal dilation. He denied recent alcohol use. Pancreatitis course was further complicated by retroperitoneal hematoma, which was found to be secondary to a 7 mm pancreatic pseudoaneurysm rupture, as revealed on repeat abdominal CT angiography (Fig. 5). He was managed conservatively and subsequently discharged. One month later he presented with dyspnea, chest pain and nausea, and was found to have large pericardial effusion with an acute decrease in ejection fraction to 10% (Fig. 6). He underwent pericardiocentesis with removal of one liter of serosanguineous fluid. Fluid analysis was indicative of hemorrhagic etiology and negative for malignancy. On review of most recent outpatient records, the patient has been maintained on high-dose suppressive steroid therapy with plans for initiation of Rituximab or Cyclophosphamide.Fig. 5 CT angiography of the Abdomen. A 7 mm arterially enhancing focus in the tail of the pancreas that follows the blood flow (Arrow), consistent with a pseudoaneurysm, with an associated large left upper quadrant hematoma and small amount of hemorrhage in the right paracolic gutter
Fig. 6 Echocardiogram. Four chamber views in diastole a and systole (c). Short axis views in Diastole b and systole (d). Echocardiography demonstrating a large circumferential pericardial effusion (Asterisks) without hemodynamic compromise, mildly dilated left ventricle (LV) with normal wall thickness, and severe globally depressed systolic function with left ventricular ejection fraction of 10%, normal right ventricle (RV) size and mildly reduced right ventricular systolic function
Discussion
Since the sentinel publications on ANCA in early 1980s and the landmark article by van der Woude et al. [5], our understanding of ANCA has significantly expanded. ANCA is currently recognized as having a central role in the pathogenesis of necrotizing vasculitis and glomerulonephritis particularly AAV, however the exact mechanism, and if a direct pathogenic role exists for ANCA, remains to be elucidated [8]. Recently an association between ANCA-induced neutrophil activation, regulated necrosis (necroptosis), neutrophil endothelial trap (NET) generation, complement activation, and endothelial cell damage leading to vasculitis and necrotizing glomerulonephritis has been identified in AAV by Schreiber et al. [9]. Nonetheless, detection of ANCA has become an essential part of the routine workup for vasculitis and many other autoimmune disorders. Currently only two ANCA antigens, PR3/ c-ANCA and MPO/ p-ANCA, critical components for neutrophil-mediated innate immunity, have been recognized to be clinically significant for AAV amongst a diverse array of ANCA antigens [9]. While indirect immunofluorescence testing on ethanol-fixed neutrophils is the reference method for ANCA detection and screening, positive results prompt specific testing for PR3 and MPO. As new ANCA detection methods have developed, the most recent revised international consensus recommends high-quality antigen-specific assays for PR3-ANCA and MPO-ANCA should be used as the primary screening method for ANCA, and if results for both are negative with strong clinical suspicion for small-vessel vasculitis, other immunoassays, indirect immunofluorescence, or referral to an experienced lab is recommended [10].
ANCA is detected in 80–90% of cases of MPA out of which 70% are positive for MPO-ANCA [3–6, 11–14]. Seronegative ANCA, also known as pauci-immune vasculitis, is similar to seronegative lupus or seronegative rheumatoid arthritis and the absence of specific markers may lead not only to a delay in diagnosis, but also misdiagnosis [1, 2]. Furthermore, ANCA, though initially negative, may become positive later in the course of disease or may not be detectable with currently available methods [3–5]. On the other hand, antibodies to antigens other than PR3 and MPO have been detected and are referred to as minor ANCA antigens [15]. Interestingly these antibodies are frequently detected in sera of MPO- and PR3-ANCA negative patients, and while they can mimic c-ANCA or p-ANCA patterns, they are detected in other types of small vessel vasculitis such as cocaine-induced vasculitis mimicking GPA as well as other autoimmune diseases such as Sjӧgren, rheumatoid arthritis, and ulcerative colitis [9, 15]. It is noteworthy to mention that ethnic differences between MPO and PR3 ANCA subtypes have also been observed with PR3 predominance in Japanese and Chinese ethnicity and MPO predominance in Northern Europeans and Middle-Eastern/Turkish groups [7].
Classically MPA presents with acute onset of rapidly progressive glomerulonephritis, however presentation is often atypical. Most commonly, patients present with constitutional symptoms—fever, weight loss, fatigue—over an acute or chronic course over weeks to months [3–5]. The most common age of presentation is in 5–6th decades of life with a slight male predominance [3, 4]. Multiple organs can be involved with the most common organs being kidneys and lungs, followed by skin, gastrointestinal, cardiac and nervous systems [5, 6, 11]. Renal involvement is reported in 80–100% of MPA cases and is classically characterized by rapidly progressive glomerulonephritis (GN), however renal involvement on initial presentation may range from minimal proteinuria to end-stage renal disease requiring dialysis [5]. Pauci-immune necrotizing and crescentic GN is the classic finding on biopsy in systemic AAV [12]. Crescentic involvement of the glomeruli is the most common form of glomerular involvement in MPA and is visualized in up to 90% of cases, however interstitial nephritis and tubular atrophy, as observed in this case, are reported on biopsies as well [1–5]. Berden et al. proposed a classification criteria for AAV GN, based on the pathologic features of the glomerulus, into four major groups of focal, crescentic, mixed and sclerotic [12]. Considering the Berden’s classification, our patient would fall into the focal subgroup with more than 50% normal glomeruli, which have a relatively preserved kidney function and an overall more favorable outcome compared to other pathologic subgroups [12]. In another study of ANCA-negative patients with pauci-immune renal vasculitis, 29% of renal biopsies revealed normal glomeruli and only 50% had crescents on histology [14].
Pulmonary involvement can occur in up to 55% of cases of MPA and mostly present as dyspnea, cough, and hemoptysis. Classically MPA is associated with diffuse alveolar hemorrhage and a pauci-immune, hemorrhagic necrotizing alveolar capillaritis characterized by an absence of granulomatous changes on lung and renal biopsy [5, 6], similar to what was observed in our patient (Fig. 3). Diffuse alveolar hemorrhage, caused by pulmonary capillaritis, is considered a serious complication and if accompanied by glomerulonephritis (pulmonary-renal syndrome) portends a poor prognosis [5, 6]. Pulmonary function testing in patients with MPA can show either obstructive or restrictive pattern with reduced carbon monoxide diffusion capacity (DLCO) [5].
Gastrointestinal bleeding has been reported in up to 29% of MPA patients [5], however additional manifestations such as colonic ulceration, bowel ischemia, perforation, and arterial aneurysms have also been reported [5]. Pancreatic involvement in MPA is rare and may present as acute pancreatitis or pancreatic mass [16]. In a study of 62 patients with small-medium vessel vasculitis, Pagnoux et al. demonstrated that only 3 patients had pancreatitis as a complication, with only one having MPA [17]. Cardiac involvement in patients with MPA is reported to occur in 17–50% of cases with pathophysiology similar to that of other organ systems such as lung and kidney [18, 19]. Cardiac involvement may present as hypertension, heart failure, pericarditis, and less commonly myocardial infarction [10, 18].
Management of MPA and other AAV’s includes an induction phase followed by a maintenance phase. Classic induction strategies include oral corticosteroids (1 mg/kg daily) and cyclophosphamide (2 mg/kg daily). Rituximab and cyclophosphamide are considered the drug of choice for both induction and maintenance of remission. Rituximab has been shown to be non-inferior to cyclophosphamide by the RAVE and RITUXVAS trials [3–6, 11–13]. The NORAM study revealed methotrexate was as effective as cyclophosphamide with regards to induction of remission in mild disease however relapse rates were higher for methotrexate [3–5]. Plasmapheresis has been used in cases of aggressive AAV and was shown to have better renal outcomes in MEPEX trial, however PEXIVAS trial (Plasma exchange and glucocorticoids for treatment of AAV), the largest trial in AAV so far, failed to show a significant difference in all-cause mortality or end-stage renal disease, and plasmapheresis use remains controversial [3, 4, 20]. Maintenance therapy is generally achieved by less toxic agents such as rituximab, azathioprine, and methotrexate, with rituximab becoming more and more favored in recent years. Other immunosuppressive agents like leflunomide, mycophenolate mofetil, and trimethoprim-sulfamethoxazole have been used and studied as maintenance therapy strategies as well [3–6, 11].
This case was differentiated from other potential autoimmune disorders such as systemic lupus erythematosus, Sjӧgren syndrome, sarcoidosis, and other small to medium sized vessel vasculitis such as granulomatosis with polyangiitis, polyarteritis nodosa, IgA vasculitis and cryoglobulinemic vasculitis based on presentation, laboratory and imaging findings and biopsy of the lung revealing capillaritis without granulomatous changes. Absence of pathognomic noncaseating granulomas on lung biopsy, ruled out sarcoidosis. In the light of absence of certain characteristics such as palpable purpura, as well as absence of immune complexes on tissue biopsy, immune complex vasculitides such as anti-glomerular basement membrane disease, IgA and cryoglobulinemic vasculitis were ruled out. While differentiation of GPA from MPA is difficult and they tend to share characteristics of AAV disease spectrum, the absence of granulomatous lesions on both biopsies and lack of certain classical features of GPA made it less likely in this case. EGPA was also deemed less likely considering lack of peripheral eosinophilia and tissue eosinophilic infiltration. We also believe the kidney biopsy results were affected by pulse steroids and possible steroid consumption in between admissions, however pauci-immunity and absence of granulomatous changes, and immune complex deposition favors MPA over other vasculitides.
Conclusion
MPA is differentiated not only by the presence of anti-MPO (p-ANCA) but also histopathologically by non-granulomatous lesions and capillaritis. ANCA serologies, however, may be negative in AAV specifically MPA in as many as 10-20% of cases. This case underscores the importance of identifying pulmonary-renal syndrome and its association with AAV, the need to maintain a high index of suspicion in cases of negative ANCA serologies, and to pursue tissue biopsy despite negative serologies in such circumstances. This case further serves to demonstrate the rapid clinical deterioration and high morbidity in those cases of AAV with delayed diagnosis or inadequate treatment.
Abbreviations
MPAMicroscopic Polyangiitis
ANCAAnti-neutrophil cytoplasmic antibody
AAVANCA-associated Vasculitis
GPAGranulomatosis with polyangiitis
EGPAEosinophilic granulomatosis with angiitis
G6PDGlucose 6 Phosphate Dehydrogenase
CTComputed Tomography
IVIntravenous
CRPC-reactive Protein
ESRErythrocyte sedimentation Rate
CAPCommunity Acquired Pneumonia
ANAAnti-Neutrophil Antibody
RFRheumatoid Factor
FVCForced Vital Capacity
FEVForced Expiratory Volume
VCVital Capacity
FRCForced Residual Capacity
RVResidual Capacity
TLCTotal Lung Capacity
DLCODiffusing Capacity of Lung for Carbon Monoxide
VATSVideo-Assisted Thoracoscopic Surgery
PMNPolymorphonuclear
FSGSFocal Segmental Glomerulonephritis
IgGImmunoglobulin G
NETNeutrophil Endothelial Trap
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Authors’ contributions
AM designed the study, gathered data and resources, drafted, edited and finalized the entire manuscript. NNC and RA gathered data and resources. JSI provided and interpreted lung biopsy. LJA provided and interpreted kidney biopsy. SHFS assisted and edited discussion section. CJH edited, critically revised and helped finalize the entire manuscript. All authors read and approved the final manuscript.
Funding
No financial support or grant was provided for the preparation of this manuscript.
Consent for publication
A written informed consent has been signed and obtained from the patient and is available upon request.
Competing interests
Authors hereby declare no personal or financial conflict of interest. | Intravenous (not otherwise specified) | DrugAdministrationRoute | CC BY | 33407881 | 19,165,871 | 2021-01-06 |
What was the administration route of drug 'CEFTRIAXONE'? | ANCA-negative microscopic polyangiitis with diffuse alveolar hemorrhage masquerading as congestive heart failure.
BACKGROUND
Microscopic polyangiitis (MPA) is a subtype of anti-neutrophil cytoplasmic antibody-associated vasculitis (AAV), involving small and medium sized vessels, often affecting the kidneys and lungs. Anti-neutrophil cytoplasmic antibody (ANCA) is detected in up to 90% of cases of MPA and its detection helps guide diagnosis, however cases of ANCA-negative MPA have been reported, hence definitive diagnosis relies on tissue biopsy.
METHODS
A 23-year-old man was evaluated for dyspnea and pleuritic chest pain, and found to have bilateral intra-alveolar opacities and hilar adenopathy. Diagnostic work up revealed positive anti-nuclear antibodies (ANA) and negative ANCA, which in the setting of a non-classical presentation, delayed diagnosis and appropriate treatment. Due to persistent symptoms and a high suspicion for autoimmune disease with pulmonary-renal syndrome, he underwent lung biopsy which revealed intra-alveolar hemorrhage and capillaritis indicative of microscopic polyangiitis (MPA). Surprisingly, kidney biopsy was not typical of classic MPA, but revealed less common features. Due to therapeutic noncompliance he was readmitted multiple times thereafter with rare complications of MPA such as acute pancreatitis and hemorrhagic pericardial effusion with tamponade.
CONCLUSIONS
This case serves as an important clinical reminder to consider AAV even in those with negative ANCA serologies and a high suspicion for pulmonary-renal syndrome. It also demonstrates the high morbidity in cases of diagnostic delay and inadequate treatment.
Background
The 2012 Chapel Hill Consensus guideline recognizes microscopic polyangiitis (MPA) as a subset of ANCA-associated vasculitis (AAV), a group of necrotizing pauci-immune vasculitides that predominantly affects small vessels—capillaries, venules, and arterioles—with few or no immune deposits [1]. AAV commonly affects the renal and pulmonary parenchyma to varying degrees, and is characterized by the presence of antibodies against neutrophilic cytoplasmic components, Proteinase-3 (PR3, c-ANCA) and Myeloperoxidase (MPO, p-ANCA). AAV include Microscopic Polyangiitis (MPA), Granulomatosis with polyangiitis (GPA; Wegener’s) and Eosinophilic granulomatosis with angiitis (EGPA; Churg-Strauss), as well as a variety of additional AAV-associated syndromes (drug-induced vasculitis, renal-limited vasculitis (RLV)), each characterized by the presence of distinct clinical presentation, ANCA subtypes, histopathological findings, and associated laboratory findings [1–4].
MPA is characterized by the presence of anti-MPO (p-ANCA) antibodies, renal and pulmonary involvement, and the absence of granulomatous inflammation on histopathology, a defining feature when compared to GPA and EGPA which, while demonstrating both renal and pulmonary involvement, are characterized by the presence of anti-PR3 (c-ANCA) and granulomatous disease. Though a widely accepted marker for AAV, the presence of ANCA is variable and not detected in all cases. ANCA is detected in 80–90% of cases of MPA and its detection has become integral in the diagnostic workup as well as classification and prognostication of all AAV [3, 4]. While current evidence indicates that ANCA plays a role in pathogenesis of MPA and other AAV, cases of ANCA-negative vasculitis, including cases of ANCA-negative MPA, GPA, and EGPA have been reported [1–7]. We present a case of ANCA-negative MPA in a young man who presented with hemoptysis and was found to have diffuse bilateral lung infiltrates, acute kidney injury, and heart failure. Following a circuitous diagnostic course masked by symptoms of heart failure, he was eventually diagnosed with MPA, however the course of his disease was further complicated by medication non-compliance as well as rare complications of AAV, including acute pancreatitis, pancreatic pseudoaneurysm, and cardiac tamponade.
Case report
A 23-year-old African-American man with past medical history of G6PD-deficiency and obesity presented with dyspnea and pleuritic chest pain that improved upon leaning forward and scant hemoptysis of two weeks duration. He was notably hypertensive to the 220/110 s mmHg and tachycardic to the 120 s, but had a preserved respiratory rate and oxygen saturation. Physical exam was remarkable for bilateral diffuse wheezing throughout all lung fields. Other parts of the exam including cardiovascular, nasopharynx, skin and musculoskeletal systems were unremarkable. Additional pertinent history was remarkable only for marijuana smoking. Electrocardiogram was unremarkable except for left atrial enlargement. Chest X-ray revealed bilateral pulmonary infiltrates, cardiomegaly, and mediastinal enlargement suggestive of bulky hilar adenopathy. Computed tomography (CT) scan of the chest with contrast was performed which was negative for pulmonary embolism, but revealed bilateral centrilobular opacities, hilar/mediastinal lymphadenopathy, and a trivial pericardial effusion (Fig. 1a). Initial laboratory diagnostics were significant for acute kidney injury with a serum creatinine of 2.03 (mg/dL), trace proteinuria, troponin elevation to 0.232 (ng/mL), and a D-Dimer of 1.3 (mcg/mL). Complete blood count revealed no leukocytosis, but concomitant eosinophilia, with no evidence of anemia. The patient was subsequently admitted to the medicine wards and a therapeutic regimen of antihypertensive agents as well as intravenous ceftriaxone and azithromycin for presumed community acquired pneumonia was initiated.Fig. 1 CT scans of the chest. a CT Scan of the chest on first day of presentation demonstrating bilateral centrilobular opacities, hilar/mediastinal lymphadenopathy, moderate cardiomegaly, a trivial pericardial effusion and enlargement of the main pulmonary artery. b Prone CT chest on day 7 of admission, revealing persistent intra-alveolar opacities with associated mediastinal lymphadenopathy
Additional diagnostic evaluation demonstrated marked elevation of CRP (80 mg/L) and ESR (67 mm/hr). Pheochromocytoma screening with serum catecholamines and metanephrines was negative. An echocardiogram revealed an ejection fraction of 40%, moderate concentric left ventricular hypertrophy, and trivial pericardial effusion without evidence of tamponade or pulmonary artery hypertension. Despite continuation of antibiotics for pneumonia and adjunctive heart failure management, the patient’s clinical status failed to improve. In the setting of an unremarkable infectious workup and concern for an autoimmune etiology, the patient was started on oral prednisone 60 mg daily. The patient remained symptomatic, experiencing episodic chest pain and shortness of breath, with blood pressure lability. Repeat chest X-ray showed worsening bilateral infiltrates. Subsequently, ANA resulted weakly positive (1:160) with a homogenous pattern and rheumatoid factor (RF) returned negative.
On the fifth day of admission, antibiotics were discontinued in light of negative cultures and lack of significant clinical improvement. The patient’s blood pressure was noted to be slightly improved with addition of prednisone however remained poorly controlled on multiple medications (Fig. 2). Autoimmune panel including ANCA (MPO/p-ANCA, and PR3/c-ANCA), anti-double-stranded DNA antibody, anti-Smith antibody, C3 and C4 complements, anti-histone antibody, as well as other autoimmune related factors and infectious serologies returned negative or within normal limits (Table 1). Renal ultrasound and renal artery duplex were performed which did not reveal any evidence of hydronephrosis or renal artery stenosis, respectively. A repeat high-resolution chest CT scan was obtained, both in supine and prone positions, to help differentiate early interstitial lung disease from intra-alveolar processes, which showed persistent intra-alveolar opacities without any change on prone position (Fig. 1b). Over the course of the following days, the patient reported improvement in his symptomatology and his blood pressure improved, therefore he was taken off prednisone on the sixth day. Pulmonary function testing was performed in the setting of bilateral hilar adenopathy and fixed infiltrates, which revealed a mixed obstructive and restrictive pattern. He eventually underwent lung biopsy by video-assisted thoracoscopic surgery (VATS) with right medial lobe wedge resection and was subsequently discharged with instructions to follow up with rheumatology for planned initiation of rituximab. The histopathological results of his lung biopsy demonstrated extensive intra-alveolar hemorrhage with linear polymorphonuclear (PMN) cell collections in alveolar septa and capillaritis without any evidence of granulomatous changes, indicative of microscopic polyangiitis (Fig. 3). Immunohistochemistry on lung biopsy samples was not performed and renal biopsy was deferred to outpatient rheumatology.Fig. 2 Blood pressure and creatinine during first and second hospitalizations. SBP Systolic Blood Pressure, DBP Diastolic Blood Pressure
Table 1 Autoimmune and infectious workup results during first admission
Lab Results Lab Results Lab Results
WBC 9.3 Neutrophils 75.9% Potassium 2.9
Hgb 13.1 Lymphocytes 12.5% Sodium 138
Hct 37.8 Eosinophils 1.3% Creatinine 2.03
Platelet 343 Monocytes 10.1% GFR 52
Troponin 0.232 D-Dimer 1.3 TSH 1.65
CRP 80 GBM Ab Negative CMV IgM Negative
ESR 67 SS-A/Ro Negative Cox A & B Ab Negative
ANA 1:160 (Homogenous) SS-B/La Negative Cryptococcal Ag Negative
RF < 10 ACA (IgG, IgM) < 9 EBV DNA Negative
Anti-CCP 4 TTG (IgA, IgG) 1, 3 HBV DNA Negative
ANCA Negative Ribosome IgG 3 HCV RNA Negative
Anti ds-DNA Negative Endomysial IgG < 1:10 HIV 1&2 Ab Negative
Anti-Smith Ab Negative Anti Gliadin < 7 Parvovirus B19 Negative
Histone auto Ab Negative Anti Gliadin < 2 Syphilis (RPR/FTA) Negative
Scl-70 Ab Negative Free Kappa 1.73 HHV6 DNA Negative
C3 130 Free Lambda 1.49 Lyme ELISA Negative
C4 32.4 K/L Ratio 1.16 Histoplasma Ag Negative
IgA 250 IgG 1160 IgM 1110
WBC White Blood Cell, Hgb Hemoglobin, Hct Hematocrit, GFR Glomerular Filtration Rate, TSH Thyroid Stimulating Hormone, Ab Antibody, Ig Immunoglobulin, ESR Erythrocyte Sedimentation Rate, CRP C-Reactive Protein, ANA Anti-Neutrophil Antibody, ANCA Anti-Neutrophil Cytoplasmic Antibody, Scl Scleroderma, C3 Complement 3, C4 Complement 4, ds-DNA Double-Stranded DNA, RF Rheumatoid Factor, CCP Cyclic Citrullinated Peptide, SS-A Sjӧgren-Syndrome-related-antigen A, SS-B Sjӧgren-syndrome-related-antigen B, ACA Anti Cardiolipin Ab, TTG Tissue trans-glutaminase, HIV Human Immunodeficiency Virus, HCV Hepatitis C Virus, HBV Hepatitis B Virus, CMV Cytomegalovirus, EBV Epstein-Barr Virus, Cox A & B Coxsackievirus A & B, HHV Human Herpes Virus, RPR: Rapid Plasma Reagin, FTA Fluorescent Treponemal Antibody
Fig. 3 Lung Biopsy. a Intra-alveolar hemorrhage (100×) b Polymorphonuclear cells in alveolar septa; capillaritis (Arrow) (400x)
Unfortunately, the patient was lost to follow up, failing to attend any of the scheduled appointments. He was subsequently readmitted six months later with similar symptoms, and once again found to be in hypertensive emergency, complicated by acute decompensated heart failure. Repeat echocardiogram revealed a further decline in his ejection fraction to 25% and a trivial pericardial effusion. Rheumatology was consulted and recommended pulse steroid therapy with methylprednisolone 250 mg four times a day for three days, which led to significant improvement in symptoms and blood pressure. Repeat ANCA and autoimmune serological workup remained negative. Following initiation of pulse steroid therapy, he underwent renal biopsy. The biopsy contained forty glomeruli, six of which were globally sclerotic. One glomerulus had segmental sclerosis. There were changes suggestive of microangiopathic injury in some arteries and glomeruli, such as bloodless glomeruli and mild intimal myxoid changes in arteries, with associated acute tubular injury. Focal tubular atrophy and interstitial fibrosis were estimated to involve approximately 10% of the cortex. No evidence of crescents or granulomatous changes were observed. Immunofluorescence was unremarkable, with only non-specific linear glomerular and tubular basement membrane staining for IgG, kappa, lambda, and albumin, indicative of pauci-immunity. Electron microscopy demonstrated segmental effacement of podocyte foot processes (40%) with vacuolation and microvillous transformation of the podocyte cytoplasm, ischemic-type capillary wall wrinkling, and subendothelial electron lucent widening (Fig. 4). He was subsequently discharged on a steroid taper with plans for outpatient rituximab. Despite extensive education about his condition he was once again lost to follow up and missed appropriate treatment.Fig. 4 Kidney Biopsy. a Glomerulus with segmental sclerosis of the right half of the tuft, Periodic Acid-Methenamine Silver (PASM, 200×) b One glomerulus (left) with an ischemic appearance including capillary wall wrinkling and tuft retraction, other glomerulus (right) has mild hypercellularity including a few neutrophils (H&E, 100×) c A glomerulus with a bloodless appearance, obliteration of capillary lumens and thickening of capillary walls with segmental duplication (Periodic Acid-Schiff (PAS), 200×) d Tubules show cytoplasmic vacuolation, apical blebbing, thinning, and focal simplification. The interstitium contains a sparse lymphocytic infiltrate (PAS, 100×) e Electron micrograph of glomerular tuft showing ischemic-type capillary wall wrinkling (asterisk) and diffuse subendothelial electron lucent widening (arrow) f Electron micrograph showing podocyte foot process effacement (arrow) and mild subendothelial electron-lucent widening (asterisk)
Over the course of the next year, he was readmitted on multiple occasions and eventually progressed to dialysis-dependent end-stage renal disease. His two most recent admissions were characterized by pancreatitis with pancreatic pseudoaneurysm complicated by retroperitoneal hematoma and cardiac tamponade, respectively. With respect to his pancreatitis, he presented in the context of acute onset abdominal pain with associated nausea and vomiting. Laboratory diagnostics demonstrated an elevated lipase (3400), normal triglycerides, and a negative IgG4 serology. Abdominal CT was significant for peripancreatic fat stranding and inflammatory changes without evidence of gallstones or biliary ductal dilation. He denied recent alcohol use. Pancreatitis course was further complicated by retroperitoneal hematoma, which was found to be secondary to a 7 mm pancreatic pseudoaneurysm rupture, as revealed on repeat abdominal CT angiography (Fig. 5). He was managed conservatively and subsequently discharged. One month later he presented with dyspnea, chest pain and nausea, and was found to have large pericardial effusion with an acute decrease in ejection fraction to 10% (Fig. 6). He underwent pericardiocentesis with removal of one liter of serosanguineous fluid. Fluid analysis was indicative of hemorrhagic etiology and negative for malignancy. On review of most recent outpatient records, the patient has been maintained on high-dose suppressive steroid therapy with plans for initiation of Rituximab or Cyclophosphamide.Fig. 5 CT angiography of the Abdomen. A 7 mm arterially enhancing focus in the tail of the pancreas that follows the blood flow (Arrow), consistent with a pseudoaneurysm, with an associated large left upper quadrant hematoma and small amount of hemorrhage in the right paracolic gutter
Fig. 6 Echocardiogram. Four chamber views in diastole a and systole (c). Short axis views in Diastole b and systole (d). Echocardiography demonstrating a large circumferential pericardial effusion (Asterisks) without hemodynamic compromise, mildly dilated left ventricle (LV) with normal wall thickness, and severe globally depressed systolic function with left ventricular ejection fraction of 10%, normal right ventricle (RV) size and mildly reduced right ventricular systolic function
Discussion
Since the sentinel publications on ANCA in early 1980s and the landmark article by van der Woude et al. [5], our understanding of ANCA has significantly expanded. ANCA is currently recognized as having a central role in the pathogenesis of necrotizing vasculitis and glomerulonephritis particularly AAV, however the exact mechanism, and if a direct pathogenic role exists for ANCA, remains to be elucidated [8]. Recently an association between ANCA-induced neutrophil activation, regulated necrosis (necroptosis), neutrophil endothelial trap (NET) generation, complement activation, and endothelial cell damage leading to vasculitis and necrotizing glomerulonephritis has been identified in AAV by Schreiber et al. [9]. Nonetheless, detection of ANCA has become an essential part of the routine workup for vasculitis and many other autoimmune disorders. Currently only two ANCA antigens, PR3/ c-ANCA and MPO/ p-ANCA, critical components for neutrophil-mediated innate immunity, have been recognized to be clinically significant for AAV amongst a diverse array of ANCA antigens [9]. While indirect immunofluorescence testing on ethanol-fixed neutrophils is the reference method for ANCA detection and screening, positive results prompt specific testing for PR3 and MPO. As new ANCA detection methods have developed, the most recent revised international consensus recommends high-quality antigen-specific assays for PR3-ANCA and MPO-ANCA should be used as the primary screening method for ANCA, and if results for both are negative with strong clinical suspicion for small-vessel vasculitis, other immunoassays, indirect immunofluorescence, or referral to an experienced lab is recommended [10].
ANCA is detected in 80–90% of cases of MPA out of which 70% are positive for MPO-ANCA [3–6, 11–14]. Seronegative ANCA, also known as pauci-immune vasculitis, is similar to seronegative lupus or seronegative rheumatoid arthritis and the absence of specific markers may lead not only to a delay in diagnosis, but also misdiagnosis [1, 2]. Furthermore, ANCA, though initially negative, may become positive later in the course of disease or may not be detectable with currently available methods [3–5]. On the other hand, antibodies to antigens other than PR3 and MPO have been detected and are referred to as minor ANCA antigens [15]. Interestingly these antibodies are frequently detected in sera of MPO- and PR3-ANCA negative patients, and while they can mimic c-ANCA or p-ANCA patterns, they are detected in other types of small vessel vasculitis such as cocaine-induced vasculitis mimicking GPA as well as other autoimmune diseases such as Sjӧgren, rheumatoid arthritis, and ulcerative colitis [9, 15]. It is noteworthy to mention that ethnic differences between MPO and PR3 ANCA subtypes have also been observed with PR3 predominance in Japanese and Chinese ethnicity and MPO predominance in Northern Europeans and Middle-Eastern/Turkish groups [7].
Classically MPA presents with acute onset of rapidly progressive glomerulonephritis, however presentation is often atypical. Most commonly, patients present with constitutional symptoms—fever, weight loss, fatigue—over an acute or chronic course over weeks to months [3–5]. The most common age of presentation is in 5–6th decades of life with a slight male predominance [3, 4]. Multiple organs can be involved with the most common organs being kidneys and lungs, followed by skin, gastrointestinal, cardiac and nervous systems [5, 6, 11]. Renal involvement is reported in 80–100% of MPA cases and is classically characterized by rapidly progressive glomerulonephritis (GN), however renal involvement on initial presentation may range from minimal proteinuria to end-stage renal disease requiring dialysis [5]. Pauci-immune necrotizing and crescentic GN is the classic finding on biopsy in systemic AAV [12]. Crescentic involvement of the glomeruli is the most common form of glomerular involvement in MPA and is visualized in up to 90% of cases, however interstitial nephritis and tubular atrophy, as observed in this case, are reported on biopsies as well [1–5]. Berden et al. proposed a classification criteria for AAV GN, based on the pathologic features of the glomerulus, into four major groups of focal, crescentic, mixed and sclerotic [12]. Considering the Berden’s classification, our patient would fall into the focal subgroup with more than 50% normal glomeruli, which have a relatively preserved kidney function and an overall more favorable outcome compared to other pathologic subgroups [12]. In another study of ANCA-negative patients with pauci-immune renal vasculitis, 29% of renal biopsies revealed normal glomeruli and only 50% had crescents on histology [14].
Pulmonary involvement can occur in up to 55% of cases of MPA and mostly present as dyspnea, cough, and hemoptysis. Classically MPA is associated with diffuse alveolar hemorrhage and a pauci-immune, hemorrhagic necrotizing alveolar capillaritis characterized by an absence of granulomatous changes on lung and renal biopsy [5, 6], similar to what was observed in our patient (Fig. 3). Diffuse alveolar hemorrhage, caused by pulmonary capillaritis, is considered a serious complication and if accompanied by glomerulonephritis (pulmonary-renal syndrome) portends a poor prognosis [5, 6]. Pulmonary function testing in patients with MPA can show either obstructive or restrictive pattern with reduced carbon monoxide diffusion capacity (DLCO) [5].
Gastrointestinal bleeding has been reported in up to 29% of MPA patients [5], however additional manifestations such as colonic ulceration, bowel ischemia, perforation, and arterial aneurysms have also been reported [5]. Pancreatic involvement in MPA is rare and may present as acute pancreatitis or pancreatic mass [16]. In a study of 62 patients with small-medium vessel vasculitis, Pagnoux et al. demonstrated that only 3 patients had pancreatitis as a complication, with only one having MPA [17]. Cardiac involvement in patients with MPA is reported to occur in 17–50% of cases with pathophysiology similar to that of other organ systems such as lung and kidney [18, 19]. Cardiac involvement may present as hypertension, heart failure, pericarditis, and less commonly myocardial infarction [10, 18].
Management of MPA and other AAV’s includes an induction phase followed by a maintenance phase. Classic induction strategies include oral corticosteroids (1 mg/kg daily) and cyclophosphamide (2 mg/kg daily). Rituximab and cyclophosphamide are considered the drug of choice for both induction and maintenance of remission. Rituximab has been shown to be non-inferior to cyclophosphamide by the RAVE and RITUXVAS trials [3–6, 11–13]. The NORAM study revealed methotrexate was as effective as cyclophosphamide with regards to induction of remission in mild disease however relapse rates were higher for methotrexate [3–5]. Plasmapheresis has been used in cases of aggressive AAV and was shown to have better renal outcomes in MEPEX trial, however PEXIVAS trial (Plasma exchange and glucocorticoids for treatment of AAV), the largest trial in AAV so far, failed to show a significant difference in all-cause mortality or end-stage renal disease, and plasmapheresis use remains controversial [3, 4, 20]. Maintenance therapy is generally achieved by less toxic agents such as rituximab, azathioprine, and methotrexate, with rituximab becoming more and more favored in recent years. Other immunosuppressive agents like leflunomide, mycophenolate mofetil, and trimethoprim-sulfamethoxazole have been used and studied as maintenance therapy strategies as well [3–6, 11].
This case was differentiated from other potential autoimmune disorders such as systemic lupus erythematosus, Sjӧgren syndrome, sarcoidosis, and other small to medium sized vessel vasculitis such as granulomatosis with polyangiitis, polyarteritis nodosa, IgA vasculitis and cryoglobulinemic vasculitis based on presentation, laboratory and imaging findings and biopsy of the lung revealing capillaritis without granulomatous changes. Absence of pathognomic noncaseating granulomas on lung biopsy, ruled out sarcoidosis. In the light of absence of certain characteristics such as palpable purpura, as well as absence of immune complexes on tissue biopsy, immune complex vasculitides such as anti-glomerular basement membrane disease, IgA and cryoglobulinemic vasculitis were ruled out. While differentiation of GPA from MPA is difficult and they tend to share characteristics of AAV disease spectrum, the absence of granulomatous lesions on both biopsies and lack of certain classical features of GPA made it less likely in this case. EGPA was also deemed less likely considering lack of peripheral eosinophilia and tissue eosinophilic infiltration. We also believe the kidney biopsy results were affected by pulse steroids and possible steroid consumption in between admissions, however pauci-immunity and absence of granulomatous changes, and immune complex deposition favors MPA over other vasculitides.
Conclusion
MPA is differentiated not only by the presence of anti-MPO (p-ANCA) but also histopathologically by non-granulomatous lesions and capillaritis. ANCA serologies, however, may be negative in AAV specifically MPA in as many as 10-20% of cases. This case underscores the importance of identifying pulmonary-renal syndrome and its association with AAV, the need to maintain a high index of suspicion in cases of negative ANCA serologies, and to pursue tissue biopsy despite negative serologies in such circumstances. This case further serves to demonstrate the rapid clinical deterioration and high morbidity in those cases of AAV with delayed diagnosis or inadequate treatment.
Abbreviations
MPAMicroscopic Polyangiitis
ANCAAnti-neutrophil cytoplasmic antibody
AAVANCA-associated Vasculitis
GPAGranulomatosis with polyangiitis
EGPAEosinophilic granulomatosis with angiitis
G6PDGlucose 6 Phosphate Dehydrogenase
CTComputed Tomography
IVIntravenous
CRPC-reactive Protein
ESRErythrocyte sedimentation Rate
CAPCommunity Acquired Pneumonia
ANAAnti-Neutrophil Antibody
RFRheumatoid Factor
FVCForced Vital Capacity
FEVForced Expiratory Volume
VCVital Capacity
FRCForced Residual Capacity
RVResidual Capacity
TLCTotal Lung Capacity
DLCODiffusing Capacity of Lung for Carbon Monoxide
VATSVideo-Assisted Thoracoscopic Surgery
PMNPolymorphonuclear
FSGSFocal Segmental Glomerulonephritis
IgGImmunoglobulin G
NETNeutrophil Endothelial Trap
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Authors’ contributions
AM designed the study, gathered data and resources, drafted, edited and finalized the entire manuscript. NNC and RA gathered data and resources. JSI provided and interpreted lung biopsy. LJA provided and interpreted kidney biopsy. SHFS assisted and edited discussion section. CJH edited, critically revised and helped finalize the entire manuscript. All authors read and approved the final manuscript.
Funding
No financial support or grant was provided for the preparation of this manuscript.
Consent for publication
A written informed consent has been signed and obtained from the patient and is available upon request.
Competing interests
Authors hereby declare no personal or financial conflict of interest. | Intravenous (not otherwise specified) | DrugAdministrationRoute | CC BY | 33407881 | 19,165,871 | 2021-01-06 |
Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Asphyxia'. | Determination of Seven Antidepressants in Pericardial Fluid by Means of Dispersive Liquid-Liquid Microextraction (DLLME) and Gas Chromatography-Mass Spectrometry (GC/MS).
Although blood is often used to detect and quantify the presence of drugs, there are some instances where samples obtained from other biological matrices, like pericardial fluid (PF), are necessary since adequate blood samples may not be available. PF is an epicardial transudate, which contains plasma components that include toxicological substances making this sample useful when blood samples are not available. This fluid is a well preserved postmortem sample and can easily be collected in larger amounts without significant contamination, compared with other body fluids. Although studies involving PF began around the 1980's, the adequacy of such fluid as a biological matrix has been poorly investigated. Antidepressants are frequently detected in postmortem samples from forensic cases. Nowadays, they constitute some of the most commonly prescribed drugs worldwide. A total of seven antidepressants (venlafaxine, mirtazapine, olanzapine, paroxetine, sertraline, fluoxetine and citalopram) were evaluated in this study. A new extraction method involving dispersive liquid-liquid microextraction (DLLME) is presented in which chloroform and acetonitrile are determined to be the best extraction and dispersing solvents. The experimental design was achieved using StatGraphics 18. The Response Surface Methodology enabled us to know the optimal volume for the two solvents used in the DLLME. The detection technique used was gas chromatography-mass spectrometry (GC-MS) with electron impact ionization as ionization source. A temperature gradient has been used and the total chromatographic separation time was 19.43 min. Validation results met the international validation guidances (FDA). Under the optimal condition, the method offered good validation parameters showing a new efficient, simple, rapid, and sensitive method. The analytical method was applied to thirty-one pericardial fluid samples. Twenty-one samples were positive with concentrations between 0.19 and 8.48 µg/mL. Venlafaxine and olanzapine were the antidepressants most frequently found.
pmcIntroduction
Depression constitutes nowadays one of the most common mental disorders either as a major condition or as a neuropsychiatric symptom characteristic of several diseases. In fact, major depressive disorder is a chronic, prevalent and pervasive brain-based disorder that significantly incapacitates the person affected (1). It is estimated that more than 350 million people worldwide are currently diagnosed with such condition, being women more frequently affected than men (2). At its worst, depression may lead to suicide. Close to 800,000 people commit suicide each year, being the second leading cause of death in 15–29-year-olds (3).
Tricyclic antidepressants (TCAs) were discovered in the 1950s, but their significant side effects led to a sustained effort in search for more selective drugs. This leads to the discovery of serotonin reuptake inhibitors, some of which (fluoxetine, sertraline and citalopram) are very commonly prescribed as first-choice drugs to treat depression. In addition, newer antidepressants, such as mirtazapine and venlafaxine, do affect both the serotonin and norepinephrine systems within the central nervous system, without the associated anticholinergic and cardiovascular side effects of older drugs such as TCAs. Mirtazapine has a dual mode of action. It is noradrenergic and specific serotonergic antidepressant that acts by antagonizing the adrenergic α2-autoreceptors and α2-heteroreceptors as well as by blocking 5-HT2 and 5-HT3 receptors. It enhances, therefore, the release of norepinephrine and 5-HT1A-mediated serotonergic transmission (4). Venlafaxine is a phenylethylamine derivative. It is a serotonin norepinephrine re-uptake inhibitor. Venlafaxine was approved by the FDA (Food and Drug Administration) for the following conditions: major depression, generalized anxiety disorder, panic disorder and social phobia (5). Olanzapine is a second-generation antipsychotic neuroleptic or “atypical antipsychotic”. These medications have more receptor-binding targets than first-generation treatments (e.g., haloperidol) do and have complex pharmacologic mechanisms of action. Olanzapine has the most binding targets in its class, binding to 10 serotonin receptors, 4 dopamine receptors, 4 acetylcholine receptors, 4 α-adrenergic receptors, 1 histamine receptor and 2 different neurotransmitter transport receptors (6).
Within the forensic practice, it is important to investigate postmortem drug concentrations to discriminate whether the cause of death was due to intoxication, side effects of the undergoing treatment or lack of compliance. Urine and blood specimens are the main biological samples used in forensic autopsy cases, being peripheral blood the most used in postmortem research. Moreover, special care must be taken in the interpretation of the data when using postmortem blood samples as these concentrations may change due to several factors such as chemical/enzymatic degradation of substances, redistribution phenomena and postmortem diffusion from solid organs or gastric content, especially with cardiac blood since it is more affected by postmortem redistribution (7). However, it should be borne in mind that blood analysis will be always a fundamental and essential step since it enables one to know the toxicological status of the deceased at the time of death. In addition to blood or urine samples, one may consider pericardial fluid (PF) as a useful alternative matrix in cases where adequate peripheral blood samples cannot be obtained. The potential use of PF samples has been considered within relatively few reports (7–13). Previous studies showed good correlation with the drug concentrations in peripheral blood (8, 10, 14, 15). PF is a well-preserved postmortem material in cases without structural damage due to injury or medical intervention and can easily be collected in large amounts without significant contamination as it is contained within a tight compartment (pericardial sac), compared with other body fluids (13). With a volume of 15–35 mL, it is believed to be a transudate generated by the net result of the hydrostatic pressure and the osmotic gradient between plasma and PF. The composition of the normal human PF is difficult to define. The hematological and biochemical analyses of the PF show that the concentration of electrolytes and small molecules (urea, uric acid, glucose and creatinine) corresponds to an ultrafiltrate of plasma (7, 13).
Previous works using liquid–liquid extraction or solid phase extraction have been reported (7–9, 12). In particular, efforts were oriented towards the development of efficient and miniaturized sample preparation methods. Liquid-phase microextraction (LPME) was introduced according to this perspective. Dispersive liquid–liquid microextraction (DLLME) is one of the LPME methods and has attracted recent interest within the analytical chemists’ community (16). The method was introduced by Assadi and co-workers in 2006 (17). It is a simple and fast microextraction technique based upon the use of an appropriate extractant (an organic solvent with high density) and a disperser solvent with high miscibility in both extractant and aqueous phases. DLLME consists of two steps: (i) injection of an appropriate mixture of extracting and disperser solvents into an aqueous sample, containing the analytes. In this step, the extracting solvent is dispersed into the aqueous sample as very fine droplets and the analytes are enriched into it. After the formation of a cloudy solution, the surface area between the extracting solvent and the aqueous sample becomes very large, so the equilibrium state is quickly attained and, therefore, the extraction time is very short. In fact, this is the principal advantage of this method. (ii) Centrifugation of the cloudy solution, thereby obtaining a settled phase that is deposited at the bottom of a conical tube. Other advantages include simplicity of operation, rapidity, low cost, high recovery, high enrichment factor and environment benignity (18). Like the other analytical methods, DLLME has some disadvantages, which result from the requirements related to the organic extraction and disperser solvents. The extraction solvent used should have some special requirements, such as a density larger than water for simple separation of the extraction phase after centrifugation and to form a cloudy solution in the presence of the disperser solvent. The potential organic solvents meeting this requirement are limited since they are hazardous chemicals (such as halogenated hydrocarbons). It is precisely because of this the choice of the extraction solvent becomes the method’s primary limitation (16). According to detection techniques, several methods were used involving liquid chromatography as well as gas chromatography (7–9, 12).
The aim of this study was to develop a gas chromatography–mass spectrometry (GC–MS) method for the determination and quantification of antidepressants in PF using DLLME as a new extraction method. The validation of the method was carried out according to the guidelines of the FDA (19). The method was then applied to PF samples collected from deceased people.
Material and Methods
Chemicals
Acetonitrile and chloroform gradient grade solvents were purchased from Merck® (Madrid, Spain) and sodium chloride from Panreac® (Barcelona, Spain). Fluoxetine, venlafaxine, mirtazapine, sertraline, citalopram, olanzapine, paroxetine and proadifen (SKF), used as internal standard, were obtained from Cerilliant®. Distilled water was processed through a Milli-Q water system (Millipore, Bedford, MA, USA).
Matrix collection
To carry out the validation procedure, antidepressant-free PF obtained from autopsies was used. For this purpose, a mixture of PF from deceased subjects was collected and stored at –20°C until use, following a previous peripheral blood and urine analysis that was negative to antidepressants.
Sample preparation
PF used for validation was previously ultracentrifuged for 5 min at 14,000 rpm. Aliquots of 0.3 mL were used for analysis, collected in a glass tube and spiked with Proadifen (SKF) (20 µL Sol. 10 µg/mL). Then, it was diluted with water (1.1 mL) and 150 mg of NaCl was also added to facilitate analytes’ transition from aqueous phase to organic phase. This mixture was submited to the DLLME. After an experimental design using StatGraphics (StatGraphics Technologies, Inc.), the optimal conditions were as follows: 175 uL of chloroform and 750 uL of acetonitrile as the best extracting and disperser solvents, respectively. Both solvents were rapidly injected into the sample with a Pasteur pipette and the mixture was gently shaken. Then, the mixture was centrifuged, and the droplet formed was collected by a 100 µL syringe and transferred to an 8 mL glass tube. The organic solvent was evaporated under a stream of nitrogen in a heated aluminum block at 40°C (VLM GmbH, HP series). The dried residue was redissolved with 40 µL of methanol prior to injection of a 2 µL aliquot into the GC–MS system.
Instrumentation
Chromatographic analyses were performed using an electron impact ionization gas chromatograph model 7890 B from Agilent Technologies® (Las Rozas, Spain) interfaced to a mass selective detector (MSD) model 5977 B, also from Agilent Technologies®. An HP5-MS capillary column (30 m × 250 µm i.d., 0.5 µm film thickness; Agilent Technologies®) with helium as carrier gas (1 mL/min) was used for the gas chromatographic separation. The injector temperature was set at 250°C and a purge time of 2 min was used. Samples were injected in the splitless mode. The following temperature program was applied: the initial temperature of the column was 100°C for 1 min, then ramped-up progressively at 35°C/min up to 220°C, held constant for 1 min, and then ramped-up again at 8°C/min up to 260°C and held for 2 min. Finally, the temperature was ramped-up at 5°C/min up to 280°C for 3 min. After that, the temperature was increased to 290°C for 5 min to clean the column. The total chromatographic separation time was 19.43 min, and the total run time was 24.43 min. The MSD was kept at 300°C, the ion source at 230°C and the quadrupole at 150°C.
Identification of compounds
Initially, neat standards of all antidepressants were injected and analyzed using the full scan mode of the GC–MS, which scanned from 50 to 550 amu. Quantifier and qualifier ions used for each analyte were selected based on their abundances and mass-to-charge ratios (m/z). Because of their reproducibilities and lack of interference, high mass ions were selected whenever possible. The ions selected for each compound studied and the retention times are shown in Table I. Upon selection of ion, the mass spectrometry was run in selected ion monitoring mode (Figure 1).
Table I. Retention Times and Ions Selected for Monitorization
Analyte Quantifier ion, m/z Qualifier ions, m/z Retention time, min
Fluoxetine 104 148, 309 7.78
Venlafaxine 58 134, 179 9.97
Mirtazapine 195 208, 245 11.78
SKF 86 99, 165 12.30
Sertraline 274 276, 262 13.55
Citalopram 58 238, 324 13.20
Paroxetine 192 138, 329 16.09
Olanzapine 242 229, 207 18.50
Figure 1. Extracted ionic chromatogram of all analytes.
Results
Experimental design
To find the best conditions for DLLME, 18 replicates were performed using a 2 × 4 factorial design with four factors: sample volume, water volume, extracting solvent volume and disperser solvent volume. The experimental design was achieved using Statgraphics 18. To make this design rotatable, for each factor, two axial points were chosen, and the runs were randomized to exclude the block effects. Response surface methodology (RSM) is a combination of mathematical and statistical techniques used to study the relationship between two or more responses that depend on several factors or independent variables. The final goal of RSM is to optimize responses determining the best conditions in the operation of the system. Our design of response surface was obtained using the statistical software StatGraphics (Figure 2).
Figure 2. Response surface graph.
Validation of the method
Validation was achieved according to the FDA Guideline for Bioanalytical Method Validation (19). The suitability of the method for quantitative analysis was studied by testing selectivity, linearity and sensitivity, precision and accuracy and recovery.
Selectivity
Selectivity is the ability of an analytical method to differentiate and quantify the analyte in the presence of other components in the sample. It should confirm that the assay is free of potential interfering substances, include endogenous matrix components, metabolites, decomposition products and medication and other exogenous xenobiotics. The selectivity of the method was demonstrated by analyzing six blank PF samples (19). No interfering peaks were found at the retention time for all analytes (Figure 3).
Figure 3. Chromatogram of a blank PF.
Linearity
Standard addition curves were obtained in six runs with the described method using drug-free control PF spiked with standard solutions to obtain the range of concentrations shown in Table II. The curves were obtained by fitting the ratio of the peak areas of analytes to that of IS versus concentrations. A linear response was observed in the studied range with a good correlation coefficient (higher than 0.99 in all cases). The sensitivity of the method was determined by calculation of the limit of detection (LOD) and the lower limit of quantification (LLOQ). LOD was determined by an empirical method that consists of analyzing a series of PF samples containing decreasing amounts of the analytes. LOD was the lowest concentration that presented a signal-to-noise ratio higher than 3 for at least three diagnostic ions for each substance. The LLOQ was the lowest concentration of analytes in a sample that can be determined with appropriate precision (20%) and accuracy (80–120%) (19) (Table II).
Table II. LOD, Limit of Quantification and Calibration Results for the Antidepressants Studied
Analyte LOD (µg/mL) LLOQ (µg/mL) C. coef. Range of calibration (µg/mL)
Fluoxetine 0.05 0.2 0.991 0.2–10
Venlafaxine 0.01 0.02 0.991 0.02–10
Mirtazapine 0.01 0.02 0.997 0.02–5
Sertraline 0.005 0.2 0.992 0.2–5
Citalopram 0.01 0.04 0.995 0.04–5
Olanzapine 0.02 0.2 0.993 0.2–10
Paroxetine 0.2 1 0.997 1–10
C. coef., correlation coefficient.
Precision and accuracy
The accuracy of an analytical method describes the closeness of mean test results obtained by the method to the true value (concentration) of the analyte. The precision of an analytical method describes the closeness of individual measures of an analyte when the procedure is applied repeatedly to multiple aliquots of a single homogeneous volume of biological matrix. Precision and accuracy were determined by inter- and intra-day assay. Inter-day precision and accuracy were calculated by analyzing negative PF samples spiked with the antidepressants at three concentrations; the LLOQ, the upper limit of quantification and an intermediate level were assessed by analyzing five replicates each day in five different days for each level of concentration. Intra-day precision and accuracy were determined at three concentrations, by preparing and analyzing five replicates for each level on the same day. Precision, expressed as the coefficient of variation of the measured values, was expected to be less than 15% at all concentrations, except for the LLOQ for which 20% was acceptable. In the same way, accuracy was evaluated using the mean relative error (ME), which had to be less than 15% of the theoretical values at each concentration level except for the LLOQ, for which 20% was acceptable (19). Data presented in Table III (Supplementary Material) satisfied the international validation rules.
Table III. Intra- and Inter-Day Precision and Accuracy (ME) of the Method
Intra-day study (n = 5) Inter-day study (n = 5)
Concentrations (μg/mL) ME (%) RSD (%) ME (%) RSD (%)
Fluoxetine
0.2 17 5 14 10
5 6 5 8 4
10 6 7 1 5
Venlafaxine
0.02 18 8 14 7
5 6 3 5 3
10 2 5 1 4
Mirtazapine
0.02 19 3 16 6
2.5 11 2 6 2
5 1 4 3 6
Sertraline
0.2 17 7 18 7
2.5 8 5 6 3
5 2 8 1 4
Citalopram
0.04 17 10 13 7
2.5 5 4 4 3
5 1 4 2 3
Paroxetine
1 13 12 13 12
5 8 15 9 12
10 14 12 1 7
Olanzapine
0.2 12 14 19 5
5 14 3 9 6
10 6 3 2 7
RSD: Relative Standard Deviation.
Recovery
The recovery of an analyte is the detector response obtained from an amount of the analyte added to an extracted from the biological matrix, compared to the detector response obtained for the true concentration of the pure authentic standard (19). The recovery of the method was examined by comparing the analytical results for extracted samples at three levels of concentration (high, medium and low) five times within three days with theoretical concentration that represent 100% recovery. The data obtained demonstrates that the extraction procedure is particularly efficient, providing a recovery values ranged from 85 to 105% for all compounds. The results are shown in Table IV (Supplementary Material).
Table IV. Intra and Inter-Day Accuracy (Analytical Recovery) of the Method
Intra-day study (n = 5) Inter-day study (n = 5)
Concentrations (μg/mL) Recovery (%) Recovery (%)
Fluoxetine
0.2 98 89
5 93 91
10 94 100
Venlafaxine
0.02 92 95
5 93 95
10 98 99
Mirtazapine
0.02 85 94
2.5 89 94
5 92 97
Sertraline
0.2 97 98
2.5 91 94
5 98 99
Citalopram
0.04 93 105
2.5 95 96
5 99 98
Paroxetine
1 93 93
5 91 91
10 94 101
Olanzapine
0.2 89 89
5 85 90
10 87 98
Application to real cases
The developed method was used to analyze 31 real PF samples obtained from the Forensic Toxicology Service of the Institute of Forensic Sciences of Santiago de Compostela from cases including suicide, overdose or death from unknown causes. Some information is described in Table V. From the 31 cases, 21 were positive for at least one of the substances analyzed. Venlafaxine and olanzapine were the two antidepressants most frequently found in 12 and 4 cases, respectively. There were also positive cases for mirtazapine, fluoxetine, sertraline and citalopram. Three samples were positive for several compounds at the same time. Figures 4 and 5 show real cases analyzed in our laboratory with their corresponding mass spectra (Figures 6 and 7). One of them corresponds to a female whose cause of death was hanging after having consumed high amounts of several drugs and the other case belongs to a male poisoned by carbon monoxide.
Table V. Real Cases
Case no. Age Sex Sample Cause of death General information and treatment Substance detected
(years) [µg/mL]
1 82 Female Blood, urine and PF Pulmonary embolism Depressive disorder Mirtazapine [0.48]
2 83 Female Blood, urine and PF Traumatic brain injury Duloxetine, bromazepam, quetiapine, tramadol and metamizol –
3 42 Female Blood, urine and PF Suicide Psychiatric treatment for schizophrenia. Lormetazepam and paliperidone Venlafaxine [0.27]
4 32 Female Blood and PF Suicide Depressive disorder. Risperidone, benzodiazepines and olanzapine Olanzapine <LLOQ
5 56 Female Blood, urine and PF Suicide Venlafaxine and benzodiazepines Venlafaxine [3.44]
6 45 Male Blood, urine, vitreous humor and PF Suicide Past history of drug abuse Venlafaxine [0.27]
7 52 Male Blood, vitreous humor and PF Acute myocardial infarction Depressive disorder –
8 45 Male Blood and PF Possible cardiac death Paranoid Schizophrenia. Valproic acid –
9 60 Female Blood, urine, gastric content, hair, PF and nail Suicide Ketazolam and bromazepam Venlafaxine [0.28]
10 67 Male Blood, urine and PF Choking suffocation Olanzapine Venlafaxine [0.28] and olanzapine <LLOQ
11 37 Male Blood, urine, bile, vitreous humor and PF – Drinker and smoker –
12 32 Male Blood, urine and PF Fall Depressive disorder. Haloperidol, olanzapine and flufenazine, Venlafaxine [0.27] and olanzapine [0.23]
13 64 Female Blood, urine, hair, vitreous humor, bile and PF Methanol poisoning – –
14 65 Male Blood, urine, gastric content and PF Suspected suicide Heptaminol hidroclorure, sertraline –
15 83 Male Blood, urine and PF Suicide Pregabaline, carbamazepine, clonazepam and mirtazapine Mirtazapine [0.19]
16 48 Male Blood, urine and PF Adverse drug reaction Fluoxetine, lormetazepam, lorazepam, alprazolam, clozapine, cocaine and dipotassium chlorazepate Fluoxetine [0.63]
17 75 Female Blood, urine, gastric content and PF Drug overdose Tramadol, ciclobenzaprine, ketazolam and lorazepam Venlafaxine [8.48]
18 70 Female Blood, urine and PF Suicide Venlafaxine and lorazepam Venlafaxine [0.81]
19 89 Female Blood, gastric content and PF Previous depressive episodes Lorazepam and olanzapine Olanzapine <LLOQ
20 75 Female Blood, urine and PF Natural Alprazolam, trazodone, venlafaxine and quietiapine Venlafaxine [0.95]
21 47 Female Blood, urine and PF Natural Depressive and personality disorder. Alprazolam and paroxetine –
22 56 Male Blood, urine and PF Cardiac death – –
23 35 Male Blood, vitreous humor and PF Choking suffocation Benzodiacepines, topiramate, fluoxetine, paliperidone, quetiapine and mirtazapine Mirtazapine [0.39] and fluoxetine [0.20]
24 36 Male Blood, urine, vitreous humor and PF Suicide Depressive disorder –
25 61 Male Blood, urine, vitreous humor and PF Natural Bipolar disorder. Alcohol consumption. Benzodiacepines, pregabaline, sertraline and olanzapine Sertraline [0.23]
26 86 Male Blood, urine, vitreous humor and PF Carbon monoxide poisoning Sertraline, trazodone and lorazepam Sertraline [0.48]
27 73 Female Blood, urine, vitreous humor and PF Suffocation from airway occlusion Benzodiacepines and venlafaxine Venlafaxine [0.62]
28 60 Female Blood, urine and PF Empyema Alcohol consumption. Mirtazapine, quetiapine and benzodiapcepines Citalopram [0.27]
29 40 Female Blood, vitreous humor and PF Suicide Depressive disorder. Venlafaxine, benzodiacepines, clomipramine and trazodone, Venlafaxine [3.84]
30 55 Female Blood, vitreous humor and PF Natural – –
31 52 Male Blood, urine, vitreous humor and PF Suicide Depressive disorder Venlafaxine [0.33]
PF, pericardial fluid.
Figure 4. Chromatogram of a real sample (positive for venlafaxine).
Figure 5. Chromatogram of a real sample (positive for sertraline).
Figure 6. Venlafaxine mass spectra.
Figure 7. Sertraline mass spectra.
Discussion
The present work aims to contribute toward the development of methods able to quantify the presence of antidepressants in samples of PF in cases where adequate blood samples may not be available. Previous literature reports comprise only a few articles where PF is used as a biological sample for the determination of drugs (7, 8, 15). The DLLME was one of the techniques used by several authors to extract antidepressants, but only one author determined the concentration of these compounds in PF (8, 16, 20–30). Most of the articles published so far used the DLLME technique coupled to another extraction method (16, 20, 22–24, 26, 27), but few papers have followed a similar method to ours (21, 25, 28–30). Most of them employed urine as the biological matrix (25, 28–30), while Lima et al. used water samples (21). Most of the published research dealt with TCAs as the particular drugs under study (16, 20, 25–27, 29, 30), and only two articles have employed GC–MS (22, 29).
On the grounds of the available evidence, it can be stated that drug concentrations in PF are mostly equivalent to those in peripheral blood (7–9, 31). In consequence, samples of PF can be considered as an alternative for drug quantification in cases where blood samples are not available. PF is usually available in quantities large enough, thus making it suitable for toxicological purposes. In addition, rather similar treatments and procedures to those customarily used for blood can be followed, a fact that constitutes an added advantage for the use of this particular fluid. Finally, as the PF is found within a closed compartment, contamination by microorganisms is less likely to occur (8) than in case of other samples.
A set of experiments were carried out in the quest for an efficient antidepressant extraction procedure by varying several DLLME parameters as the quantity of water, salt amounts, types of extraction and disperser solvents and quantity of biological matrix used. With respect to the volume of sample used, our method uses 0.3 mL, while other authors employ larger volumes (7, 9, 31). The use of chloroform as extracting solvent and acetonitrile as disperser solvent was also determined by Fernández et al. in a study published in 2016 (23). Finally, the method here developed was fully validated with good results in accordance with the limits approved by the FDA. The developed method was used to determine 31 PF samples. The results confirmed the presence of venlafaxine in most cases (12 cases), followed by olanzapine (4 cases), mirtazapine (3 cases), fluoxetine and sertraline (2 cases) and citalopram (1 case). No positive cases for paroxetine have been found. Fernández et al. also found venlafaxine as the most frequently used antidepressant in his study (23). However, citalopram and mirtazapine were the two antidepressants most frequently detected in Leere et al.’s study (8) followed by venlafaxine and sertraline. In the study just referred to, venlafaxine was detected in six cases, having found within four of those cases drug concentrations above the therapeutic range. In addition, one of the cases here studied revealed the presence of extremely high concentrations. Paroxetine was also poorly detected (8). In our study, high concentrations of venlafaxine were also found in three cases. All antidepressants, except one, were found in concentrations above LLOQ. Of the four cases detected for olanzapine, three of them were detected at concentrations below LLOQ.
In view of the present results, we recommend that PF should be added to the list of biological samples used in a forensic laboratory. To conclude, it is worth remarking the increase in use of PF in toxicological practice as pointed out by Contreras et al. in their analysis of morphine and cocaine (11, 32).
Conclusions
The aim of the present article is to report on an optimized analytical method to determine antidepressants using PF as a biological matrix. Sample preparation based on DLLME was employed. An experimental design setup using StatGraphics 18 and 175 µL of chloroform and 750 µL of acetonitrile as the best quantities for the extracting and disperser solvents was employed. A gas chromatograph using HP5-MS capillary column was used for the separation, and a mass spectrometer was used for the identification. Analytes were identified by their retention times and mass spectra. The method provides high precision, accuracy and recovery within the linear range of detection. Therefore, our method was found to be specific, sensitive and selective enough for the routine analysis of antidepressants in PF and for the application of the method in forensic practice. In conclusion, we have shown the usefulness of PF samples in cases where adequate blood specimens cannot be made available. The existing literature regarding drug concentrations in PF is however scarce, so further studies are in order.
Supplementary Material
bkab003_Supp Click here for additional data file.
Supplementary Data
Supplementary Data is available at Journal of Analytical Toxicology online.
Funding
This research did not receive any specific grant from funding agencies in the public, commercial, or not-for-profit sectors. | BENZODIAZEPINE, FLUOXETINE HYDROCHLORIDE, MIRTAZAPINE, PALIPERIDONE, QUETIAPINE, TOPIRAMATE | DrugsGivenReaction | CC BY | 33410888 | 18,752,851 | 2021-01-07 |
Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Choking'. | Determination of Seven Antidepressants in Pericardial Fluid by Means of Dispersive Liquid-Liquid Microextraction (DLLME) and Gas Chromatography-Mass Spectrometry (GC/MS).
Although blood is often used to detect and quantify the presence of drugs, there are some instances where samples obtained from other biological matrices, like pericardial fluid (PF), are necessary since adequate blood samples may not be available. PF is an epicardial transudate, which contains plasma components that include toxicological substances making this sample useful when blood samples are not available. This fluid is a well preserved postmortem sample and can easily be collected in larger amounts without significant contamination, compared with other body fluids. Although studies involving PF began around the 1980's, the adequacy of such fluid as a biological matrix has been poorly investigated. Antidepressants are frequently detected in postmortem samples from forensic cases. Nowadays, they constitute some of the most commonly prescribed drugs worldwide. A total of seven antidepressants (venlafaxine, mirtazapine, olanzapine, paroxetine, sertraline, fluoxetine and citalopram) were evaluated in this study. A new extraction method involving dispersive liquid-liquid microextraction (DLLME) is presented in which chloroform and acetonitrile are determined to be the best extraction and dispersing solvents. The experimental design was achieved using StatGraphics 18. The Response Surface Methodology enabled us to know the optimal volume for the two solvents used in the DLLME. The detection technique used was gas chromatography-mass spectrometry (GC-MS) with electron impact ionization as ionization source. A temperature gradient has been used and the total chromatographic separation time was 19.43 min. Validation results met the international validation guidances (FDA). Under the optimal condition, the method offered good validation parameters showing a new efficient, simple, rapid, and sensitive method. The analytical method was applied to thirty-one pericardial fluid samples. Twenty-one samples were positive with concentrations between 0.19 and 8.48 µg/mL. Venlafaxine and olanzapine were the antidepressants most frequently found.
pmcIntroduction
Depression constitutes nowadays one of the most common mental disorders either as a major condition or as a neuropsychiatric symptom characteristic of several diseases. In fact, major depressive disorder is a chronic, prevalent and pervasive brain-based disorder that significantly incapacitates the person affected (1). It is estimated that more than 350 million people worldwide are currently diagnosed with such condition, being women more frequently affected than men (2). At its worst, depression may lead to suicide. Close to 800,000 people commit suicide each year, being the second leading cause of death in 15–29-year-olds (3).
Tricyclic antidepressants (TCAs) were discovered in the 1950s, but their significant side effects led to a sustained effort in search for more selective drugs. This leads to the discovery of serotonin reuptake inhibitors, some of which (fluoxetine, sertraline and citalopram) are very commonly prescribed as first-choice drugs to treat depression. In addition, newer antidepressants, such as mirtazapine and venlafaxine, do affect both the serotonin and norepinephrine systems within the central nervous system, without the associated anticholinergic and cardiovascular side effects of older drugs such as TCAs. Mirtazapine has a dual mode of action. It is noradrenergic and specific serotonergic antidepressant that acts by antagonizing the adrenergic α2-autoreceptors and α2-heteroreceptors as well as by blocking 5-HT2 and 5-HT3 receptors. It enhances, therefore, the release of norepinephrine and 5-HT1A-mediated serotonergic transmission (4). Venlafaxine is a phenylethylamine derivative. It is a serotonin norepinephrine re-uptake inhibitor. Venlafaxine was approved by the FDA (Food and Drug Administration) for the following conditions: major depression, generalized anxiety disorder, panic disorder and social phobia (5). Olanzapine is a second-generation antipsychotic neuroleptic or “atypical antipsychotic”. These medications have more receptor-binding targets than first-generation treatments (e.g., haloperidol) do and have complex pharmacologic mechanisms of action. Olanzapine has the most binding targets in its class, binding to 10 serotonin receptors, 4 dopamine receptors, 4 acetylcholine receptors, 4 α-adrenergic receptors, 1 histamine receptor and 2 different neurotransmitter transport receptors (6).
Within the forensic practice, it is important to investigate postmortem drug concentrations to discriminate whether the cause of death was due to intoxication, side effects of the undergoing treatment or lack of compliance. Urine and blood specimens are the main biological samples used in forensic autopsy cases, being peripheral blood the most used in postmortem research. Moreover, special care must be taken in the interpretation of the data when using postmortem blood samples as these concentrations may change due to several factors such as chemical/enzymatic degradation of substances, redistribution phenomena and postmortem diffusion from solid organs or gastric content, especially with cardiac blood since it is more affected by postmortem redistribution (7). However, it should be borne in mind that blood analysis will be always a fundamental and essential step since it enables one to know the toxicological status of the deceased at the time of death. In addition to blood or urine samples, one may consider pericardial fluid (PF) as a useful alternative matrix in cases where adequate peripheral blood samples cannot be obtained. The potential use of PF samples has been considered within relatively few reports (7–13). Previous studies showed good correlation with the drug concentrations in peripheral blood (8, 10, 14, 15). PF is a well-preserved postmortem material in cases without structural damage due to injury or medical intervention and can easily be collected in large amounts without significant contamination as it is contained within a tight compartment (pericardial sac), compared with other body fluids (13). With a volume of 15–35 mL, it is believed to be a transudate generated by the net result of the hydrostatic pressure and the osmotic gradient between plasma and PF. The composition of the normal human PF is difficult to define. The hematological and biochemical analyses of the PF show that the concentration of electrolytes and small molecules (urea, uric acid, glucose and creatinine) corresponds to an ultrafiltrate of plasma (7, 13).
Previous works using liquid–liquid extraction or solid phase extraction have been reported (7–9, 12). In particular, efforts were oriented towards the development of efficient and miniaturized sample preparation methods. Liquid-phase microextraction (LPME) was introduced according to this perspective. Dispersive liquid–liquid microextraction (DLLME) is one of the LPME methods and has attracted recent interest within the analytical chemists’ community (16). The method was introduced by Assadi and co-workers in 2006 (17). It is a simple and fast microextraction technique based upon the use of an appropriate extractant (an organic solvent with high density) and a disperser solvent with high miscibility in both extractant and aqueous phases. DLLME consists of two steps: (i) injection of an appropriate mixture of extracting and disperser solvents into an aqueous sample, containing the analytes. In this step, the extracting solvent is dispersed into the aqueous sample as very fine droplets and the analytes are enriched into it. After the formation of a cloudy solution, the surface area between the extracting solvent and the aqueous sample becomes very large, so the equilibrium state is quickly attained and, therefore, the extraction time is very short. In fact, this is the principal advantage of this method. (ii) Centrifugation of the cloudy solution, thereby obtaining a settled phase that is deposited at the bottom of a conical tube. Other advantages include simplicity of operation, rapidity, low cost, high recovery, high enrichment factor and environment benignity (18). Like the other analytical methods, DLLME has some disadvantages, which result from the requirements related to the organic extraction and disperser solvents. The extraction solvent used should have some special requirements, such as a density larger than water for simple separation of the extraction phase after centrifugation and to form a cloudy solution in the presence of the disperser solvent. The potential organic solvents meeting this requirement are limited since they are hazardous chemicals (such as halogenated hydrocarbons). It is precisely because of this the choice of the extraction solvent becomes the method’s primary limitation (16). According to detection techniques, several methods were used involving liquid chromatography as well as gas chromatography (7–9, 12).
The aim of this study was to develop a gas chromatography–mass spectrometry (GC–MS) method for the determination and quantification of antidepressants in PF using DLLME as a new extraction method. The validation of the method was carried out according to the guidelines of the FDA (19). The method was then applied to PF samples collected from deceased people.
Material and Methods
Chemicals
Acetonitrile and chloroform gradient grade solvents were purchased from Merck® (Madrid, Spain) and sodium chloride from Panreac® (Barcelona, Spain). Fluoxetine, venlafaxine, mirtazapine, sertraline, citalopram, olanzapine, paroxetine and proadifen (SKF), used as internal standard, were obtained from Cerilliant®. Distilled water was processed through a Milli-Q water system (Millipore, Bedford, MA, USA).
Matrix collection
To carry out the validation procedure, antidepressant-free PF obtained from autopsies was used. For this purpose, a mixture of PF from deceased subjects was collected and stored at –20°C until use, following a previous peripheral blood and urine analysis that was negative to antidepressants.
Sample preparation
PF used for validation was previously ultracentrifuged for 5 min at 14,000 rpm. Aliquots of 0.3 mL were used for analysis, collected in a glass tube and spiked with Proadifen (SKF) (20 µL Sol. 10 µg/mL). Then, it was diluted with water (1.1 mL) and 150 mg of NaCl was also added to facilitate analytes’ transition from aqueous phase to organic phase. This mixture was submited to the DLLME. After an experimental design using StatGraphics (StatGraphics Technologies, Inc.), the optimal conditions were as follows: 175 uL of chloroform and 750 uL of acetonitrile as the best extracting and disperser solvents, respectively. Both solvents were rapidly injected into the sample with a Pasteur pipette and the mixture was gently shaken. Then, the mixture was centrifuged, and the droplet formed was collected by a 100 µL syringe and transferred to an 8 mL glass tube. The organic solvent was evaporated under a stream of nitrogen in a heated aluminum block at 40°C (VLM GmbH, HP series). The dried residue was redissolved with 40 µL of methanol prior to injection of a 2 µL aliquot into the GC–MS system.
Instrumentation
Chromatographic analyses were performed using an electron impact ionization gas chromatograph model 7890 B from Agilent Technologies® (Las Rozas, Spain) interfaced to a mass selective detector (MSD) model 5977 B, also from Agilent Technologies®. An HP5-MS capillary column (30 m × 250 µm i.d., 0.5 µm film thickness; Agilent Technologies®) with helium as carrier gas (1 mL/min) was used for the gas chromatographic separation. The injector temperature was set at 250°C and a purge time of 2 min was used. Samples were injected in the splitless mode. The following temperature program was applied: the initial temperature of the column was 100°C for 1 min, then ramped-up progressively at 35°C/min up to 220°C, held constant for 1 min, and then ramped-up again at 8°C/min up to 260°C and held for 2 min. Finally, the temperature was ramped-up at 5°C/min up to 280°C for 3 min. After that, the temperature was increased to 290°C for 5 min to clean the column. The total chromatographic separation time was 19.43 min, and the total run time was 24.43 min. The MSD was kept at 300°C, the ion source at 230°C and the quadrupole at 150°C.
Identification of compounds
Initially, neat standards of all antidepressants were injected and analyzed using the full scan mode of the GC–MS, which scanned from 50 to 550 amu. Quantifier and qualifier ions used for each analyte were selected based on their abundances and mass-to-charge ratios (m/z). Because of their reproducibilities and lack of interference, high mass ions were selected whenever possible. The ions selected for each compound studied and the retention times are shown in Table I. Upon selection of ion, the mass spectrometry was run in selected ion monitoring mode (Figure 1).
Table I. Retention Times and Ions Selected for Monitorization
Analyte Quantifier ion, m/z Qualifier ions, m/z Retention time, min
Fluoxetine 104 148, 309 7.78
Venlafaxine 58 134, 179 9.97
Mirtazapine 195 208, 245 11.78
SKF 86 99, 165 12.30
Sertraline 274 276, 262 13.55
Citalopram 58 238, 324 13.20
Paroxetine 192 138, 329 16.09
Olanzapine 242 229, 207 18.50
Figure 1. Extracted ionic chromatogram of all analytes.
Results
Experimental design
To find the best conditions for DLLME, 18 replicates were performed using a 2 × 4 factorial design with four factors: sample volume, water volume, extracting solvent volume and disperser solvent volume. The experimental design was achieved using Statgraphics 18. To make this design rotatable, for each factor, two axial points were chosen, and the runs were randomized to exclude the block effects. Response surface methodology (RSM) is a combination of mathematical and statistical techniques used to study the relationship between two or more responses that depend on several factors or independent variables. The final goal of RSM is to optimize responses determining the best conditions in the operation of the system. Our design of response surface was obtained using the statistical software StatGraphics (Figure 2).
Figure 2. Response surface graph.
Validation of the method
Validation was achieved according to the FDA Guideline for Bioanalytical Method Validation (19). The suitability of the method for quantitative analysis was studied by testing selectivity, linearity and sensitivity, precision and accuracy and recovery.
Selectivity
Selectivity is the ability of an analytical method to differentiate and quantify the analyte in the presence of other components in the sample. It should confirm that the assay is free of potential interfering substances, include endogenous matrix components, metabolites, decomposition products and medication and other exogenous xenobiotics. The selectivity of the method was demonstrated by analyzing six blank PF samples (19). No interfering peaks were found at the retention time for all analytes (Figure 3).
Figure 3. Chromatogram of a blank PF.
Linearity
Standard addition curves were obtained in six runs with the described method using drug-free control PF spiked with standard solutions to obtain the range of concentrations shown in Table II. The curves were obtained by fitting the ratio of the peak areas of analytes to that of IS versus concentrations. A linear response was observed in the studied range with a good correlation coefficient (higher than 0.99 in all cases). The sensitivity of the method was determined by calculation of the limit of detection (LOD) and the lower limit of quantification (LLOQ). LOD was determined by an empirical method that consists of analyzing a series of PF samples containing decreasing amounts of the analytes. LOD was the lowest concentration that presented a signal-to-noise ratio higher than 3 for at least three diagnostic ions for each substance. The LLOQ was the lowest concentration of analytes in a sample that can be determined with appropriate precision (20%) and accuracy (80–120%) (19) (Table II).
Table II. LOD, Limit of Quantification and Calibration Results for the Antidepressants Studied
Analyte LOD (µg/mL) LLOQ (µg/mL) C. coef. Range of calibration (µg/mL)
Fluoxetine 0.05 0.2 0.991 0.2–10
Venlafaxine 0.01 0.02 0.991 0.02–10
Mirtazapine 0.01 0.02 0.997 0.02–5
Sertraline 0.005 0.2 0.992 0.2–5
Citalopram 0.01 0.04 0.995 0.04–5
Olanzapine 0.02 0.2 0.993 0.2–10
Paroxetine 0.2 1 0.997 1–10
C. coef., correlation coefficient.
Precision and accuracy
The accuracy of an analytical method describes the closeness of mean test results obtained by the method to the true value (concentration) of the analyte. The precision of an analytical method describes the closeness of individual measures of an analyte when the procedure is applied repeatedly to multiple aliquots of a single homogeneous volume of biological matrix. Precision and accuracy were determined by inter- and intra-day assay. Inter-day precision and accuracy were calculated by analyzing negative PF samples spiked with the antidepressants at three concentrations; the LLOQ, the upper limit of quantification and an intermediate level were assessed by analyzing five replicates each day in five different days for each level of concentration. Intra-day precision and accuracy were determined at three concentrations, by preparing and analyzing five replicates for each level on the same day. Precision, expressed as the coefficient of variation of the measured values, was expected to be less than 15% at all concentrations, except for the LLOQ for which 20% was acceptable. In the same way, accuracy was evaluated using the mean relative error (ME), which had to be less than 15% of the theoretical values at each concentration level except for the LLOQ, for which 20% was acceptable (19). Data presented in Table III (Supplementary Material) satisfied the international validation rules.
Table III. Intra- and Inter-Day Precision and Accuracy (ME) of the Method
Intra-day study (n = 5) Inter-day study (n = 5)
Concentrations (μg/mL) ME (%) RSD (%) ME (%) RSD (%)
Fluoxetine
0.2 17 5 14 10
5 6 5 8 4
10 6 7 1 5
Venlafaxine
0.02 18 8 14 7
5 6 3 5 3
10 2 5 1 4
Mirtazapine
0.02 19 3 16 6
2.5 11 2 6 2
5 1 4 3 6
Sertraline
0.2 17 7 18 7
2.5 8 5 6 3
5 2 8 1 4
Citalopram
0.04 17 10 13 7
2.5 5 4 4 3
5 1 4 2 3
Paroxetine
1 13 12 13 12
5 8 15 9 12
10 14 12 1 7
Olanzapine
0.2 12 14 19 5
5 14 3 9 6
10 6 3 2 7
RSD: Relative Standard Deviation.
Recovery
The recovery of an analyte is the detector response obtained from an amount of the analyte added to an extracted from the biological matrix, compared to the detector response obtained for the true concentration of the pure authentic standard (19). The recovery of the method was examined by comparing the analytical results for extracted samples at three levels of concentration (high, medium and low) five times within three days with theoretical concentration that represent 100% recovery. The data obtained demonstrates that the extraction procedure is particularly efficient, providing a recovery values ranged from 85 to 105% for all compounds. The results are shown in Table IV (Supplementary Material).
Table IV. Intra and Inter-Day Accuracy (Analytical Recovery) of the Method
Intra-day study (n = 5) Inter-day study (n = 5)
Concentrations (μg/mL) Recovery (%) Recovery (%)
Fluoxetine
0.2 98 89
5 93 91
10 94 100
Venlafaxine
0.02 92 95
5 93 95
10 98 99
Mirtazapine
0.02 85 94
2.5 89 94
5 92 97
Sertraline
0.2 97 98
2.5 91 94
5 98 99
Citalopram
0.04 93 105
2.5 95 96
5 99 98
Paroxetine
1 93 93
5 91 91
10 94 101
Olanzapine
0.2 89 89
5 85 90
10 87 98
Application to real cases
The developed method was used to analyze 31 real PF samples obtained from the Forensic Toxicology Service of the Institute of Forensic Sciences of Santiago de Compostela from cases including suicide, overdose or death from unknown causes. Some information is described in Table V. From the 31 cases, 21 were positive for at least one of the substances analyzed. Venlafaxine and olanzapine were the two antidepressants most frequently found in 12 and 4 cases, respectively. There were also positive cases for mirtazapine, fluoxetine, sertraline and citalopram. Three samples were positive for several compounds at the same time. Figures 4 and 5 show real cases analyzed in our laboratory with their corresponding mass spectra (Figures 6 and 7). One of them corresponds to a female whose cause of death was hanging after having consumed high amounts of several drugs and the other case belongs to a male poisoned by carbon monoxide.
Table V. Real Cases
Case no. Age Sex Sample Cause of death General information and treatment Substance detected
(years) [µg/mL]
1 82 Female Blood, urine and PF Pulmonary embolism Depressive disorder Mirtazapine [0.48]
2 83 Female Blood, urine and PF Traumatic brain injury Duloxetine, bromazepam, quetiapine, tramadol and metamizol –
3 42 Female Blood, urine and PF Suicide Psychiatric treatment for schizophrenia. Lormetazepam and paliperidone Venlafaxine [0.27]
4 32 Female Blood and PF Suicide Depressive disorder. Risperidone, benzodiazepines and olanzapine Olanzapine <LLOQ
5 56 Female Blood, urine and PF Suicide Venlafaxine and benzodiazepines Venlafaxine [3.44]
6 45 Male Blood, urine, vitreous humor and PF Suicide Past history of drug abuse Venlafaxine [0.27]
7 52 Male Blood, vitreous humor and PF Acute myocardial infarction Depressive disorder –
8 45 Male Blood and PF Possible cardiac death Paranoid Schizophrenia. Valproic acid –
9 60 Female Blood, urine, gastric content, hair, PF and nail Suicide Ketazolam and bromazepam Venlafaxine [0.28]
10 67 Male Blood, urine and PF Choking suffocation Olanzapine Venlafaxine [0.28] and olanzapine <LLOQ
11 37 Male Blood, urine, bile, vitreous humor and PF – Drinker and smoker –
12 32 Male Blood, urine and PF Fall Depressive disorder. Haloperidol, olanzapine and flufenazine, Venlafaxine [0.27] and olanzapine [0.23]
13 64 Female Blood, urine, hair, vitreous humor, bile and PF Methanol poisoning – –
14 65 Male Blood, urine, gastric content and PF Suspected suicide Heptaminol hidroclorure, sertraline –
15 83 Male Blood, urine and PF Suicide Pregabaline, carbamazepine, clonazepam and mirtazapine Mirtazapine [0.19]
16 48 Male Blood, urine and PF Adverse drug reaction Fluoxetine, lormetazepam, lorazepam, alprazolam, clozapine, cocaine and dipotassium chlorazepate Fluoxetine [0.63]
17 75 Female Blood, urine, gastric content and PF Drug overdose Tramadol, ciclobenzaprine, ketazolam and lorazepam Venlafaxine [8.48]
18 70 Female Blood, urine and PF Suicide Venlafaxine and lorazepam Venlafaxine [0.81]
19 89 Female Blood, gastric content and PF Previous depressive episodes Lorazepam and olanzapine Olanzapine <LLOQ
20 75 Female Blood, urine and PF Natural Alprazolam, trazodone, venlafaxine and quietiapine Venlafaxine [0.95]
21 47 Female Blood, urine and PF Natural Depressive and personality disorder. Alprazolam and paroxetine –
22 56 Male Blood, urine and PF Cardiac death – –
23 35 Male Blood, vitreous humor and PF Choking suffocation Benzodiacepines, topiramate, fluoxetine, paliperidone, quetiapine and mirtazapine Mirtazapine [0.39] and fluoxetine [0.20]
24 36 Male Blood, urine, vitreous humor and PF Suicide Depressive disorder –
25 61 Male Blood, urine, vitreous humor and PF Natural Bipolar disorder. Alcohol consumption. Benzodiacepines, pregabaline, sertraline and olanzapine Sertraline [0.23]
26 86 Male Blood, urine, vitreous humor and PF Carbon monoxide poisoning Sertraline, trazodone and lorazepam Sertraline [0.48]
27 73 Female Blood, urine, vitreous humor and PF Suffocation from airway occlusion Benzodiacepines and venlafaxine Venlafaxine [0.62]
28 60 Female Blood, urine and PF Empyema Alcohol consumption. Mirtazapine, quetiapine and benzodiapcepines Citalopram [0.27]
29 40 Female Blood, vitreous humor and PF Suicide Depressive disorder. Venlafaxine, benzodiacepines, clomipramine and trazodone, Venlafaxine [3.84]
30 55 Female Blood, vitreous humor and PF Natural – –
31 52 Male Blood, urine, vitreous humor and PF Suicide Depressive disorder Venlafaxine [0.33]
PF, pericardial fluid.
Figure 4. Chromatogram of a real sample (positive for venlafaxine).
Figure 5. Chromatogram of a real sample (positive for sertraline).
Figure 6. Venlafaxine mass spectra.
Figure 7. Sertraline mass spectra.
Discussion
The present work aims to contribute toward the development of methods able to quantify the presence of antidepressants in samples of PF in cases where adequate blood samples may not be available. Previous literature reports comprise only a few articles where PF is used as a biological sample for the determination of drugs (7, 8, 15). The DLLME was one of the techniques used by several authors to extract antidepressants, but only one author determined the concentration of these compounds in PF (8, 16, 20–30). Most of the articles published so far used the DLLME technique coupled to another extraction method (16, 20, 22–24, 26, 27), but few papers have followed a similar method to ours (21, 25, 28–30). Most of them employed urine as the biological matrix (25, 28–30), while Lima et al. used water samples (21). Most of the published research dealt with TCAs as the particular drugs under study (16, 20, 25–27, 29, 30), and only two articles have employed GC–MS (22, 29).
On the grounds of the available evidence, it can be stated that drug concentrations in PF are mostly equivalent to those in peripheral blood (7–9, 31). In consequence, samples of PF can be considered as an alternative for drug quantification in cases where blood samples are not available. PF is usually available in quantities large enough, thus making it suitable for toxicological purposes. In addition, rather similar treatments and procedures to those customarily used for blood can be followed, a fact that constitutes an added advantage for the use of this particular fluid. Finally, as the PF is found within a closed compartment, contamination by microorganisms is less likely to occur (8) than in case of other samples.
A set of experiments were carried out in the quest for an efficient antidepressant extraction procedure by varying several DLLME parameters as the quantity of water, salt amounts, types of extraction and disperser solvents and quantity of biological matrix used. With respect to the volume of sample used, our method uses 0.3 mL, while other authors employ larger volumes (7, 9, 31). The use of chloroform as extracting solvent and acetonitrile as disperser solvent was also determined by Fernández et al. in a study published in 2016 (23). Finally, the method here developed was fully validated with good results in accordance with the limits approved by the FDA. The developed method was used to determine 31 PF samples. The results confirmed the presence of venlafaxine in most cases (12 cases), followed by olanzapine (4 cases), mirtazapine (3 cases), fluoxetine and sertraline (2 cases) and citalopram (1 case). No positive cases for paroxetine have been found. Fernández et al. also found venlafaxine as the most frequently used antidepressant in his study (23). However, citalopram and mirtazapine were the two antidepressants most frequently detected in Leere et al.’s study (8) followed by venlafaxine and sertraline. In the study just referred to, venlafaxine was detected in six cases, having found within four of those cases drug concentrations above the therapeutic range. In addition, one of the cases here studied revealed the presence of extremely high concentrations. Paroxetine was also poorly detected (8). In our study, high concentrations of venlafaxine were also found in three cases. All antidepressants, except one, were found in concentrations above LLOQ. Of the four cases detected for olanzapine, three of them were detected at concentrations below LLOQ.
In view of the present results, we recommend that PF should be added to the list of biological samples used in a forensic laboratory. To conclude, it is worth remarking the increase in use of PF in toxicological practice as pointed out by Contreras et al. in their analysis of morphine and cocaine (11, 32).
Conclusions
The aim of the present article is to report on an optimized analytical method to determine antidepressants using PF as a biological matrix. Sample preparation based on DLLME was employed. An experimental design setup using StatGraphics 18 and 175 µL of chloroform and 750 µL of acetonitrile as the best quantities for the extracting and disperser solvents was employed. A gas chromatograph using HP5-MS capillary column was used for the separation, and a mass spectrometer was used for the identification. Analytes were identified by their retention times and mass spectra. The method provides high precision, accuracy and recovery within the linear range of detection. Therefore, our method was found to be specific, sensitive and selective enough for the routine analysis of antidepressants in PF and for the application of the method in forensic practice. In conclusion, we have shown the usefulness of PF samples in cases where adequate blood specimens cannot be made available. The existing literature regarding drug concentrations in PF is however scarce, so further studies are in order.
Supplementary Material
bkab003_Supp Click here for additional data file.
Supplementary Data
Supplementary Data is available at Journal of Analytical Toxicology online.
Funding
This research did not receive any specific grant from funding agencies in the public, commercial, or not-for-profit sectors. | BENZODIAZEPINE, FLUOXETINE HYDROCHLORIDE, MIRTAZAPINE, PALIPERIDONE, QUETIAPINE, TOPIRAMATE | DrugsGivenReaction | CC BY | 33410888 | 18,752,851 | 2021-01-07 |
Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Off label use'. | Determination of Seven Antidepressants in Pericardial Fluid by Means of Dispersive Liquid-Liquid Microextraction (DLLME) and Gas Chromatography-Mass Spectrometry (GC/MS).
Although blood is often used to detect and quantify the presence of drugs, there are some instances where samples obtained from other biological matrices, like pericardial fluid (PF), are necessary since adequate blood samples may not be available. PF is an epicardial transudate, which contains plasma components that include toxicological substances making this sample useful when blood samples are not available. This fluid is a well preserved postmortem sample and can easily be collected in larger amounts without significant contamination, compared with other body fluids. Although studies involving PF began around the 1980's, the adequacy of such fluid as a biological matrix has been poorly investigated. Antidepressants are frequently detected in postmortem samples from forensic cases. Nowadays, they constitute some of the most commonly prescribed drugs worldwide. A total of seven antidepressants (venlafaxine, mirtazapine, olanzapine, paroxetine, sertraline, fluoxetine and citalopram) were evaluated in this study. A new extraction method involving dispersive liquid-liquid microextraction (DLLME) is presented in which chloroform and acetonitrile are determined to be the best extraction and dispersing solvents. The experimental design was achieved using StatGraphics 18. The Response Surface Methodology enabled us to know the optimal volume for the two solvents used in the DLLME. The detection technique used was gas chromatography-mass spectrometry (GC-MS) with electron impact ionization as ionization source. A temperature gradient has been used and the total chromatographic separation time was 19.43 min. Validation results met the international validation guidances (FDA). Under the optimal condition, the method offered good validation parameters showing a new efficient, simple, rapid, and sensitive method. The analytical method was applied to thirty-one pericardial fluid samples. Twenty-one samples were positive with concentrations between 0.19 and 8.48 µg/mL. Venlafaxine and olanzapine were the antidepressants most frequently found.
pmcIntroduction
Depression constitutes nowadays one of the most common mental disorders either as a major condition or as a neuropsychiatric symptom characteristic of several diseases. In fact, major depressive disorder is a chronic, prevalent and pervasive brain-based disorder that significantly incapacitates the person affected (1). It is estimated that more than 350 million people worldwide are currently diagnosed with such condition, being women more frequently affected than men (2). At its worst, depression may lead to suicide. Close to 800,000 people commit suicide each year, being the second leading cause of death in 15–29-year-olds (3).
Tricyclic antidepressants (TCAs) were discovered in the 1950s, but their significant side effects led to a sustained effort in search for more selective drugs. This leads to the discovery of serotonin reuptake inhibitors, some of which (fluoxetine, sertraline and citalopram) are very commonly prescribed as first-choice drugs to treat depression. In addition, newer antidepressants, such as mirtazapine and venlafaxine, do affect both the serotonin and norepinephrine systems within the central nervous system, without the associated anticholinergic and cardiovascular side effects of older drugs such as TCAs. Mirtazapine has a dual mode of action. It is noradrenergic and specific serotonergic antidepressant that acts by antagonizing the adrenergic α2-autoreceptors and α2-heteroreceptors as well as by blocking 5-HT2 and 5-HT3 receptors. It enhances, therefore, the release of norepinephrine and 5-HT1A-mediated serotonergic transmission (4). Venlafaxine is a phenylethylamine derivative. It is a serotonin norepinephrine re-uptake inhibitor. Venlafaxine was approved by the FDA (Food and Drug Administration) for the following conditions: major depression, generalized anxiety disorder, panic disorder and social phobia (5). Olanzapine is a second-generation antipsychotic neuroleptic or “atypical antipsychotic”. These medications have more receptor-binding targets than first-generation treatments (e.g., haloperidol) do and have complex pharmacologic mechanisms of action. Olanzapine has the most binding targets in its class, binding to 10 serotonin receptors, 4 dopamine receptors, 4 acetylcholine receptors, 4 α-adrenergic receptors, 1 histamine receptor and 2 different neurotransmitter transport receptors (6).
Within the forensic practice, it is important to investigate postmortem drug concentrations to discriminate whether the cause of death was due to intoxication, side effects of the undergoing treatment or lack of compliance. Urine and blood specimens are the main biological samples used in forensic autopsy cases, being peripheral blood the most used in postmortem research. Moreover, special care must be taken in the interpretation of the data when using postmortem blood samples as these concentrations may change due to several factors such as chemical/enzymatic degradation of substances, redistribution phenomena and postmortem diffusion from solid organs or gastric content, especially with cardiac blood since it is more affected by postmortem redistribution (7). However, it should be borne in mind that blood analysis will be always a fundamental and essential step since it enables one to know the toxicological status of the deceased at the time of death. In addition to blood or urine samples, one may consider pericardial fluid (PF) as a useful alternative matrix in cases where adequate peripheral blood samples cannot be obtained. The potential use of PF samples has been considered within relatively few reports (7–13). Previous studies showed good correlation with the drug concentrations in peripheral blood (8, 10, 14, 15). PF is a well-preserved postmortem material in cases without structural damage due to injury or medical intervention and can easily be collected in large amounts without significant contamination as it is contained within a tight compartment (pericardial sac), compared with other body fluids (13). With a volume of 15–35 mL, it is believed to be a transudate generated by the net result of the hydrostatic pressure and the osmotic gradient between plasma and PF. The composition of the normal human PF is difficult to define. The hematological and biochemical analyses of the PF show that the concentration of electrolytes and small molecules (urea, uric acid, glucose and creatinine) corresponds to an ultrafiltrate of plasma (7, 13).
Previous works using liquid–liquid extraction or solid phase extraction have been reported (7–9, 12). In particular, efforts were oriented towards the development of efficient and miniaturized sample preparation methods. Liquid-phase microextraction (LPME) was introduced according to this perspective. Dispersive liquid–liquid microextraction (DLLME) is one of the LPME methods and has attracted recent interest within the analytical chemists’ community (16). The method was introduced by Assadi and co-workers in 2006 (17). It is a simple and fast microextraction technique based upon the use of an appropriate extractant (an organic solvent with high density) and a disperser solvent with high miscibility in both extractant and aqueous phases. DLLME consists of two steps: (i) injection of an appropriate mixture of extracting and disperser solvents into an aqueous sample, containing the analytes. In this step, the extracting solvent is dispersed into the aqueous sample as very fine droplets and the analytes are enriched into it. After the formation of a cloudy solution, the surface area between the extracting solvent and the aqueous sample becomes very large, so the equilibrium state is quickly attained and, therefore, the extraction time is very short. In fact, this is the principal advantage of this method. (ii) Centrifugation of the cloudy solution, thereby obtaining a settled phase that is deposited at the bottom of a conical tube. Other advantages include simplicity of operation, rapidity, low cost, high recovery, high enrichment factor and environment benignity (18). Like the other analytical methods, DLLME has some disadvantages, which result from the requirements related to the organic extraction and disperser solvents. The extraction solvent used should have some special requirements, such as a density larger than water for simple separation of the extraction phase after centrifugation and to form a cloudy solution in the presence of the disperser solvent. The potential organic solvents meeting this requirement are limited since they are hazardous chemicals (such as halogenated hydrocarbons). It is precisely because of this the choice of the extraction solvent becomes the method’s primary limitation (16). According to detection techniques, several methods were used involving liquid chromatography as well as gas chromatography (7–9, 12).
The aim of this study was to develop a gas chromatography–mass spectrometry (GC–MS) method for the determination and quantification of antidepressants in PF using DLLME as a new extraction method. The validation of the method was carried out according to the guidelines of the FDA (19). The method was then applied to PF samples collected from deceased people.
Material and Methods
Chemicals
Acetonitrile and chloroform gradient grade solvents were purchased from Merck® (Madrid, Spain) and sodium chloride from Panreac® (Barcelona, Spain). Fluoxetine, venlafaxine, mirtazapine, sertraline, citalopram, olanzapine, paroxetine and proadifen (SKF), used as internal standard, were obtained from Cerilliant®. Distilled water was processed through a Milli-Q water system (Millipore, Bedford, MA, USA).
Matrix collection
To carry out the validation procedure, antidepressant-free PF obtained from autopsies was used. For this purpose, a mixture of PF from deceased subjects was collected and stored at –20°C until use, following a previous peripheral blood and urine analysis that was negative to antidepressants.
Sample preparation
PF used for validation was previously ultracentrifuged for 5 min at 14,000 rpm. Aliquots of 0.3 mL were used for analysis, collected in a glass tube and spiked with Proadifen (SKF) (20 µL Sol. 10 µg/mL). Then, it was diluted with water (1.1 mL) and 150 mg of NaCl was also added to facilitate analytes’ transition from aqueous phase to organic phase. This mixture was submited to the DLLME. After an experimental design using StatGraphics (StatGraphics Technologies, Inc.), the optimal conditions were as follows: 175 uL of chloroform and 750 uL of acetonitrile as the best extracting and disperser solvents, respectively. Both solvents were rapidly injected into the sample with a Pasteur pipette and the mixture was gently shaken. Then, the mixture was centrifuged, and the droplet formed was collected by a 100 µL syringe and transferred to an 8 mL glass tube. The organic solvent was evaporated under a stream of nitrogen in a heated aluminum block at 40°C (VLM GmbH, HP series). The dried residue was redissolved with 40 µL of methanol prior to injection of a 2 µL aliquot into the GC–MS system.
Instrumentation
Chromatographic analyses were performed using an electron impact ionization gas chromatograph model 7890 B from Agilent Technologies® (Las Rozas, Spain) interfaced to a mass selective detector (MSD) model 5977 B, also from Agilent Technologies®. An HP5-MS capillary column (30 m × 250 µm i.d., 0.5 µm film thickness; Agilent Technologies®) with helium as carrier gas (1 mL/min) was used for the gas chromatographic separation. The injector temperature was set at 250°C and a purge time of 2 min was used. Samples were injected in the splitless mode. The following temperature program was applied: the initial temperature of the column was 100°C for 1 min, then ramped-up progressively at 35°C/min up to 220°C, held constant for 1 min, and then ramped-up again at 8°C/min up to 260°C and held for 2 min. Finally, the temperature was ramped-up at 5°C/min up to 280°C for 3 min. After that, the temperature was increased to 290°C for 5 min to clean the column. The total chromatographic separation time was 19.43 min, and the total run time was 24.43 min. The MSD was kept at 300°C, the ion source at 230°C and the quadrupole at 150°C.
Identification of compounds
Initially, neat standards of all antidepressants were injected and analyzed using the full scan mode of the GC–MS, which scanned from 50 to 550 amu. Quantifier and qualifier ions used for each analyte were selected based on their abundances and mass-to-charge ratios (m/z). Because of their reproducibilities and lack of interference, high mass ions were selected whenever possible. The ions selected for each compound studied and the retention times are shown in Table I. Upon selection of ion, the mass spectrometry was run in selected ion monitoring mode (Figure 1).
Table I. Retention Times and Ions Selected for Monitorization
Analyte Quantifier ion, m/z Qualifier ions, m/z Retention time, min
Fluoxetine 104 148, 309 7.78
Venlafaxine 58 134, 179 9.97
Mirtazapine 195 208, 245 11.78
SKF 86 99, 165 12.30
Sertraline 274 276, 262 13.55
Citalopram 58 238, 324 13.20
Paroxetine 192 138, 329 16.09
Olanzapine 242 229, 207 18.50
Figure 1. Extracted ionic chromatogram of all analytes.
Results
Experimental design
To find the best conditions for DLLME, 18 replicates were performed using a 2 × 4 factorial design with four factors: sample volume, water volume, extracting solvent volume and disperser solvent volume. The experimental design was achieved using Statgraphics 18. To make this design rotatable, for each factor, two axial points were chosen, and the runs were randomized to exclude the block effects. Response surface methodology (RSM) is a combination of mathematical and statistical techniques used to study the relationship between two or more responses that depend on several factors or independent variables. The final goal of RSM is to optimize responses determining the best conditions in the operation of the system. Our design of response surface was obtained using the statistical software StatGraphics (Figure 2).
Figure 2. Response surface graph.
Validation of the method
Validation was achieved according to the FDA Guideline for Bioanalytical Method Validation (19). The suitability of the method for quantitative analysis was studied by testing selectivity, linearity and sensitivity, precision and accuracy and recovery.
Selectivity
Selectivity is the ability of an analytical method to differentiate and quantify the analyte in the presence of other components in the sample. It should confirm that the assay is free of potential interfering substances, include endogenous matrix components, metabolites, decomposition products and medication and other exogenous xenobiotics. The selectivity of the method was demonstrated by analyzing six blank PF samples (19). No interfering peaks were found at the retention time for all analytes (Figure 3).
Figure 3. Chromatogram of a blank PF.
Linearity
Standard addition curves were obtained in six runs with the described method using drug-free control PF spiked with standard solutions to obtain the range of concentrations shown in Table II. The curves were obtained by fitting the ratio of the peak areas of analytes to that of IS versus concentrations. A linear response was observed in the studied range with a good correlation coefficient (higher than 0.99 in all cases). The sensitivity of the method was determined by calculation of the limit of detection (LOD) and the lower limit of quantification (LLOQ). LOD was determined by an empirical method that consists of analyzing a series of PF samples containing decreasing amounts of the analytes. LOD was the lowest concentration that presented a signal-to-noise ratio higher than 3 for at least three diagnostic ions for each substance. The LLOQ was the lowest concentration of analytes in a sample that can be determined with appropriate precision (20%) and accuracy (80–120%) (19) (Table II).
Table II. LOD, Limit of Quantification and Calibration Results for the Antidepressants Studied
Analyte LOD (µg/mL) LLOQ (µg/mL) C. coef. Range of calibration (µg/mL)
Fluoxetine 0.05 0.2 0.991 0.2–10
Venlafaxine 0.01 0.02 0.991 0.02–10
Mirtazapine 0.01 0.02 0.997 0.02–5
Sertraline 0.005 0.2 0.992 0.2–5
Citalopram 0.01 0.04 0.995 0.04–5
Olanzapine 0.02 0.2 0.993 0.2–10
Paroxetine 0.2 1 0.997 1–10
C. coef., correlation coefficient.
Precision and accuracy
The accuracy of an analytical method describes the closeness of mean test results obtained by the method to the true value (concentration) of the analyte. The precision of an analytical method describes the closeness of individual measures of an analyte when the procedure is applied repeatedly to multiple aliquots of a single homogeneous volume of biological matrix. Precision and accuracy were determined by inter- and intra-day assay. Inter-day precision and accuracy were calculated by analyzing negative PF samples spiked with the antidepressants at three concentrations; the LLOQ, the upper limit of quantification and an intermediate level were assessed by analyzing five replicates each day in five different days for each level of concentration. Intra-day precision and accuracy were determined at three concentrations, by preparing and analyzing five replicates for each level on the same day. Precision, expressed as the coefficient of variation of the measured values, was expected to be less than 15% at all concentrations, except for the LLOQ for which 20% was acceptable. In the same way, accuracy was evaluated using the mean relative error (ME), which had to be less than 15% of the theoretical values at each concentration level except for the LLOQ, for which 20% was acceptable (19). Data presented in Table III (Supplementary Material) satisfied the international validation rules.
Table III. Intra- and Inter-Day Precision and Accuracy (ME) of the Method
Intra-day study (n = 5) Inter-day study (n = 5)
Concentrations (μg/mL) ME (%) RSD (%) ME (%) RSD (%)
Fluoxetine
0.2 17 5 14 10
5 6 5 8 4
10 6 7 1 5
Venlafaxine
0.02 18 8 14 7
5 6 3 5 3
10 2 5 1 4
Mirtazapine
0.02 19 3 16 6
2.5 11 2 6 2
5 1 4 3 6
Sertraline
0.2 17 7 18 7
2.5 8 5 6 3
5 2 8 1 4
Citalopram
0.04 17 10 13 7
2.5 5 4 4 3
5 1 4 2 3
Paroxetine
1 13 12 13 12
5 8 15 9 12
10 14 12 1 7
Olanzapine
0.2 12 14 19 5
5 14 3 9 6
10 6 3 2 7
RSD: Relative Standard Deviation.
Recovery
The recovery of an analyte is the detector response obtained from an amount of the analyte added to an extracted from the biological matrix, compared to the detector response obtained for the true concentration of the pure authentic standard (19). The recovery of the method was examined by comparing the analytical results for extracted samples at three levels of concentration (high, medium and low) five times within three days with theoretical concentration that represent 100% recovery. The data obtained demonstrates that the extraction procedure is particularly efficient, providing a recovery values ranged from 85 to 105% for all compounds. The results are shown in Table IV (Supplementary Material).
Table IV. Intra and Inter-Day Accuracy (Analytical Recovery) of the Method
Intra-day study (n = 5) Inter-day study (n = 5)
Concentrations (μg/mL) Recovery (%) Recovery (%)
Fluoxetine
0.2 98 89
5 93 91
10 94 100
Venlafaxine
0.02 92 95
5 93 95
10 98 99
Mirtazapine
0.02 85 94
2.5 89 94
5 92 97
Sertraline
0.2 97 98
2.5 91 94
5 98 99
Citalopram
0.04 93 105
2.5 95 96
5 99 98
Paroxetine
1 93 93
5 91 91
10 94 101
Olanzapine
0.2 89 89
5 85 90
10 87 98
Application to real cases
The developed method was used to analyze 31 real PF samples obtained from the Forensic Toxicology Service of the Institute of Forensic Sciences of Santiago de Compostela from cases including suicide, overdose or death from unknown causes. Some information is described in Table V. From the 31 cases, 21 were positive for at least one of the substances analyzed. Venlafaxine and olanzapine were the two antidepressants most frequently found in 12 and 4 cases, respectively. There were also positive cases for mirtazapine, fluoxetine, sertraline and citalopram. Three samples were positive for several compounds at the same time. Figures 4 and 5 show real cases analyzed in our laboratory with their corresponding mass spectra (Figures 6 and 7). One of them corresponds to a female whose cause of death was hanging after having consumed high amounts of several drugs and the other case belongs to a male poisoned by carbon monoxide.
Table V. Real Cases
Case no. Age Sex Sample Cause of death General information and treatment Substance detected
(years) [µg/mL]
1 82 Female Blood, urine and PF Pulmonary embolism Depressive disorder Mirtazapine [0.48]
2 83 Female Blood, urine and PF Traumatic brain injury Duloxetine, bromazepam, quetiapine, tramadol and metamizol –
3 42 Female Blood, urine and PF Suicide Psychiatric treatment for schizophrenia. Lormetazepam and paliperidone Venlafaxine [0.27]
4 32 Female Blood and PF Suicide Depressive disorder. Risperidone, benzodiazepines and olanzapine Olanzapine <LLOQ
5 56 Female Blood, urine and PF Suicide Venlafaxine and benzodiazepines Venlafaxine [3.44]
6 45 Male Blood, urine, vitreous humor and PF Suicide Past history of drug abuse Venlafaxine [0.27]
7 52 Male Blood, vitreous humor and PF Acute myocardial infarction Depressive disorder –
8 45 Male Blood and PF Possible cardiac death Paranoid Schizophrenia. Valproic acid –
9 60 Female Blood, urine, gastric content, hair, PF and nail Suicide Ketazolam and bromazepam Venlafaxine [0.28]
10 67 Male Blood, urine and PF Choking suffocation Olanzapine Venlafaxine [0.28] and olanzapine <LLOQ
11 37 Male Blood, urine, bile, vitreous humor and PF – Drinker and smoker –
12 32 Male Blood, urine and PF Fall Depressive disorder. Haloperidol, olanzapine and flufenazine, Venlafaxine [0.27] and olanzapine [0.23]
13 64 Female Blood, urine, hair, vitreous humor, bile and PF Methanol poisoning – –
14 65 Male Blood, urine, gastric content and PF Suspected suicide Heptaminol hidroclorure, sertraline –
15 83 Male Blood, urine and PF Suicide Pregabaline, carbamazepine, clonazepam and mirtazapine Mirtazapine [0.19]
16 48 Male Blood, urine and PF Adverse drug reaction Fluoxetine, lormetazepam, lorazepam, alprazolam, clozapine, cocaine and dipotassium chlorazepate Fluoxetine [0.63]
17 75 Female Blood, urine, gastric content and PF Drug overdose Tramadol, ciclobenzaprine, ketazolam and lorazepam Venlafaxine [8.48]
18 70 Female Blood, urine and PF Suicide Venlafaxine and lorazepam Venlafaxine [0.81]
19 89 Female Blood, gastric content and PF Previous depressive episodes Lorazepam and olanzapine Olanzapine <LLOQ
20 75 Female Blood, urine and PF Natural Alprazolam, trazodone, venlafaxine and quietiapine Venlafaxine [0.95]
21 47 Female Blood, urine and PF Natural Depressive and personality disorder. Alprazolam and paroxetine –
22 56 Male Blood, urine and PF Cardiac death – –
23 35 Male Blood, vitreous humor and PF Choking suffocation Benzodiacepines, topiramate, fluoxetine, paliperidone, quetiapine and mirtazapine Mirtazapine [0.39] and fluoxetine [0.20]
24 36 Male Blood, urine, vitreous humor and PF Suicide Depressive disorder –
25 61 Male Blood, urine, vitreous humor and PF Natural Bipolar disorder. Alcohol consumption. Benzodiacepines, pregabaline, sertraline and olanzapine Sertraline [0.23]
26 86 Male Blood, urine, vitreous humor and PF Carbon monoxide poisoning Sertraline, trazodone and lorazepam Sertraline [0.48]
27 73 Female Blood, urine, vitreous humor and PF Suffocation from airway occlusion Benzodiacepines and venlafaxine Venlafaxine [0.62]
28 60 Female Blood, urine and PF Empyema Alcohol consumption. Mirtazapine, quetiapine and benzodiapcepines Citalopram [0.27]
29 40 Female Blood, vitreous humor and PF Suicide Depressive disorder. Venlafaxine, benzodiacepines, clomipramine and trazodone, Venlafaxine [3.84]
30 55 Female Blood, vitreous humor and PF Natural – –
31 52 Male Blood, urine, vitreous humor and PF Suicide Depressive disorder Venlafaxine [0.33]
PF, pericardial fluid.
Figure 4. Chromatogram of a real sample (positive for venlafaxine).
Figure 5. Chromatogram of a real sample (positive for sertraline).
Figure 6. Venlafaxine mass spectra.
Figure 7. Sertraline mass spectra.
Discussion
The present work aims to contribute toward the development of methods able to quantify the presence of antidepressants in samples of PF in cases where adequate blood samples may not be available. Previous literature reports comprise only a few articles where PF is used as a biological sample for the determination of drugs (7, 8, 15). The DLLME was one of the techniques used by several authors to extract antidepressants, but only one author determined the concentration of these compounds in PF (8, 16, 20–30). Most of the articles published so far used the DLLME technique coupled to another extraction method (16, 20, 22–24, 26, 27), but few papers have followed a similar method to ours (21, 25, 28–30). Most of them employed urine as the biological matrix (25, 28–30), while Lima et al. used water samples (21). Most of the published research dealt with TCAs as the particular drugs under study (16, 20, 25–27, 29, 30), and only two articles have employed GC–MS (22, 29).
On the grounds of the available evidence, it can be stated that drug concentrations in PF are mostly equivalent to those in peripheral blood (7–9, 31). In consequence, samples of PF can be considered as an alternative for drug quantification in cases where blood samples are not available. PF is usually available in quantities large enough, thus making it suitable for toxicological purposes. In addition, rather similar treatments and procedures to those customarily used for blood can be followed, a fact that constitutes an added advantage for the use of this particular fluid. Finally, as the PF is found within a closed compartment, contamination by microorganisms is less likely to occur (8) than in case of other samples.
A set of experiments were carried out in the quest for an efficient antidepressant extraction procedure by varying several DLLME parameters as the quantity of water, salt amounts, types of extraction and disperser solvents and quantity of biological matrix used. With respect to the volume of sample used, our method uses 0.3 mL, while other authors employ larger volumes (7, 9, 31). The use of chloroform as extracting solvent and acetonitrile as disperser solvent was also determined by Fernández et al. in a study published in 2016 (23). Finally, the method here developed was fully validated with good results in accordance with the limits approved by the FDA. The developed method was used to determine 31 PF samples. The results confirmed the presence of venlafaxine in most cases (12 cases), followed by olanzapine (4 cases), mirtazapine (3 cases), fluoxetine and sertraline (2 cases) and citalopram (1 case). No positive cases for paroxetine have been found. Fernández et al. also found venlafaxine as the most frequently used antidepressant in his study (23). However, citalopram and mirtazapine were the two antidepressants most frequently detected in Leere et al.’s study (8) followed by venlafaxine and sertraline. In the study just referred to, venlafaxine was detected in six cases, having found within four of those cases drug concentrations above the therapeutic range. In addition, one of the cases here studied revealed the presence of extremely high concentrations. Paroxetine was also poorly detected (8). In our study, high concentrations of venlafaxine were also found in three cases. All antidepressants, except one, were found in concentrations above LLOQ. Of the four cases detected for olanzapine, three of them were detected at concentrations below LLOQ.
In view of the present results, we recommend that PF should be added to the list of biological samples used in a forensic laboratory. To conclude, it is worth remarking the increase in use of PF in toxicological practice as pointed out by Contreras et al. in their analysis of morphine and cocaine (11, 32).
Conclusions
The aim of the present article is to report on an optimized analytical method to determine antidepressants using PF as a biological matrix. Sample preparation based on DLLME was employed. An experimental design setup using StatGraphics 18 and 175 µL of chloroform and 750 µL of acetonitrile as the best quantities for the extracting and disperser solvents was employed. A gas chromatograph using HP5-MS capillary column was used for the separation, and a mass spectrometer was used for the identification. Analytes were identified by their retention times and mass spectra. The method provides high precision, accuracy and recovery within the linear range of detection. Therefore, our method was found to be specific, sensitive and selective enough for the routine analysis of antidepressants in PF and for the application of the method in forensic practice. In conclusion, we have shown the usefulness of PF samples in cases where adequate blood specimens cannot be made available. The existing literature regarding drug concentrations in PF is however scarce, so further studies are in order.
Supplementary Material
bkab003_Supp Click here for additional data file.
Supplementary Data
Supplementary Data is available at Journal of Analytical Toxicology online.
Funding
This research did not receive any specific grant from funding agencies in the public, commercial, or not-for-profit sectors. | BENZODIAZEPINE, FLUOXETINE HYDROCHLORIDE, MIRTAZAPINE, PALIPERIDONE, QUETIAPINE, TOPIRAMATE | DrugsGivenReaction | CC BY | 33410888 | 18,752,851 | 2021-01-07 |
What was the outcome of reaction 'Asphyxia'? | Determination of Seven Antidepressants in Pericardial Fluid by Means of Dispersive Liquid-Liquid Microextraction (DLLME) and Gas Chromatography-Mass Spectrometry (GC/MS).
Although blood is often used to detect and quantify the presence of drugs, there are some instances where samples obtained from other biological matrices, like pericardial fluid (PF), are necessary since adequate blood samples may not be available. PF is an epicardial transudate, which contains plasma components that include toxicological substances making this sample useful when blood samples are not available. This fluid is a well preserved postmortem sample and can easily be collected in larger amounts without significant contamination, compared with other body fluids. Although studies involving PF began around the 1980's, the adequacy of such fluid as a biological matrix has been poorly investigated. Antidepressants are frequently detected in postmortem samples from forensic cases. Nowadays, they constitute some of the most commonly prescribed drugs worldwide. A total of seven antidepressants (venlafaxine, mirtazapine, olanzapine, paroxetine, sertraline, fluoxetine and citalopram) were evaluated in this study. A new extraction method involving dispersive liquid-liquid microextraction (DLLME) is presented in which chloroform and acetonitrile are determined to be the best extraction and dispersing solvents. The experimental design was achieved using StatGraphics 18. The Response Surface Methodology enabled us to know the optimal volume for the two solvents used in the DLLME. The detection technique used was gas chromatography-mass spectrometry (GC-MS) with electron impact ionization as ionization source. A temperature gradient has been used and the total chromatographic separation time was 19.43 min. Validation results met the international validation guidances (FDA). Under the optimal condition, the method offered good validation parameters showing a new efficient, simple, rapid, and sensitive method. The analytical method was applied to thirty-one pericardial fluid samples. Twenty-one samples were positive with concentrations between 0.19 and 8.48 µg/mL. Venlafaxine and olanzapine were the antidepressants most frequently found.
pmcIntroduction
Depression constitutes nowadays one of the most common mental disorders either as a major condition or as a neuropsychiatric symptom characteristic of several diseases. In fact, major depressive disorder is a chronic, prevalent and pervasive brain-based disorder that significantly incapacitates the person affected (1). It is estimated that more than 350 million people worldwide are currently diagnosed with such condition, being women more frequently affected than men (2). At its worst, depression may lead to suicide. Close to 800,000 people commit suicide each year, being the second leading cause of death in 15–29-year-olds (3).
Tricyclic antidepressants (TCAs) were discovered in the 1950s, but their significant side effects led to a sustained effort in search for more selective drugs. This leads to the discovery of serotonin reuptake inhibitors, some of which (fluoxetine, sertraline and citalopram) are very commonly prescribed as first-choice drugs to treat depression. In addition, newer antidepressants, such as mirtazapine and venlafaxine, do affect both the serotonin and norepinephrine systems within the central nervous system, without the associated anticholinergic and cardiovascular side effects of older drugs such as TCAs. Mirtazapine has a dual mode of action. It is noradrenergic and specific serotonergic antidepressant that acts by antagonizing the adrenergic α2-autoreceptors and α2-heteroreceptors as well as by blocking 5-HT2 and 5-HT3 receptors. It enhances, therefore, the release of norepinephrine and 5-HT1A-mediated serotonergic transmission (4). Venlafaxine is a phenylethylamine derivative. It is a serotonin norepinephrine re-uptake inhibitor. Venlafaxine was approved by the FDA (Food and Drug Administration) for the following conditions: major depression, generalized anxiety disorder, panic disorder and social phobia (5). Olanzapine is a second-generation antipsychotic neuroleptic or “atypical antipsychotic”. These medications have more receptor-binding targets than first-generation treatments (e.g., haloperidol) do and have complex pharmacologic mechanisms of action. Olanzapine has the most binding targets in its class, binding to 10 serotonin receptors, 4 dopamine receptors, 4 acetylcholine receptors, 4 α-adrenergic receptors, 1 histamine receptor and 2 different neurotransmitter transport receptors (6).
Within the forensic practice, it is important to investigate postmortem drug concentrations to discriminate whether the cause of death was due to intoxication, side effects of the undergoing treatment or lack of compliance. Urine and blood specimens are the main biological samples used in forensic autopsy cases, being peripheral blood the most used in postmortem research. Moreover, special care must be taken in the interpretation of the data when using postmortem blood samples as these concentrations may change due to several factors such as chemical/enzymatic degradation of substances, redistribution phenomena and postmortem diffusion from solid organs or gastric content, especially with cardiac blood since it is more affected by postmortem redistribution (7). However, it should be borne in mind that blood analysis will be always a fundamental and essential step since it enables one to know the toxicological status of the deceased at the time of death. In addition to blood or urine samples, one may consider pericardial fluid (PF) as a useful alternative matrix in cases where adequate peripheral blood samples cannot be obtained. The potential use of PF samples has been considered within relatively few reports (7–13). Previous studies showed good correlation with the drug concentrations in peripheral blood (8, 10, 14, 15). PF is a well-preserved postmortem material in cases without structural damage due to injury or medical intervention and can easily be collected in large amounts without significant contamination as it is contained within a tight compartment (pericardial sac), compared with other body fluids (13). With a volume of 15–35 mL, it is believed to be a transudate generated by the net result of the hydrostatic pressure and the osmotic gradient between plasma and PF. The composition of the normal human PF is difficult to define. The hematological and biochemical analyses of the PF show that the concentration of electrolytes and small molecules (urea, uric acid, glucose and creatinine) corresponds to an ultrafiltrate of plasma (7, 13).
Previous works using liquid–liquid extraction or solid phase extraction have been reported (7–9, 12). In particular, efforts were oriented towards the development of efficient and miniaturized sample preparation methods. Liquid-phase microextraction (LPME) was introduced according to this perspective. Dispersive liquid–liquid microextraction (DLLME) is one of the LPME methods and has attracted recent interest within the analytical chemists’ community (16). The method was introduced by Assadi and co-workers in 2006 (17). It is a simple and fast microextraction technique based upon the use of an appropriate extractant (an organic solvent with high density) and a disperser solvent with high miscibility in both extractant and aqueous phases. DLLME consists of two steps: (i) injection of an appropriate mixture of extracting and disperser solvents into an aqueous sample, containing the analytes. In this step, the extracting solvent is dispersed into the aqueous sample as very fine droplets and the analytes are enriched into it. After the formation of a cloudy solution, the surface area between the extracting solvent and the aqueous sample becomes very large, so the equilibrium state is quickly attained and, therefore, the extraction time is very short. In fact, this is the principal advantage of this method. (ii) Centrifugation of the cloudy solution, thereby obtaining a settled phase that is deposited at the bottom of a conical tube. Other advantages include simplicity of operation, rapidity, low cost, high recovery, high enrichment factor and environment benignity (18). Like the other analytical methods, DLLME has some disadvantages, which result from the requirements related to the organic extraction and disperser solvents. The extraction solvent used should have some special requirements, such as a density larger than water for simple separation of the extraction phase after centrifugation and to form a cloudy solution in the presence of the disperser solvent. The potential organic solvents meeting this requirement are limited since they are hazardous chemicals (such as halogenated hydrocarbons). It is precisely because of this the choice of the extraction solvent becomes the method’s primary limitation (16). According to detection techniques, several methods were used involving liquid chromatography as well as gas chromatography (7–9, 12).
The aim of this study was to develop a gas chromatography–mass spectrometry (GC–MS) method for the determination and quantification of antidepressants in PF using DLLME as a new extraction method. The validation of the method was carried out according to the guidelines of the FDA (19). The method was then applied to PF samples collected from deceased people.
Material and Methods
Chemicals
Acetonitrile and chloroform gradient grade solvents were purchased from Merck® (Madrid, Spain) and sodium chloride from Panreac® (Barcelona, Spain). Fluoxetine, venlafaxine, mirtazapine, sertraline, citalopram, olanzapine, paroxetine and proadifen (SKF), used as internal standard, were obtained from Cerilliant®. Distilled water was processed through a Milli-Q water system (Millipore, Bedford, MA, USA).
Matrix collection
To carry out the validation procedure, antidepressant-free PF obtained from autopsies was used. For this purpose, a mixture of PF from deceased subjects was collected and stored at –20°C until use, following a previous peripheral blood and urine analysis that was negative to antidepressants.
Sample preparation
PF used for validation was previously ultracentrifuged for 5 min at 14,000 rpm. Aliquots of 0.3 mL were used for analysis, collected in a glass tube and spiked with Proadifen (SKF) (20 µL Sol. 10 µg/mL). Then, it was diluted with water (1.1 mL) and 150 mg of NaCl was also added to facilitate analytes’ transition from aqueous phase to organic phase. This mixture was submited to the DLLME. After an experimental design using StatGraphics (StatGraphics Technologies, Inc.), the optimal conditions were as follows: 175 uL of chloroform and 750 uL of acetonitrile as the best extracting and disperser solvents, respectively. Both solvents were rapidly injected into the sample with a Pasteur pipette and the mixture was gently shaken. Then, the mixture was centrifuged, and the droplet formed was collected by a 100 µL syringe and transferred to an 8 mL glass tube. The organic solvent was evaporated under a stream of nitrogen in a heated aluminum block at 40°C (VLM GmbH, HP series). The dried residue was redissolved with 40 µL of methanol prior to injection of a 2 µL aliquot into the GC–MS system.
Instrumentation
Chromatographic analyses were performed using an electron impact ionization gas chromatograph model 7890 B from Agilent Technologies® (Las Rozas, Spain) interfaced to a mass selective detector (MSD) model 5977 B, also from Agilent Technologies®. An HP5-MS capillary column (30 m × 250 µm i.d., 0.5 µm film thickness; Agilent Technologies®) with helium as carrier gas (1 mL/min) was used for the gas chromatographic separation. The injector temperature was set at 250°C and a purge time of 2 min was used. Samples were injected in the splitless mode. The following temperature program was applied: the initial temperature of the column was 100°C for 1 min, then ramped-up progressively at 35°C/min up to 220°C, held constant for 1 min, and then ramped-up again at 8°C/min up to 260°C and held for 2 min. Finally, the temperature was ramped-up at 5°C/min up to 280°C for 3 min. After that, the temperature was increased to 290°C for 5 min to clean the column. The total chromatographic separation time was 19.43 min, and the total run time was 24.43 min. The MSD was kept at 300°C, the ion source at 230°C and the quadrupole at 150°C.
Identification of compounds
Initially, neat standards of all antidepressants were injected and analyzed using the full scan mode of the GC–MS, which scanned from 50 to 550 amu. Quantifier and qualifier ions used for each analyte were selected based on their abundances and mass-to-charge ratios (m/z). Because of their reproducibilities and lack of interference, high mass ions were selected whenever possible. The ions selected for each compound studied and the retention times are shown in Table I. Upon selection of ion, the mass spectrometry was run in selected ion monitoring mode (Figure 1).
Table I. Retention Times and Ions Selected for Monitorization
Analyte Quantifier ion, m/z Qualifier ions, m/z Retention time, min
Fluoxetine 104 148, 309 7.78
Venlafaxine 58 134, 179 9.97
Mirtazapine 195 208, 245 11.78
SKF 86 99, 165 12.30
Sertraline 274 276, 262 13.55
Citalopram 58 238, 324 13.20
Paroxetine 192 138, 329 16.09
Olanzapine 242 229, 207 18.50
Figure 1. Extracted ionic chromatogram of all analytes.
Results
Experimental design
To find the best conditions for DLLME, 18 replicates were performed using a 2 × 4 factorial design with four factors: sample volume, water volume, extracting solvent volume and disperser solvent volume. The experimental design was achieved using Statgraphics 18. To make this design rotatable, for each factor, two axial points were chosen, and the runs were randomized to exclude the block effects. Response surface methodology (RSM) is a combination of mathematical and statistical techniques used to study the relationship between two or more responses that depend on several factors or independent variables. The final goal of RSM is to optimize responses determining the best conditions in the operation of the system. Our design of response surface was obtained using the statistical software StatGraphics (Figure 2).
Figure 2. Response surface graph.
Validation of the method
Validation was achieved according to the FDA Guideline for Bioanalytical Method Validation (19). The suitability of the method for quantitative analysis was studied by testing selectivity, linearity and sensitivity, precision and accuracy and recovery.
Selectivity
Selectivity is the ability of an analytical method to differentiate and quantify the analyte in the presence of other components in the sample. It should confirm that the assay is free of potential interfering substances, include endogenous matrix components, metabolites, decomposition products and medication and other exogenous xenobiotics. The selectivity of the method was demonstrated by analyzing six blank PF samples (19). No interfering peaks were found at the retention time for all analytes (Figure 3).
Figure 3. Chromatogram of a blank PF.
Linearity
Standard addition curves were obtained in six runs with the described method using drug-free control PF spiked with standard solutions to obtain the range of concentrations shown in Table II. The curves were obtained by fitting the ratio of the peak areas of analytes to that of IS versus concentrations. A linear response was observed in the studied range with a good correlation coefficient (higher than 0.99 in all cases). The sensitivity of the method was determined by calculation of the limit of detection (LOD) and the lower limit of quantification (LLOQ). LOD was determined by an empirical method that consists of analyzing a series of PF samples containing decreasing amounts of the analytes. LOD was the lowest concentration that presented a signal-to-noise ratio higher than 3 for at least three diagnostic ions for each substance. The LLOQ was the lowest concentration of analytes in a sample that can be determined with appropriate precision (20%) and accuracy (80–120%) (19) (Table II).
Table II. LOD, Limit of Quantification and Calibration Results for the Antidepressants Studied
Analyte LOD (µg/mL) LLOQ (µg/mL) C. coef. Range of calibration (µg/mL)
Fluoxetine 0.05 0.2 0.991 0.2–10
Venlafaxine 0.01 0.02 0.991 0.02–10
Mirtazapine 0.01 0.02 0.997 0.02–5
Sertraline 0.005 0.2 0.992 0.2–5
Citalopram 0.01 0.04 0.995 0.04–5
Olanzapine 0.02 0.2 0.993 0.2–10
Paroxetine 0.2 1 0.997 1–10
C. coef., correlation coefficient.
Precision and accuracy
The accuracy of an analytical method describes the closeness of mean test results obtained by the method to the true value (concentration) of the analyte. The precision of an analytical method describes the closeness of individual measures of an analyte when the procedure is applied repeatedly to multiple aliquots of a single homogeneous volume of biological matrix. Precision and accuracy were determined by inter- and intra-day assay. Inter-day precision and accuracy were calculated by analyzing negative PF samples spiked with the antidepressants at three concentrations; the LLOQ, the upper limit of quantification and an intermediate level were assessed by analyzing five replicates each day in five different days for each level of concentration. Intra-day precision and accuracy were determined at three concentrations, by preparing and analyzing five replicates for each level on the same day. Precision, expressed as the coefficient of variation of the measured values, was expected to be less than 15% at all concentrations, except for the LLOQ for which 20% was acceptable. In the same way, accuracy was evaluated using the mean relative error (ME), which had to be less than 15% of the theoretical values at each concentration level except for the LLOQ, for which 20% was acceptable (19). Data presented in Table III (Supplementary Material) satisfied the international validation rules.
Table III. Intra- and Inter-Day Precision and Accuracy (ME) of the Method
Intra-day study (n = 5) Inter-day study (n = 5)
Concentrations (μg/mL) ME (%) RSD (%) ME (%) RSD (%)
Fluoxetine
0.2 17 5 14 10
5 6 5 8 4
10 6 7 1 5
Venlafaxine
0.02 18 8 14 7
5 6 3 5 3
10 2 5 1 4
Mirtazapine
0.02 19 3 16 6
2.5 11 2 6 2
5 1 4 3 6
Sertraline
0.2 17 7 18 7
2.5 8 5 6 3
5 2 8 1 4
Citalopram
0.04 17 10 13 7
2.5 5 4 4 3
5 1 4 2 3
Paroxetine
1 13 12 13 12
5 8 15 9 12
10 14 12 1 7
Olanzapine
0.2 12 14 19 5
5 14 3 9 6
10 6 3 2 7
RSD: Relative Standard Deviation.
Recovery
The recovery of an analyte is the detector response obtained from an amount of the analyte added to an extracted from the biological matrix, compared to the detector response obtained for the true concentration of the pure authentic standard (19). The recovery of the method was examined by comparing the analytical results for extracted samples at three levels of concentration (high, medium and low) five times within three days with theoretical concentration that represent 100% recovery. The data obtained demonstrates that the extraction procedure is particularly efficient, providing a recovery values ranged from 85 to 105% for all compounds. The results are shown in Table IV (Supplementary Material).
Table IV. Intra and Inter-Day Accuracy (Analytical Recovery) of the Method
Intra-day study (n = 5) Inter-day study (n = 5)
Concentrations (μg/mL) Recovery (%) Recovery (%)
Fluoxetine
0.2 98 89
5 93 91
10 94 100
Venlafaxine
0.02 92 95
5 93 95
10 98 99
Mirtazapine
0.02 85 94
2.5 89 94
5 92 97
Sertraline
0.2 97 98
2.5 91 94
5 98 99
Citalopram
0.04 93 105
2.5 95 96
5 99 98
Paroxetine
1 93 93
5 91 91
10 94 101
Olanzapine
0.2 89 89
5 85 90
10 87 98
Application to real cases
The developed method was used to analyze 31 real PF samples obtained from the Forensic Toxicology Service of the Institute of Forensic Sciences of Santiago de Compostela from cases including suicide, overdose or death from unknown causes. Some information is described in Table V. From the 31 cases, 21 were positive for at least one of the substances analyzed. Venlafaxine and olanzapine were the two antidepressants most frequently found in 12 and 4 cases, respectively. There were also positive cases for mirtazapine, fluoxetine, sertraline and citalopram. Three samples were positive for several compounds at the same time. Figures 4 and 5 show real cases analyzed in our laboratory with their corresponding mass spectra (Figures 6 and 7). One of them corresponds to a female whose cause of death was hanging after having consumed high amounts of several drugs and the other case belongs to a male poisoned by carbon monoxide.
Table V. Real Cases
Case no. Age Sex Sample Cause of death General information and treatment Substance detected
(years) [µg/mL]
1 82 Female Blood, urine and PF Pulmonary embolism Depressive disorder Mirtazapine [0.48]
2 83 Female Blood, urine and PF Traumatic brain injury Duloxetine, bromazepam, quetiapine, tramadol and metamizol –
3 42 Female Blood, urine and PF Suicide Psychiatric treatment for schizophrenia. Lormetazepam and paliperidone Venlafaxine [0.27]
4 32 Female Blood and PF Suicide Depressive disorder. Risperidone, benzodiazepines and olanzapine Olanzapine <LLOQ
5 56 Female Blood, urine and PF Suicide Venlafaxine and benzodiazepines Venlafaxine [3.44]
6 45 Male Blood, urine, vitreous humor and PF Suicide Past history of drug abuse Venlafaxine [0.27]
7 52 Male Blood, vitreous humor and PF Acute myocardial infarction Depressive disorder –
8 45 Male Blood and PF Possible cardiac death Paranoid Schizophrenia. Valproic acid –
9 60 Female Blood, urine, gastric content, hair, PF and nail Suicide Ketazolam and bromazepam Venlafaxine [0.28]
10 67 Male Blood, urine and PF Choking suffocation Olanzapine Venlafaxine [0.28] and olanzapine <LLOQ
11 37 Male Blood, urine, bile, vitreous humor and PF – Drinker and smoker –
12 32 Male Blood, urine and PF Fall Depressive disorder. Haloperidol, olanzapine and flufenazine, Venlafaxine [0.27] and olanzapine [0.23]
13 64 Female Blood, urine, hair, vitreous humor, bile and PF Methanol poisoning – –
14 65 Male Blood, urine, gastric content and PF Suspected suicide Heptaminol hidroclorure, sertraline –
15 83 Male Blood, urine and PF Suicide Pregabaline, carbamazepine, clonazepam and mirtazapine Mirtazapine [0.19]
16 48 Male Blood, urine and PF Adverse drug reaction Fluoxetine, lormetazepam, lorazepam, alprazolam, clozapine, cocaine and dipotassium chlorazepate Fluoxetine [0.63]
17 75 Female Blood, urine, gastric content and PF Drug overdose Tramadol, ciclobenzaprine, ketazolam and lorazepam Venlafaxine [8.48]
18 70 Female Blood, urine and PF Suicide Venlafaxine and lorazepam Venlafaxine [0.81]
19 89 Female Blood, gastric content and PF Previous depressive episodes Lorazepam and olanzapine Olanzapine <LLOQ
20 75 Female Blood, urine and PF Natural Alprazolam, trazodone, venlafaxine and quietiapine Venlafaxine [0.95]
21 47 Female Blood, urine and PF Natural Depressive and personality disorder. Alprazolam and paroxetine –
22 56 Male Blood, urine and PF Cardiac death – –
23 35 Male Blood, vitreous humor and PF Choking suffocation Benzodiacepines, topiramate, fluoxetine, paliperidone, quetiapine and mirtazapine Mirtazapine [0.39] and fluoxetine [0.20]
24 36 Male Blood, urine, vitreous humor and PF Suicide Depressive disorder –
25 61 Male Blood, urine, vitreous humor and PF Natural Bipolar disorder. Alcohol consumption. Benzodiacepines, pregabaline, sertraline and olanzapine Sertraline [0.23]
26 86 Male Blood, urine, vitreous humor and PF Carbon monoxide poisoning Sertraline, trazodone and lorazepam Sertraline [0.48]
27 73 Female Blood, urine, vitreous humor and PF Suffocation from airway occlusion Benzodiacepines and venlafaxine Venlafaxine [0.62]
28 60 Female Blood, urine and PF Empyema Alcohol consumption. Mirtazapine, quetiapine and benzodiapcepines Citalopram [0.27]
29 40 Female Blood, vitreous humor and PF Suicide Depressive disorder. Venlafaxine, benzodiacepines, clomipramine and trazodone, Venlafaxine [3.84]
30 55 Female Blood, vitreous humor and PF Natural – –
31 52 Male Blood, urine, vitreous humor and PF Suicide Depressive disorder Venlafaxine [0.33]
PF, pericardial fluid.
Figure 4. Chromatogram of a real sample (positive for venlafaxine).
Figure 5. Chromatogram of a real sample (positive for sertraline).
Figure 6. Venlafaxine mass spectra.
Figure 7. Sertraline mass spectra.
Discussion
The present work aims to contribute toward the development of methods able to quantify the presence of antidepressants in samples of PF in cases where adequate blood samples may not be available. Previous literature reports comprise only a few articles where PF is used as a biological sample for the determination of drugs (7, 8, 15). The DLLME was one of the techniques used by several authors to extract antidepressants, but only one author determined the concentration of these compounds in PF (8, 16, 20–30). Most of the articles published so far used the DLLME technique coupled to another extraction method (16, 20, 22–24, 26, 27), but few papers have followed a similar method to ours (21, 25, 28–30). Most of them employed urine as the biological matrix (25, 28–30), while Lima et al. used water samples (21). Most of the published research dealt with TCAs as the particular drugs under study (16, 20, 25–27, 29, 30), and only two articles have employed GC–MS (22, 29).
On the grounds of the available evidence, it can be stated that drug concentrations in PF are mostly equivalent to those in peripheral blood (7–9, 31). In consequence, samples of PF can be considered as an alternative for drug quantification in cases where blood samples are not available. PF is usually available in quantities large enough, thus making it suitable for toxicological purposes. In addition, rather similar treatments and procedures to those customarily used for blood can be followed, a fact that constitutes an added advantage for the use of this particular fluid. Finally, as the PF is found within a closed compartment, contamination by microorganisms is less likely to occur (8) than in case of other samples.
A set of experiments were carried out in the quest for an efficient antidepressant extraction procedure by varying several DLLME parameters as the quantity of water, salt amounts, types of extraction and disperser solvents and quantity of biological matrix used. With respect to the volume of sample used, our method uses 0.3 mL, while other authors employ larger volumes (7, 9, 31). The use of chloroform as extracting solvent and acetonitrile as disperser solvent was also determined by Fernández et al. in a study published in 2016 (23). Finally, the method here developed was fully validated with good results in accordance with the limits approved by the FDA. The developed method was used to determine 31 PF samples. The results confirmed the presence of venlafaxine in most cases (12 cases), followed by olanzapine (4 cases), mirtazapine (3 cases), fluoxetine and sertraline (2 cases) and citalopram (1 case). No positive cases for paroxetine have been found. Fernández et al. also found venlafaxine as the most frequently used antidepressant in his study (23). However, citalopram and mirtazapine were the two antidepressants most frequently detected in Leere et al.’s study (8) followed by venlafaxine and sertraline. In the study just referred to, venlafaxine was detected in six cases, having found within four of those cases drug concentrations above the therapeutic range. In addition, one of the cases here studied revealed the presence of extremely high concentrations. Paroxetine was also poorly detected (8). In our study, high concentrations of venlafaxine were also found in three cases. All antidepressants, except one, were found in concentrations above LLOQ. Of the four cases detected for olanzapine, three of them were detected at concentrations below LLOQ.
In view of the present results, we recommend that PF should be added to the list of biological samples used in a forensic laboratory. To conclude, it is worth remarking the increase in use of PF in toxicological practice as pointed out by Contreras et al. in their analysis of morphine and cocaine (11, 32).
Conclusions
The aim of the present article is to report on an optimized analytical method to determine antidepressants using PF as a biological matrix. Sample preparation based on DLLME was employed. An experimental design setup using StatGraphics 18 and 175 µL of chloroform and 750 µL of acetonitrile as the best quantities for the extracting and disperser solvents was employed. A gas chromatograph using HP5-MS capillary column was used for the separation, and a mass spectrometer was used for the identification. Analytes were identified by their retention times and mass spectra. The method provides high precision, accuracy and recovery within the linear range of detection. Therefore, our method was found to be specific, sensitive and selective enough for the routine analysis of antidepressants in PF and for the application of the method in forensic practice. In conclusion, we have shown the usefulness of PF samples in cases where adequate blood specimens cannot be made available. The existing literature regarding drug concentrations in PF is however scarce, so further studies are in order.
Supplementary Material
bkab003_Supp Click here for additional data file.
Supplementary Data
Supplementary Data is available at Journal of Analytical Toxicology online.
Funding
This research did not receive any specific grant from funding agencies in the public, commercial, or not-for-profit sectors. | Fatal | ReactionOutcome | CC BY | 33410888 | 18,752,851 | 2021-01-07 |
What was the outcome of reaction 'Choking'? | Determination of Seven Antidepressants in Pericardial Fluid by Means of Dispersive Liquid-Liquid Microextraction (DLLME) and Gas Chromatography-Mass Spectrometry (GC/MS).
Although blood is often used to detect and quantify the presence of drugs, there are some instances where samples obtained from other biological matrices, like pericardial fluid (PF), are necessary since adequate blood samples may not be available. PF is an epicardial transudate, which contains plasma components that include toxicological substances making this sample useful when blood samples are not available. This fluid is a well preserved postmortem sample and can easily be collected in larger amounts without significant contamination, compared with other body fluids. Although studies involving PF began around the 1980's, the adequacy of such fluid as a biological matrix has been poorly investigated. Antidepressants are frequently detected in postmortem samples from forensic cases. Nowadays, they constitute some of the most commonly prescribed drugs worldwide. A total of seven antidepressants (venlafaxine, mirtazapine, olanzapine, paroxetine, sertraline, fluoxetine and citalopram) were evaluated in this study. A new extraction method involving dispersive liquid-liquid microextraction (DLLME) is presented in which chloroform and acetonitrile are determined to be the best extraction and dispersing solvents. The experimental design was achieved using StatGraphics 18. The Response Surface Methodology enabled us to know the optimal volume for the two solvents used in the DLLME. The detection technique used was gas chromatography-mass spectrometry (GC-MS) with electron impact ionization as ionization source. A temperature gradient has been used and the total chromatographic separation time was 19.43 min. Validation results met the international validation guidances (FDA). Under the optimal condition, the method offered good validation parameters showing a new efficient, simple, rapid, and sensitive method. The analytical method was applied to thirty-one pericardial fluid samples. Twenty-one samples were positive with concentrations between 0.19 and 8.48 µg/mL. Venlafaxine and olanzapine were the antidepressants most frequently found.
pmcIntroduction
Depression constitutes nowadays one of the most common mental disorders either as a major condition or as a neuropsychiatric symptom characteristic of several diseases. In fact, major depressive disorder is a chronic, prevalent and pervasive brain-based disorder that significantly incapacitates the person affected (1). It is estimated that more than 350 million people worldwide are currently diagnosed with such condition, being women more frequently affected than men (2). At its worst, depression may lead to suicide. Close to 800,000 people commit suicide each year, being the second leading cause of death in 15–29-year-olds (3).
Tricyclic antidepressants (TCAs) were discovered in the 1950s, but their significant side effects led to a sustained effort in search for more selective drugs. This leads to the discovery of serotonin reuptake inhibitors, some of which (fluoxetine, sertraline and citalopram) are very commonly prescribed as first-choice drugs to treat depression. In addition, newer antidepressants, such as mirtazapine and venlafaxine, do affect both the serotonin and norepinephrine systems within the central nervous system, without the associated anticholinergic and cardiovascular side effects of older drugs such as TCAs. Mirtazapine has a dual mode of action. It is noradrenergic and specific serotonergic antidepressant that acts by antagonizing the adrenergic α2-autoreceptors and α2-heteroreceptors as well as by blocking 5-HT2 and 5-HT3 receptors. It enhances, therefore, the release of norepinephrine and 5-HT1A-mediated serotonergic transmission (4). Venlafaxine is a phenylethylamine derivative. It is a serotonin norepinephrine re-uptake inhibitor. Venlafaxine was approved by the FDA (Food and Drug Administration) for the following conditions: major depression, generalized anxiety disorder, panic disorder and social phobia (5). Olanzapine is a second-generation antipsychotic neuroleptic or “atypical antipsychotic”. These medications have more receptor-binding targets than first-generation treatments (e.g., haloperidol) do and have complex pharmacologic mechanisms of action. Olanzapine has the most binding targets in its class, binding to 10 serotonin receptors, 4 dopamine receptors, 4 acetylcholine receptors, 4 α-adrenergic receptors, 1 histamine receptor and 2 different neurotransmitter transport receptors (6).
Within the forensic practice, it is important to investigate postmortem drug concentrations to discriminate whether the cause of death was due to intoxication, side effects of the undergoing treatment or lack of compliance. Urine and blood specimens are the main biological samples used in forensic autopsy cases, being peripheral blood the most used in postmortem research. Moreover, special care must be taken in the interpretation of the data when using postmortem blood samples as these concentrations may change due to several factors such as chemical/enzymatic degradation of substances, redistribution phenomena and postmortem diffusion from solid organs or gastric content, especially with cardiac blood since it is more affected by postmortem redistribution (7). However, it should be borne in mind that blood analysis will be always a fundamental and essential step since it enables one to know the toxicological status of the deceased at the time of death. In addition to blood or urine samples, one may consider pericardial fluid (PF) as a useful alternative matrix in cases where adequate peripheral blood samples cannot be obtained. The potential use of PF samples has been considered within relatively few reports (7–13). Previous studies showed good correlation with the drug concentrations in peripheral blood (8, 10, 14, 15). PF is a well-preserved postmortem material in cases without structural damage due to injury or medical intervention and can easily be collected in large amounts without significant contamination as it is contained within a tight compartment (pericardial sac), compared with other body fluids (13). With a volume of 15–35 mL, it is believed to be a transudate generated by the net result of the hydrostatic pressure and the osmotic gradient between plasma and PF. The composition of the normal human PF is difficult to define. The hematological and biochemical analyses of the PF show that the concentration of electrolytes and small molecules (urea, uric acid, glucose and creatinine) corresponds to an ultrafiltrate of plasma (7, 13).
Previous works using liquid–liquid extraction or solid phase extraction have been reported (7–9, 12). In particular, efforts were oriented towards the development of efficient and miniaturized sample preparation methods. Liquid-phase microextraction (LPME) was introduced according to this perspective. Dispersive liquid–liquid microextraction (DLLME) is one of the LPME methods and has attracted recent interest within the analytical chemists’ community (16). The method was introduced by Assadi and co-workers in 2006 (17). It is a simple and fast microextraction technique based upon the use of an appropriate extractant (an organic solvent with high density) and a disperser solvent with high miscibility in both extractant and aqueous phases. DLLME consists of two steps: (i) injection of an appropriate mixture of extracting and disperser solvents into an aqueous sample, containing the analytes. In this step, the extracting solvent is dispersed into the aqueous sample as very fine droplets and the analytes are enriched into it. After the formation of a cloudy solution, the surface area between the extracting solvent and the aqueous sample becomes very large, so the equilibrium state is quickly attained and, therefore, the extraction time is very short. In fact, this is the principal advantage of this method. (ii) Centrifugation of the cloudy solution, thereby obtaining a settled phase that is deposited at the bottom of a conical tube. Other advantages include simplicity of operation, rapidity, low cost, high recovery, high enrichment factor and environment benignity (18). Like the other analytical methods, DLLME has some disadvantages, which result from the requirements related to the organic extraction and disperser solvents. The extraction solvent used should have some special requirements, such as a density larger than water for simple separation of the extraction phase after centrifugation and to form a cloudy solution in the presence of the disperser solvent. The potential organic solvents meeting this requirement are limited since they are hazardous chemicals (such as halogenated hydrocarbons). It is precisely because of this the choice of the extraction solvent becomes the method’s primary limitation (16). According to detection techniques, several methods were used involving liquid chromatography as well as gas chromatography (7–9, 12).
The aim of this study was to develop a gas chromatography–mass spectrometry (GC–MS) method for the determination and quantification of antidepressants in PF using DLLME as a new extraction method. The validation of the method was carried out according to the guidelines of the FDA (19). The method was then applied to PF samples collected from deceased people.
Material and Methods
Chemicals
Acetonitrile and chloroform gradient grade solvents were purchased from Merck® (Madrid, Spain) and sodium chloride from Panreac® (Barcelona, Spain). Fluoxetine, venlafaxine, mirtazapine, sertraline, citalopram, olanzapine, paroxetine and proadifen (SKF), used as internal standard, were obtained from Cerilliant®. Distilled water was processed through a Milli-Q water system (Millipore, Bedford, MA, USA).
Matrix collection
To carry out the validation procedure, antidepressant-free PF obtained from autopsies was used. For this purpose, a mixture of PF from deceased subjects was collected and stored at –20°C until use, following a previous peripheral blood and urine analysis that was negative to antidepressants.
Sample preparation
PF used for validation was previously ultracentrifuged for 5 min at 14,000 rpm. Aliquots of 0.3 mL were used for analysis, collected in a glass tube and spiked with Proadifen (SKF) (20 µL Sol. 10 µg/mL). Then, it was diluted with water (1.1 mL) and 150 mg of NaCl was also added to facilitate analytes’ transition from aqueous phase to organic phase. This mixture was submited to the DLLME. After an experimental design using StatGraphics (StatGraphics Technologies, Inc.), the optimal conditions were as follows: 175 uL of chloroform and 750 uL of acetonitrile as the best extracting and disperser solvents, respectively. Both solvents were rapidly injected into the sample with a Pasteur pipette and the mixture was gently shaken. Then, the mixture was centrifuged, and the droplet formed was collected by a 100 µL syringe and transferred to an 8 mL glass tube. The organic solvent was evaporated under a stream of nitrogen in a heated aluminum block at 40°C (VLM GmbH, HP series). The dried residue was redissolved with 40 µL of methanol prior to injection of a 2 µL aliquot into the GC–MS system.
Instrumentation
Chromatographic analyses were performed using an electron impact ionization gas chromatograph model 7890 B from Agilent Technologies® (Las Rozas, Spain) interfaced to a mass selective detector (MSD) model 5977 B, also from Agilent Technologies®. An HP5-MS capillary column (30 m × 250 µm i.d., 0.5 µm film thickness; Agilent Technologies®) with helium as carrier gas (1 mL/min) was used for the gas chromatographic separation. The injector temperature was set at 250°C and a purge time of 2 min was used. Samples were injected in the splitless mode. The following temperature program was applied: the initial temperature of the column was 100°C for 1 min, then ramped-up progressively at 35°C/min up to 220°C, held constant for 1 min, and then ramped-up again at 8°C/min up to 260°C and held for 2 min. Finally, the temperature was ramped-up at 5°C/min up to 280°C for 3 min. After that, the temperature was increased to 290°C for 5 min to clean the column. The total chromatographic separation time was 19.43 min, and the total run time was 24.43 min. The MSD was kept at 300°C, the ion source at 230°C and the quadrupole at 150°C.
Identification of compounds
Initially, neat standards of all antidepressants were injected and analyzed using the full scan mode of the GC–MS, which scanned from 50 to 550 amu. Quantifier and qualifier ions used for each analyte were selected based on their abundances and mass-to-charge ratios (m/z). Because of their reproducibilities and lack of interference, high mass ions were selected whenever possible. The ions selected for each compound studied and the retention times are shown in Table I. Upon selection of ion, the mass spectrometry was run in selected ion monitoring mode (Figure 1).
Table I. Retention Times and Ions Selected for Monitorization
Analyte Quantifier ion, m/z Qualifier ions, m/z Retention time, min
Fluoxetine 104 148, 309 7.78
Venlafaxine 58 134, 179 9.97
Mirtazapine 195 208, 245 11.78
SKF 86 99, 165 12.30
Sertraline 274 276, 262 13.55
Citalopram 58 238, 324 13.20
Paroxetine 192 138, 329 16.09
Olanzapine 242 229, 207 18.50
Figure 1. Extracted ionic chromatogram of all analytes.
Results
Experimental design
To find the best conditions for DLLME, 18 replicates were performed using a 2 × 4 factorial design with four factors: sample volume, water volume, extracting solvent volume and disperser solvent volume. The experimental design was achieved using Statgraphics 18. To make this design rotatable, for each factor, two axial points were chosen, and the runs were randomized to exclude the block effects. Response surface methodology (RSM) is a combination of mathematical and statistical techniques used to study the relationship between two or more responses that depend on several factors or independent variables. The final goal of RSM is to optimize responses determining the best conditions in the operation of the system. Our design of response surface was obtained using the statistical software StatGraphics (Figure 2).
Figure 2. Response surface graph.
Validation of the method
Validation was achieved according to the FDA Guideline for Bioanalytical Method Validation (19). The suitability of the method for quantitative analysis was studied by testing selectivity, linearity and sensitivity, precision and accuracy and recovery.
Selectivity
Selectivity is the ability of an analytical method to differentiate and quantify the analyte in the presence of other components in the sample. It should confirm that the assay is free of potential interfering substances, include endogenous matrix components, metabolites, decomposition products and medication and other exogenous xenobiotics. The selectivity of the method was demonstrated by analyzing six blank PF samples (19). No interfering peaks were found at the retention time for all analytes (Figure 3).
Figure 3. Chromatogram of a blank PF.
Linearity
Standard addition curves were obtained in six runs with the described method using drug-free control PF spiked with standard solutions to obtain the range of concentrations shown in Table II. The curves were obtained by fitting the ratio of the peak areas of analytes to that of IS versus concentrations. A linear response was observed in the studied range with a good correlation coefficient (higher than 0.99 in all cases). The sensitivity of the method was determined by calculation of the limit of detection (LOD) and the lower limit of quantification (LLOQ). LOD was determined by an empirical method that consists of analyzing a series of PF samples containing decreasing amounts of the analytes. LOD was the lowest concentration that presented a signal-to-noise ratio higher than 3 for at least three diagnostic ions for each substance. The LLOQ was the lowest concentration of analytes in a sample that can be determined with appropriate precision (20%) and accuracy (80–120%) (19) (Table II).
Table II. LOD, Limit of Quantification and Calibration Results for the Antidepressants Studied
Analyte LOD (µg/mL) LLOQ (µg/mL) C. coef. Range of calibration (µg/mL)
Fluoxetine 0.05 0.2 0.991 0.2–10
Venlafaxine 0.01 0.02 0.991 0.02–10
Mirtazapine 0.01 0.02 0.997 0.02–5
Sertraline 0.005 0.2 0.992 0.2–5
Citalopram 0.01 0.04 0.995 0.04–5
Olanzapine 0.02 0.2 0.993 0.2–10
Paroxetine 0.2 1 0.997 1–10
C. coef., correlation coefficient.
Precision and accuracy
The accuracy of an analytical method describes the closeness of mean test results obtained by the method to the true value (concentration) of the analyte. The precision of an analytical method describes the closeness of individual measures of an analyte when the procedure is applied repeatedly to multiple aliquots of a single homogeneous volume of biological matrix. Precision and accuracy were determined by inter- and intra-day assay. Inter-day precision and accuracy were calculated by analyzing negative PF samples spiked with the antidepressants at three concentrations; the LLOQ, the upper limit of quantification and an intermediate level were assessed by analyzing five replicates each day in five different days for each level of concentration. Intra-day precision and accuracy were determined at three concentrations, by preparing and analyzing five replicates for each level on the same day. Precision, expressed as the coefficient of variation of the measured values, was expected to be less than 15% at all concentrations, except for the LLOQ for which 20% was acceptable. In the same way, accuracy was evaluated using the mean relative error (ME), which had to be less than 15% of the theoretical values at each concentration level except for the LLOQ, for which 20% was acceptable (19). Data presented in Table III (Supplementary Material) satisfied the international validation rules.
Table III. Intra- and Inter-Day Precision and Accuracy (ME) of the Method
Intra-day study (n = 5) Inter-day study (n = 5)
Concentrations (μg/mL) ME (%) RSD (%) ME (%) RSD (%)
Fluoxetine
0.2 17 5 14 10
5 6 5 8 4
10 6 7 1 5
Venlafaxine
0.02 18 8 14 7
5 6 3 5 3
10 2 5 1 4
Mirtazapine
0.02 19 3 16 6
2.5 11 2 6 2
5 1 4 3 6
Sertraline
0.2 17 7 18 7
2.5 8 5 6 3
5 2 8 1 4
Citalopram
0.04 17 10 13 7
2.5 5 4 4 3
5 1 4 2 3
Paroxetine
1 13 12 13 12
5 8 15 9 12
10 14 12 1 7
Olanzapine
0.2 12 14 19 5
5 14 3 9 6
10 6 3 2 7
RSD: Relative Standard Deviation.
Recovery
The recovery of an analyte is the detector response obtained from an amount of the analyte added to an extracted from the biological matrix, compared to the detector response obtained for the true concentration of the pure authentic standard (19). The recovery of the method was examined by comparing the analytical results for extracted samples at three levels of concentration (high, medium and low) five times within three days with theoretical concentration that represent 100% recovery. The data obtained demonstrates that the extraction procedure is particularly efficient, providing a recovery values ranged from 85 to 105% for all compounds. The results are shown in Table IV (Supplementary Material).
Table IV. Intra and Inter-Day Accuracy (Analytical Recovery) of the Method
Intra-day study (n = 5) Inter-day study (n = 5)
Concentrations (μg/mL) Recovery (%) Recovery (%)
Fluoxetine
0.2 98 89
5 93 91
10 94 100
Venlafaxine
0.02 92 95
5 93 95
10 98 99
Mirtazapine
0.02 85 94
2.5 89 94
5 92 97
Sertraline
0.2 97 98
2.5 91 94
5 98 99
Citalopram
0.04 93 105
2.5 95 96
5 99 98
Paroxetine
1 93 93
5 91 91
10 94 101
Olanzapine
0.2 89 89
5 85 90
10 87 98
Application to real cases
The developed method was used to analyze 31 real PF samples obtained from the Forensic Toxicology Service of the Institute of Forensic Sciences of Santiago de Compostela from cases including suicide, overdose or death from unknown causes. Some information is described in Table V. From the 31 cases, 21 were positive for at least one of the substances analyzed. Venlafaxine and olanzapine were the two antidepressants most frequently found in 12 and 4 cases, respectively. There were also positive cases for mirtazapine, fluoxetine, sertraline and citalopram. Three samples were positive for several compounds at the same time. Figures 4 and 5 show real cases analyzed in our laboratory with their corresponding mass spectra (Figures 6 and 7). One of them corresponds to a female whose cause of death was hanging after having consumed high amounts of several drugs and the other case belongs to a male poisoned by carbon monoxide.
Table V. Real Cases
Case no. Age Sex Sample Cause of death General information and treatment Substance detected
(years) [µg/mL]
1 82 Female Blood, urine and PF Pulmonary embolism Depressive disorder Mirtazapine [0.48]
2 83 Female Blood, urine and PF Traumatic brain injury Duloxetine, bromazepam, quetiapine, tramadol and metamizol –
3 42 Female Blood, urine and PF Suicide Psychiatric treatment for schizophrenia. Lormetazepam and paliperidone Venlafaxine [0.27]
4 32 Female Blood and PF Suicide Depressive disorder. Risperidone, benzodiazepines and olanzapine Olanzapine <LLOQ
5 56 Female Blood, urine and PF Suicide Venlafaxine and benzodiazepines Venlafaxine [3.44]
6 45 Male Blood, urine, vitreous humor and PF Suicide Past history of drug abuse Venlafaxine [0.27]
7 52 Male Blood, vitreous humor and PF Acute myocardial infarction Depressive disorder –
8 45 Male Blood and PF Possible cardiac death Paranoid Schizophrenia. Valproic acid –
9 60 Female Blood, urine, gastric content, hair, PF and nail Suicide Ketazolam and bromazepam Venlafaxine [0.28]
10 67 Male Blood, urine and PF Choking suffocation Olanzapine Venlafaxine [0.28] and olanzapine <LLOQ
11 37 Male Blood, urine, bile, vitreous humor and PF – Drinker and smoker –
12 32 Male Blood, urine and PF Fall Depressive disorder. Haloperidol, olanzapine and flufenazine, Venlafaxine [0.27] and olanzapine [0.23]
13 64 Female Blood, urine, hair, vitreous humor, bile and PF Methanol poisoning – –
14 65 Male Blood, urine, gastric content and PF Suspected suicide Heptaminol hidroclorure, sertraline –
15 83 Male Blood, urine and PF Suicide Pregabaline, carbamazepine, clonazepam and mirtazapine Mirtazapine [0.19]
16 48 Male Blood, urine and PF Adverse drug reaction Fluoxetine, lormetazepam, lorazepam, alprazolam, clozapine, cocaine and dipotassium chlorazepate Fluoxetine [0.63]
17 75 Female Blood, urine, gastric content and PF Drug overdose Tramadol, ciclobenzaprine, ketazolam and lorazepam Venlafaxine [8.48]
18 70 Female Blood, urine and PF Suicide Venlafaxine and lorazepam Venlafaxine [0.81]
19 89 Female Blood, gastric content and PF Previous depressive episodes Lorazepam and olanzapine Olanzapine <LLOQ
20 75 Female Blood, urine and PF Natural Alprazolam, trazodone, venlafaxine and quietiapine Venlafaxine [0.95]
21 47 Female Blood, urine and PF Natural Depressive and personality disorder. Alprazolam and paroxetine –
22 56 Male Blood, urine and PF Cardiac death – –
23 35 Male Blood, vitreous humor and PF Choking suffocation Benzodiacepines, topiramate, fluoxetine, paliperidone, quetiapine and mirtazapine Mirtazapine [0.39] and fluoxetine [0.20]
24 36 Male Blood, urine, vitreous humor and PF Suicide Depressive disorder –
25 61 Male Blood, urine, vitreous humor and PF Natural Bipolar disorder. Alcohol consumption. Benzodiacepines, pregabaline, sertraline and olanzapine Sertraline [0.23]
26 86 Male Blood, urine, vitreous humor and PF Carbon monoxide poisoning Sertraline, trazodone and lorazepam Sertraline [0.48]
27 73 Female Blood, urine, vitreous humor and PF Suffocation from airway occlusion Benzodiacepines and venlafaxine Venlafaxine [0.62]
28 60 Female Blood, urine and PF Empyema Alcohol consumption. Mirtazapine, quetiapine and benzodiapcepines Citalopram [0.27]
29 40 Female Blood, vitreous humor and PF Suicide Depressive disorder. Venlafaxine, benzodiacepines, clomipramine and trazodone, Venlafaxine [3.84]
30 55 Female Blood, vitreous humor and PF Natural – –
31 52 Male Blood, urine, vitreous humor and PF Suicide Depressive disorder Venlafaxine [0.33]
PF, pericardial fluid.
Figure 4. Chromatogram of a real sample (positive for venlafaxine).
Figure 5. Chromatogram of a real sample (positive for sertraline).
Figure 6. Venlafaxine mass spectra.
Figure 7. Sertraline mass spectra.
Discussion
The present work aims to contribute toward the development of methods able to quantify the presence of antidepressants in samples of PF in cases where adequate blood samples may not be available. Previous literature reports comprise only a few articles where PF is used as a biological sample for the determination of drugs (7, 8, 15). The DLLME was one of the techniques used by several authors to extract antidepressants, but only one author determined the concentration of these compounds in PF (8, 16, 20–30). Most of the articles published so far used the DLLME technique coupled to another extraction method (16, 20, 22–24, 26, 27), but few papers have followed a similar method to ours (21, 25, 28–30). Most of them employed urine as the biological matrix (25, 28–30), while Lima et al. used water samples (21). Most of the published research dealt with TCAs as the particular drugs under study (16, 20, 25–27, 29, 30), and only two articles have employed GC–MS (22, 29).
On the grounds of the available evidence, it can be stated that drug concentrations in PF are mostly equivalent to those in peripheral blood (7–9, 31). In consequence, samples of PF can be considered as an alternative for drug quantification in cases where blood samples are not available. PF is usually available in quantities large enough, thus making it suitable for toxicological purposes. In addition, rather similar treatments and procedures to those customarily used for blood can be followed, a fact that constitutes an added advantage for the use of this particular fluid. Finally, as the PF is found within a closed compartment, contamination by microorganisms is less likely to occur (8) than in case of other samples.
A set of experiments were carried out in the quest for an efficient antidepressant extraction procedure by varying several DLLME parameters as the quantity of water, salt amounts, types of extraction and disperser solvents and quantity of biological matrix used. With respect to the volume of sample used, our method uses 0.3 mL, while other authors employ larger volumes (7, 9, 31). The use of chloroform as extracting solvent and acetonitrile as disperser solvent was also determined by Fernández et al. in a study published in 2016 (23). Finally, the method here developed was fully validated with good results in accordance with the limits approved by the FDA. The developed method was used to determine 31 PF samples. The results confirmed the presence of venlafaxine in most cases (12 cases), followed by olanzapine (4 cases), mirtazapine (3 cases), fluoxetine and sertraline (2 cases) and citalopram (1 case). No positive cases for paroxetine have been found. Fernández et al. also found venlafaxine as the most frequently used antidepressant in his study (23). However, citalopram and mirtazapine were the two antidepressants most frequently detected in Leere et al.’s study (8) followed by venlafaxine and sertraline. In the study just referred to, venlafaxine was detected in six cases, having found within four of those cases drug concentrations above the therapeutic range. In addition, one of the cases here studied revealed the presence of extremely high concentrations. Paroxetine was also poorly detected (8). In our study, high concentrations of venlafaxine were also found in three cases. All antidepressants, except one, were found in concentrations above LLOQ. Of the four cases detected for olanzapine, three of them were detected at concentrations below LLOQ.
In view of the present results, we recommend that PF should be added to the list of biological samples used in a forensic laboratory. To conclude, it is worth remarking the increase in use of PF in toxicological practice as pointed out by Contreras et al. in their analysis of morphine and cocaine (11, 32).
Conclusions
The aim of the present article is to report on an optimized analytical method to determine antidepressants using PF as a biological matrix. Sample preparation based on DLLME was employed. An experimental design setup using StatGraphics 18 and 175 µL of chloroform and 750 µL of acetonitrile as the best quantities for the extracting and disperser solvents was employed. A gas chromatograph using HP5-MS capillary column was used for the separation, and a mass spectrometer was used for the identification. Analytes were identified by their retention times and mass spectra. The method provides high precision, accuracy and recovery within the linear range of detection. Therefore, our method was found to be specific, sensitive and selective enough for the routine analysis of antidepressants in PF and for the application of the method in forensic practice. In conclusion, we have shown the usefulness of PF samples in cases where adequate blood specimens cannot be made available. The existing literature regarding drug concentrations in PF is however scarce, so further studies are in order.
Supplementary Material
bkab003_Supp Click here for additional data file.
Supplementary Data
Supplementary Data is available at Journal of Analytical Toxicology online.
Funding
This research did not receive any specific grant from funding agencies in the public, commercial, or not-for-profit sectors. | Fatal | ReactionOutcome | CC BY | 33410888 | 18,752,851 | 2021-01-07 |
Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Opisthotonus'. | Non-surgical treatment of tetanus infection associated with breast cancer skin ulcer: a case report and literature review.
BACKGROUND
Previous studies have reported poor prognosis in cases of tetanus that develops after bacteria enters via breast cancer-related skin ulcers that are not treated with surgical debridement. Herein, we review the literature concerning this presentation and report the first case of complete remission from tetanus without surgical debridement of the skin ulcer.
METHODS
An Asian woman aged over 60 years had a history of skin ulcer caused by breast cancer. She was diagnosed with tetanus due to trismus and opisthotonus. Based on the suspicion that the skin ulcer was the portal of entry for tetanus bacteria, we considered several debridement and thoracic surgical options for tetanus treatment. However, debridement was not performed as the surgery was considered high risk and the patient did not consent to it. The patient received treatment with anti-tetanus globulin and metronidazole; sound insulation and shielding were also performed in a dark room. Subsequently, the patient's symptoms improved, and sound insulation and deep sedation management were completed on 19th day of hospitalization. With no symptom recurrence, the patient was discharged on Day 54. To date, over 3 years after treatment, no evidence of tetanus recurrence has been observed. The case was characterized by a lack of autonomic hyperactivity. The tetanus severity was likely representative of the low amount of toxin that the patient was exposed to.
CONCLUSIONS
This case involved moderate severity tetanus originating from a chronic skin ulcer related to breast cancer. The patient survived without undergoing extensive debridement. No evidence of tetanus relapse was observed during the follow-up period, likely due to vaccination that might have restored the patient's active immunity. Debridement is not always necessary for tetanus complicated by breast cancer skin ulcers. Furthermore, appropriate toxoid vaccination is critical for preventing the onset and recurrence of tetanus in these patients.
Background
Tetanus is caused by Clostridium tetani, an obligate anaerobic bacterium, that enters the body and releases toxins. The tetanus toxin causes severe spastic paralysis and autonomic hyperactivity, which may lead to death [1, 2]. Patients with chronic wounds such as skin ulcer are at a high risk of tetanus as these wounds provide an entry route for tetanus bacteria [3]. In fact, previous studies have shown that patients with skin ulcer due to advanced breast cancer are at a particularly high risk of developing tetanus and that removing the ulcer is the only effective treatment in such cases [4–17]. A cancerous skin ulcer contains necrotic tissue, which constitutes anaerobic environment that is conducive to the growth of tetanus bacteria and the production of toxins [3, 18, 19]. As blood flow to necrotic tissues is restricted, treatment with antibiotics tends to be ineffective in such cases due to the body’s inability to deliver the treatment to the site of infection. In addition, tetanus bacteria can form spores, which may reduce the effectiveness of antibacterial drugs. As a result, in cases of tetanus associated with chronic wounds, debridement of the wound has been considered an essential element of treatment [1, 3, 19–21]. Herein, we report about a patient with tetanus due to skin ulcer associated with breast cancer who was treated without debridement and who presented with no sign of recurrence 3 years after treatment completion.
Case presentation
An Asian woman aged over 60 years had a history of left-sided breast cancer (Fig. 1). She had received two tetanus vaccinations: first as an infant and second at around 10 years of age. She underwent cancer resection in her 40s; however, the cancer recurred and was initially treated with chemotherapy until the patient declined further treatment and stopped attending her hospital appointments. After several years, as she was no longer a patient, her medical records were discarded, leading to the loss of clinical data, including her breast cancer histopathological findings and information on disease stage and treatment. At the time of recurrence, the patient presented with an untreated breast cancer that had invaded the skin and formed a sizable tumor and ulcer in the precordial region. The patient attempted to treat her own wounds without visiting a hospital. Approximately a week before hospitalization, the patient presented with trismus. As trismus progressed, she visited a dental clinic, where the severity of her trismus precluded treatment. The patient had no disease that caused dental trismus but a cervical flexion disorder and was therefore suspected of having tetanus and subsequently referred to the Emergency Department of our hospital on the same day.
Fig. 1 Timeline of case management from admission to discharge from the intensive care unit
During admission, the patient was awake and alert; however, she could open her mouth only to the width of a single finger. In addition, she was unable to flex her neck due to involuntary overextension and pain in the posterior cervical muscles. Her blood pressure was 155/109 mmHg, heart rate was 120 beats/min, respiratory rate was 16 breaths/min, body temperature (axillary) was 36.4 °C, and SpO2 was 99% (room air). After excluding other conditions that could account for the presenting symptoms, the patient was diagnosed with tetanus.
Advanced breast cancer in the precordial region was suspected to account for the presence of a large tumor and skin ulcer (Fig. 2). Blood tests revealed a mild increase in the levels of inflammatory reaction parameters, likely occurring due to the skin ulcer. Computed tomography revealed no obvious cranial abnormalities; however, it showed that the precordial tumor had invaded the rib cage. Contralateral axillary lymph node metastasis was also observed; however, there was no evidence of distant organ metastases (Fig. 3). Since there was no history of minor or major trauma during 1 month prior to symptom onset, the skin ulcer was considered the most likely site of infection. As the patient reported being an avid gardener, she was at high risk of exposure to tetanus bacteria that may be present in the soil. The skin ulcer was extensive in width and depth; thus, highly invasive thoracoplasty was considered required to achieve sufficient debridement. However, progressing tetanus could cause postoperative complications such as flap necrosis. As the patient refused to consent to surgery, we did not perform surgical debridement but simply provided medical treatment.
Fig. 2 Front view of the breast cancer skin ulcer on Day 4 of hospitalization. The tumor was approximately 20 × 20 cm in size with extensive necrosis. The image is anonymized to protect the patient’s privacy
Fig. 3 Computed tomography performed on the day of admission showing that the tumor had invaded the rib cage
On the first day of hospitalization, the patient received an intramuscular injection of tetanus toxoid and an intravenous injection of tetanus immunoglobulin at a dose of 4500 U. After the patient was admitted to the intensive care unit (ICU), tracheal intubation and deep sedation were performed; in addition, artificial respiration management was performed in a room that was sound- and light-shielded. Concurrently, the patient received an infusion of metronidazole at a dose of 500 mg every 8 h. Fentanyl and dexmedetomidine were administered by continuous intravenous infusion for analgesia and sedation. Magnesium sulfate was intravenously injected at 2 g/day to control muscle rigidity and convulsions.
On Day 7, the patient presented with mild opisthotonus. However, there was no significant change in the autonomic nervous system function to suggest autonomic hyperactivity.
We assessed the severity of her tetanus using the Ablett classification [22]; all symptoms were in the moderate category.
On Day 16, no sign of opisthotonus was observed, suggesting that the patient had entered a recovery period. Tracheotomy was performed on Day 19 to relieve the remaining grinding trismus. On Day 20, sound insulation and shading and sedation management were completed. Oral intake and rehabilitation commenced on Day 22. The patient was discharged from the ICU on Day 25. On Day 33, the tracheal cannula was removed, and the tracheostomy was closed.
Wound treatment consisted of daily cleaning with soap and application of the petroleum jelly Vaseline. A wound care specialist nurse instructed the patient on wound care.
On Day 45 post-tetanus onset, the patient received a second dose of tetanus toxoid. The patient was discharged on Day 54. Three years after she left the hospital, she underwent an excision of a breast cancer skin ulcer. At present, 5 years post-discharge, the patient resides at home and has shown no evidence of tetanus recurrence or long-term adverse events. At the time of writing (July 2020), the patient continues to receive chemotherapy.
Discussion and conclusion
C. tetani grow and germinate in an anaerobic environment (necrotic tissue) and produce toxins. Although antibacterial agents tend to be effective in killing germinated tetanus bacteria, their effectiveness in killing these bacteria in the spore state is reduced; thus, treatment of tetanus in the necrotic tissue requires an approach that includes elements other than an antibacterial agent alone. An ulcer resulting from advanced breast cancer tends to move toward the surface of the body, exposing the chest wall in the process. This lesion is associated with anaerobic infection;
cases of tetanus infection from a breast cancer skin ulcer have been reported among other types of anaerobic infection.
The spore-forming C. tetani are resilient and can survive for a long time in an environment that is unsuitable for their activity. However, when the environment does become favorable, the host develops tetanus due to bacterial germination and the production of C. tetani toxins. Furthermore, a previous experimental study examining the impact of inoculating cancer-bearing animals showed that C. tetani spores that invade through a fresh wound can quickly migrate to and colonize necrotic tissues of cancer, leading to the development of tetanus [19]. In essence, a breast cancer skin ulcer functions as a reservoir of C. tetani toxins, even if they originally developed elsewhere.
Chronic wounds other than breast cancer skin ulcers can also be an entry point for tetanus bacteria. Barogui et al. reported a case of tetanus infection from a Bruli ulcer, which is an endemic disease in the tropics. The patient was cured of tetanus via debridement performed for the treatment of a Bruli ulcer [23]. Evidence suggests that active debridement of the infection site is important for the treatment of tetanus [1, 3, 19–21].
Recent studies have reported 15 cases of tetanus in patients with breast cancer skin ulcer (Table 1) [4–17]. Twelve of these cases (A-L) underwent surgical debridement. Two cases (C, I) died of tetanus after debridement was performed. One case (G) recovered from tetanus, but the patient died of sequela. Overall, this evidence suggests that tetanus originating from breast cancer skin ulcers is associated with a high risk of death and recurrence. As in the present case, debridement itself can be life threatening, resulting in patients refusing consent to surgery. In such cases, alternatives to debridement should be considered to help achieve good patient outcomes.
Table 1 Summary of previously reported cases of tetanus associated with breast cancer-related skin ulcer. No previous studies reported long-term antimicrobial therapy for the prevention of tetanus recurrence
Case Age Debridement Antibiotics Tetanus immunoglobulin Toxoid (after tetanus infection) Autonomic hyperactivity Recurrence Outcome Reference number
A 62 Yes Penicillin and metronidazole N/A One time N/A N/A Survival [4]
B 55 Yes Yes (specifics unknown) Yes N/A No No Survival [5]a
C 53 Yes Penicillin, ceftazidime, imipenem, and gentamycin Yes One time Yes No Deceased [6]
D 46 Yes Penicillin Yes N/A Yes N/A Survival [7]
E 59 Yes Penicillin Yes One time N/A N/A Survival [8]
F 75 Yes Piperacillin Yes N/A Yes N/A Survival [9]
G 56 Yes N/A Yes N/A N/A N/A Deceased [10]
H 55 Yes Penicillin Yes N/A Yes N/A Survival [11]
I 60 Yes N/A N/A N/A Yes No Deceased [12]
J 60 Yes Penicillin Yes Two times Yes N/A Survival [13]
K 67 Yes Penicillin Yes One time Yes No Survival [14]
L 65 Yes Penicillin, metronidazole, and cefepime Yes One time Yes No Survival [15]
M 50s No Meropenem Yes No Yes No Deceased [16]a
N 40 No Metronidazole Yes One time Yes Yes Deceased [17]
O 54 No Metronidazole, piperacillin/tazobactam, and ceftriaxone Yes One time No Yes Survival [17]
aWe contacted the authors of these papers directly and included the information they provided in this table
Three cases (M-O) of skin ulcer-related tetanus treated without debridement were previously reported. Among them, one patient (M) died as a result of tetanus, while the remaining two patients (N, O) achieved remission. However, both patients experienced recurrence: one patient (N) died of recurrent tetanus and the other patient (O) experienced tetanus remission and recurrence at least twice, but the patient’s subsequent course is unknown. Autonomic hyperactivity due to tetanus was not seen in the first remission of either case (N, O). At the time of recurrence, one of the patients (N) died due to autonomic hyperactivity, whereas the other patient (O), whose tetanus was localized, subsequently went into remission.
The severity of tetanus depends on the amount of bacterial toxin present. The most serious cases of tetanus show autonomic symptoms [24].
Severe tetanus is associated with poor prognosis compared to that associated its mild form [1, 24]. Although toxin levels may determine patient prognosis, no previous study has examined this association.
The amount of toxins present in the body is associated with the severity of tetanus and the amount of time that passes between bacterial invasion and treatment commencement. In the present case, we observed rapid remission with no recurrence. There are two reasons that may account for this finding. First, the administration of metronidazole might have killed all the tetanus bacteria before they were able to sporulate further. Concurrently, the administration of antitoxin antibodies might have neutralized the activity of the remaining toxin. However, as similar cases (M, N) have previously shown, tetanus bacillus can remain latent in the body and may cause tetanus recurrence. In animal studies in which tetanus bacteria were inoculated into cancer-bearing rats, tetanus bacteria were established in the tumor within 48 h [19]. In the present case, the patient presented more than a week after the onset of disease; the delay made it difficult to eliminate all tetanus bacteria and toxins with the use of antimicrobials and antitoxin antibodies. Second, the present patient may have acquired active immunity through two vaccinations, which may in turn have inhibited the recurrence of tetanus. The present case differs from cases N and O in that there has been no recurrence for at least 3 years after remission. Our patient had a booster shot before discharge from our hospital, while cases N and O received toxoid only once at the time of admission. Antibody titers rarely rise sufficiently with a single inoculation of toxoid. In fact, some cases of tetanus that recurred after vaccination involved antibody titers below the onset arrest concentration of 0.01 IU/ml [2, 25, 26].
Surgical resection of chronic wounds is the most reliable method of reducing the risk of tetanus recurrence. In cases where surgery cannot be performed, active immunity is required to suppress recurrence. The present patient did not experience tetanus recurrence for 3 years since the completion of treatment likely due to acquired active immunity. Tetanus can be a life-threatening disease whose occurrence can be prevented by vaccination. Cancer patients with lesions susceptible to tetanus should be actively vaccinated [3].
Nevertheless, a case of malignant tumor-associated tetanus, in which three inoculations of toxoid failed to activate immunity, likely due to the effect of cancer-induced immunodeficiency, has been reported [27]. At present, these is no clear evidence on how many toxoid inoculations should be given to cancer-bearing patients. Therefore, tetanus antibody titers should be measured in conjunction with vaccination administration to ensure that adequate antibody titers are maintained.
The tetanus antibody titer value required to prevent tetanus or maintain its remission in cancer patients remains unclear. In fact, no previous study has investigated the optimum dose, frequency, or duration of toxoid inoculation required for such patients. Further research is required to elucidate these parameters.
In summary, tetanus with chronic skin ulcer without autonomic hyperactivity can be ameliorated without debridement. However, as tetanus is prone to recurrence, the acquisition of active immunity is essential to prevent recurrence after remission. Multiple doses of vaccination may be required to ensure adequate antibody titers and immunity to tetanus are achieved in cancer patients [17, 25–27].
Abbreviation
ICUIntensive care unit
Publisher’s Note
Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
All authors express their deep gratitude to the paramedical staff for their professional and devoted service.
Authors’ contributions
KN (corresponding author) wrote the entire manuscript and performed the literature review. ES compiled the patient’s medical history and laboratory data. AY, WA, ES, SS, HO, YT, SU, and EN contributed to the interpretation of the clinical manifestations and revised the manuscript for critical intellectual content. All authors have read and approved the manuscript.
Funding
This study received no specific funding.
Availability of data and materials
The datasets used and/or analyzed during the current study available from the corresponding author on reasonable request.
Ethics approval and consent to participate
Not applicable.
Consent for publication
Written consent to publish our case was obtained from the patient. A copy of the written consent is available to be reviewed by the editorial committee of this journal.
Competing interests
The authors declare that they have no competing interests. | DEXMEDETOMIDINE, FENTANYL, HUMAN CLOSTRIDIUM TETANI TOXOID IMMUNE GLOBULIN, MAGNESIUM SULFATE, METRONIDAZOLE, TETANUS TOXOIDS | DrugsGivenReaction | CC BY | 33413196 | 18,794,500 | 2021-01-07 |
What was the administration route of drug 'DEXMEDETOMIDINE'? | Non-surgical treatment of tetanus infection associated with breast cancer skin ulcer: a case report and literature review.
BACKGROUND
Previous studies have reported poor prognosis in cases of tetanus that develops after bacteria enters via breast cancer-related skin ulcers that are not treated with surgical debridement. Herein, we review the literature concerning this presentation and report the first case of complete remission from tetanus without surgical debridement of the skin ulcer.
METHODS
An Asian woman aged over 60 years had a history of skin ulcer caused by breast cancer. She was diagnosed with tetanus due to trismus and opisthotonus. Based on the suspicion that the skin ulcer was the portal of entry for tetanus bacteria, we considered several debridement and thoracic surgical options for tetanus treatment. However, debridement was not performed as the surgery was considered high risk and the patient did not consent to it. The patient received treatment with anti-tetanus globulin and metronidazole; sound insulation and shielding were also performed in a dark room. Subsequently, the patient's symptoms improved, and sound insulation and deep sedation management were completed on 19th day of hospitalization. With no symptom recurrence, the patient was discharged on Day 54. To date, over 3 years after treatment, no evidence of tetanus recurrence has been observed. The case was characterized by a lack of autonomic hyperactivity. The tetanus severity was likely representative of the low amount of toxin that the patient was exposed to.
CONCLUSIONS
This case involved moderate severity tetanus originating from a chronic skin ulcer related to breast cancer. The patient survived without undergoing extensive debridement. No evidence of tetanus relapse was observed during the follow-up period, likely due to vaccination that might have restored the patient's active immunity. Debridement is not always necessary for tetanus complicated by breast cancer skin ulcers. Furthermore, appropriate toxoid vaccination is critical for preventing the onset and recurrence of tetanus in these patients.
Background
Tetanus is caused by Clostridium tetani, an obligate anaerobic bacterium, that enters the body and releases toxins. The tetanus toxin causes severe spastic paralysis and autonomic hyperactivity, which may lead to death [1, 2]. Patients with chronic wounds such as skin ulcer are at a high risk of tetanus as these wounds provide an entry route for tetanus bacteria [3]. In fact, previous studies have shown that patients with skin ulcer due to advanced breast cancer are at a particularly high risk of developing tetanus and that removing the ulcer is the only effective treatment in such cases [4–17]. A cancerous skin ulcer contains necrotic tissue, which constitutes anaerobic environment that is conducive to the growth of tetanus bacteria and the production of toxins [3, 18, 19]. As blood flow to necrotic tissues is restricted, treatment with antibiotics tends to be ineffective in such cases due to the body’s inability to deliver the treatment to the site of infection. In addition, tetanus bacteria can form spores, which may reduce the effectiveness of antibacterial drugs. As a result, in cases of tetanus associated with chronic wounds, debridement of the wound has been considered an essential element of treatment [1, 3, 19–21]. Herein, we report about a patient with tetanus due to skin ulcer associated with breast cancer who was treated without debridement and who presented with no sign of recurrence 3 years after treatment completion.
Case presentation
An Asian woman aged over 60 years had a history of left-sided breast cancer (Fig. 1). She had received two tetanus vaccinations: first as an infant and second at around 10 years of age. She underwent cancer resection in her 40s; however, the cancer recurred and was initially treated with chemotherapy until the patient declined further treatment and stopped attending her hospital appointments. After several years, as she was no longer a patient, her medical records were discarded, leading to the loss of clinical data, including her breast cancer histopathological findings and information on disease stage and treatment. At the time of recurrence, the patient presented with an untreated breast cancer that had invaded the skin and formed a sizable tumor and ulcer in the precordial region. The patient attempted to treat her own wounds without visiting a hospital. Approximately a week before hospitalization, the patient presented with trismus. As trismus progressed, she visited a dental clinic, where the severity of her trismus precluded treatment. The patient had no disease that caused dental trismus but a cervical flexion disorder and was therefore suspected of having tetanus and subsequently referred to the Emergency Department of our hospital on the same day.
Fig. 1 Timeline of case management from admission to discharge from the intensive care unit
During admission, the patient was awake and alert; however, she could open her mouth only to the width of a single finger. In addition, she was unable to flex her neck due to involuntary overextension and pain in the posterior cervical muscles. Her blood pressure was 155/109 mmHg, heart rate was 120 beats/min, respiratory rate was 16 breaths/min, body temperature (axillary) was 36.4 °C, and SpO2 was 99% (room air). After excluding other conditions that could account for the presenting symptoms, the patient was diagnosed with tetanus.
Advanced breast cancer in the precordial region was suspected to account for the presence of a large tumor and skin ulcer (Fig. 2). Blood tests revealed a mild increase in the levels of inflammatory reaction parameters, likely occurring due to the skin ulcer. Computed tomography revealed no obvious cranial abnormalities; however, it showed that the precordial tumor had invaded the rib cage. Contralateral axillary lymph node metastasis was also observed; however, there was no evidence of distant organ metastases (Fig. 3). Since there was no history of minor or major trauma during 1 month prior to symptom onset, the skin ulcer was considered the most likely site of infection. As the patient reported being an avid gardener, she was at high risk of exposure to tetanus bacteria that may be present in the soil. The skin ulcer was extensive in width and depth; thus, highly invasive thoracoplasty was considered required to achieve sufficient debridement. However, progressing tetanus could cause postoperative complications such as flap necrosis. As the patient refused to consent to surgery, we did not perform surgical debridement but simply provided medical treatment.
Fig. 2 Front view of the breast cancer skin ulcer on Day 4 of hospitalization. The tumor was approximately 20 × 20 cm in size with extensive necrosis. The image is anonymized to protect the patient’s privacy
Fig. 3 Computed tomography performed on the day of admission showing that the tumor had invaded the rib cage
On the first day of hospitalization, the patient received an intramuscular injection of tetanus toxoid and an intravenous injection of tetanus immunoglobulin at a dose of 4500 U. After the patient was admitted to the intensive care unit (ICU), tracheal intubation and deep sedation were performed; in addition, artificial respiration management was performed in a room that was sound- and light-shielded. Concurrently, the patient received an infusion of metronidazole at a dose of 500 mg every 8 h. Fentanyl and dexmedetomidine were administered by continuous intravenous infusion for analgesia and sedation. Magnesium sulfate was intravenously injected at 2 g/day to control muscle rigidity and convulsions.
On Day 7, the patient presented with mild opisthotonus. However, there was no significant change in the autonomic nervous system function to suggest autonomic hyperactivity.
We assessed the severity of her tetanus using the Ablett classification [22]; all symptoms were in the moderate category.
On Day 16, no sign of opisthotonus was observed, suggesting that the patient had entered a recovery period. Tracheotomy was performed on Day 19 to relieve the remaining grinding trismus. On Day 20, sound insulation and shading and sedation management were completed. Oral intake and rehabilitation commenced on Day 22. The patient was discharged from the ICU on Day 25. On Day 33, the tracheal cannula was removed, and the tracheostomy was closed.
Wound treatment consisted of daily cleaning with soap and application of the petroleum jelly Vaseline. A wound care specialist nurse instructed the patient on wound care.
On Day 45 post-tetanus onset, the patient received a second dose of tetanus toxoid. The patient was discharged on Day 54. Three years after she left the hospital, she underwent an excision of a breast cancer skin ulcer. At present, 5 years post-discharge, the patient resides at home and has shown no evidence of tetanus recurrence or long-term adverse events. At the time of writing (July 2020), the patient continues to receive chemotherapy.
Discussion and conclusion
C. tetani grow and germinate in an anaerobic environment (necrotic tissue) and produce toxins. Although antibacterial agents tend to be effective in killing germinated tetanus bacteria, their effectiveness in killing these bacteria in the spore state is reduced; thus, treatment of tetanus in the necrotic tissue requires an approach that includes elements other than an antibacterial agent alone. An ulcer resulting from advanced breast cancer tends to move toward the surface of the body, exposing the chest wall in the process. This lesion is associated with anaerobic infection;
cases of tetanus infection from a breast cancer skin ulcer have been reported among other types of anaerobic infection.
The spore-forming C. tetani are resilient and can survive for a long time in an environment that is unsuitable for their activity. However, when the environment does become favorable, the host develops tetanus due to bacterial germination and the production of C. tetani toxins. Furthermore, a previous experimental study examining the impact of inoculating cancer-bearing animals showed that C. tetani spores that invade through a fresh wound can quickly migrate to and colonize necrotic tissues of cancer, leading to the development of tetanus [19]. In essence, a breast cancer skin ulcer functions as a reservoir of C. tetani toxins, even if they originally developed elsewhere.
Chronic wounds other than breast cancer skin ulcers can also be an entry point for tetanus bacteria. Barogui et al. reported a case of tetanus infection from a Bruli ulcer, which is an endemic disease in the tropics. The patient was cured of tetanus via debridement performed for the treatment of a Bruli ulcer [23]. Evidence suggests that active debridement of the infection site is important for the treatment of tetanus [1, 3, 19–21].
Recent studies have reported 15 cases of tetanus in patients with breast cancer skin ulcer (Table 1) [4–17]. Twelve of these cases (A-L) underwent surgical debridement. Two cases (C, I) died of tetanus after debridement was performed. One case (G) recovered from tetanus, but the patient died of sequela. Overall, this evidence suggests that tetanus originating from breast cancer skin ulcers is associated with a high risk of death and recurrence. As in the present case, debridement itself can be life threatening, resulting in patients refusing consent to surgery. In such cases, alternatives to debridement should be considered to help achieve good patient outcomes.
Table 1 Summary of previously reported cases of tetanus associated with breast cancer-related skin ulcer. No previous studies reported long-term antimicrobial therapy for the prevention of tetanus recurrence
Case Age Debridement Antibiotics Tetanus immunoglobulin Toxoid (after tetanus infection) Autonomic hyperactivity Recurrence Outcome Reference number
A 62 Yes Penicillin and metronidazole N/A One time N/A N/A Survival [4]
B 55 Yes Yes (specifics unknown) Yes N/A No No Survival [5]a
C 53 Yes Penicillin, ceftazidime, imipenem, and gentamycin Yes One time Yes No Deceased [6]
D 46 Yes Penicillin Yes N/A Yes N/A Survival [7]
E 59 Yes Penicillin Yes One time N/A N/A Survival [8]
F 75 Yes Piperacillin Yes N/A Yes N/A Survival [9]
G 56 Yes N/A Yes N/A N/A N/A Deceased [10]
H 55 Yes Penicillin Yes N/A Yes N/A Survival [11]
I 60 Yes N/A N/A N/A Yes No Deceased [12]
J 60 Yes Penicillin Yes Two times Yes N/A Survival [13]
K 67 Yes Penicillin Yes One time Yes No Survival [14]
L 65 Yes Penicillin, metronidazole, and cefepime Yes One time Yes No Survival [15]
M 50s No Meropenem Yes No Yes No Deceased [16]a
N 40 No Metronidazole Yes One time Yes Yes Deceased [17]
O 54 No Metronidazole, piperacillin/tazobactam, and ceftriaxone Yes One time No Yes Survival [17]
aWe contacted the authors of these papers directly and included the information they provided in this table
Three cases (M-O) of skin ulcer-related tetanus treated without debridement were previously reported. Among them, one patient (M) died as a result of tetanus, while the remaining two patients (N, O) achieved remission. However, both patients experienced recurrence: one patient (N) died of recurrent tetanus and the other patient (O) experienced tetanus remission and recurrence at least twice, but the patient’s subsequent course is unknown. Autonomic hyperactivity due to tetanus was not seen in the first remission of either case (N, O). At the time of recurrence, one of the patients (N) died due to autonomic hyperactivity, whereas the other patient (O), whose tetanus was localized, subsequently went into remission.
The severity of tetanus depends on the amount of bacterial toxin present. The most serious cases of tetanus show autonomic symptoms [24].
Severe tetanus is associated with poor prognosis compared to that associated its mild form [1, 24]. Although toxin levels may determine patient prognosis, no previous study has examined this association.
The amount of toxins present in the body is associated with the severity of tetanus and the amount of time that passes between bacterial invasion and treatment commencement. In the present case, we observed rapid remission with no recurrence. There are two reasons that may account for this finding. First, the administration of metronidazole might have killed all the tetanus bacteria before they were able to sporulate further. Concurrently, the administration of antitoxin antibodies might have neutralized the activity of the remaining toxin. However, as similar cases (M, N) have previously shown, tetanus bacillus can remain latent in the body and may cause tetanus recurrence. In animal studies in which tetanus bacteria were inoculated into cancer-bearing rats, tetanus bacteria were established in the tumor within 48 h [19]. In the present case, the patient presented more than a week after the onset of disease; the delay made it difficult to eliminate all tetanus bacteria and toxins with the use of antimicrobials and antitoxin antibodies. Second, the present patient may have acquired active immunity through two vaccinations, which may in turn have inhibited the recurrence of tetanus. The present case differs from cases N and O in that there has been no recurrence for at least 3 years after remission. Our patient had a booster shot before discharge from our hospital, while cases N and O received toxoid only once at the time of admission. Antibody titers rarely rise sufficiently with a single inoculation of toxoid. In fact, some cases of tetanus that recurred after vaccination involved antibody titers below the onset arrest concentration of 0.01 IU/ml [2, 25, 26].
Surgical resection of chronic wounds is the most reliable method of reducing the risk of tetanus recurrence. In cases where surgery cannot be performed, active immunity is required to suppress recurrence. The present patient did not experience tetanus recurrence for 3 years since the completion of treatment likely due to acquired active immunity. Tetanus can be a life-threatening disease whose occurrence can be prevented by vaccination. Cancer patients with lesions susceptible to tetanus should be actively vaccinated [3].
Nevertheless, a case of malignant tumor-associated tetanus, in which three inoculations of toxoid failed to activate immunity, likely due to the effect of cancer-induced immunodeficiency, has been reported [27]. At present, these is no clear evidence on how many toxoid inoculations should be given to cancer-bearing patients. Therefore, tetanus antibody titers should be measured in conjunction with vaccination administration to ensure that adequate antibody titers are maintained.
The tetanus antibody titer value required to prevent tetanus or maintain its remission in cancer patients remains unclear. In fact, no previous study has investigated the optimum dose, frequency, or duration of toxoid inoculation required for such patients. Further research is required to elucidate these parameters.
In summary, tetanus with chronic skin ulcer without autonomic hyperactivity can be ameliorated without debridement. However, as tetanus is prone to recurrence, the acquisition of active immunity is essential to prevent recurrence after remission. Multiple doses of vaccination may be required to ensure adequate antibody titers and immunity to tetanus are achieved in cancer patients [17, 25–27].
Abbreviation
ICUIntensive care unit
Publisher’s Note
Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
All authors express their deep gratitude to the paramedical staff for their professional and devoted service.
Authors’ contributions
KN (corresponding author) wrote the entire manuscript and performed the literature review. ES compiled the patient’s medical history and laboratory data. AY, WA, ES, SS, HO, YT, SU, and EN contributed to the interpretation of the clinical manifestations and revised the manuscript for critical intellectual content. All authors have read and approved the manuscript.
Funding
This study received no specific funding.
Availability of data and materials
The datasets used and/or analyzed during the current study available from the corresponding author on reasonable request.
Ethics approval and consent to participate
Not applicable.
Consent for publication
Written consent to publish our case was obtained from the patient. A copy of the written consent is available to be reviewed by the editorial committee of this journal.
Competing interests
The authors declare that they have no competing interests. | Intravenous (not otherwise specified) | DrugAdministrationRoute | CC BY | 33413196 | 18,794,500 | 2021-01-07 |
What was the administration route of drug 'FENTANYL'? | Non-surgical treatment of tetanus infection associated with breast cancer skin ulcer: a case report and literature review.
BACKGROUND
Previous studies have reported poor prognosis in cases of tetanus that develops after bacteria enters via breast cancer-related skin ulcers that are not treated with surgical debridement. Herein, we review the literature concerning this presentation and report the first case of complete remission from tetanus without surgical debridement of the skin ulcer.
METHODS
An Asian woman aged over 60 years had a history of skin ulcer caused by breast cancer. She was diagnosed with tetanus due to trismus and opisthotonus. Based on the suspicion that the skin ulcer was the portal of entry for tetanus bacteria, we considered several debridement and thoracic surgical options for tetanus treatment. However, debridement was not performed as the surgery was considered high risk and the patient did not consent to it. The patient received treatment with anti-tetanus globulin and metronidazole; sound insulation and shielding were also performed in a dark room. Subsequently, the patient's symptoms improved, and sound insulation and deep sedation management were completed on 19th day of hospitalization. With no symptom recurrence, the patient was discharged on Day 54. To date, over 3 years after treatment, no evidence of tetanus recurrence has been observed. The case was characterized by a lack of autonomic hyperactivity. The tetanus severity was likely representative of the low amount of toxin that the patient was exposed to.
CONCLUSIONS
This case involved moderate severity tetanus originating from a chronic skin ulcer related to breast cancer. The patient survived without undergoing extensive debridement. No evidence of tetanus relapse was observed during the follow-up period, likely due to vaccination that might have restored the patient's active immunity. Debridement is not always necessary for tetanus complicated by breast cancer skin ulcers. Furthermore, appropriate toxoid vaccination is critical for preventing the onset and recurrence of tetanus in these patients.
Background
Tetanus is caused by Clostridium tetani, an obligate anaerobic bacterium, that enters the body and releases toxins. The tetanus toxin causes severe spastic paralysis and autonomic hyperactivity, which may lead to death [1, 2]. Patients with chronic wounds such as skin ulcer are at a high risk of tetanus as these wounds provide an entry route for tetanus bacteria [3]. In fact, previous studies have shown that patients with skin ulcer due to advanced breast cancer are at a particularly high risk of developing tetanus and that removing the ulcer is the only effective treatment in such cases [4–17]. A cancerous skin ulcer contains necrotic tissue, which constitutes anaerobic environment that is conducive to the growth of tetanus bacteria and the production of toxins [3, 18, 19]. As blood flow to necrotic tissues is restricted, treatment with antibiotics tends to be ineffective in such cases due to the body’s inability to deliver the treatment to the site of infection. In addition, tetanus bacteria can form spores, which may reduce the effectiveness of antibacterial drugs. As a result, in cases of tetanus associated with chronic wounds, debridement of the wound has been considered an essential element of treatment [1, 3, 19–21]. Herein, we report about a patient with tetanus due to skin ulcer associated with breast cancer who was treated without debridement and who presented with no sign of recurrence 3 years after treatment completion.
Case presentation
An Asian woman aged over 60 years had a history of left-sided breast cancer (Fig. 1). She had received two tetanus vaccinations: first as an infant and second at around 10 years of age. She underwent cancer resection in her 40s; however, the cancer recurred and was initially treated with chemotherapy until the patient declined further treatment and stopped attending her hospital appointments. After several years, as she was no longer a patient, her medical records were discarded, leading to the loss of clinical data, including her breast cancer histopathological findings and information on disease stage and treatment. At the time of recurrence, the patient presented with an untreated breast cancer that had invaded the skin and formed a sizable tumor and ulcer in the precordial region. The patient attempted to treat her own wounds without visiting a hospital. Approximately a week before hospitalization, the patient presented with trismus. As trismus progressed, she visited a dental clinic, where the severity of her trismus precluded treatment. The patient had no disease that caused dental trismus but a cervical flexion disorder and was therefore suspected of having tetanus and subsequently referred to the Emergency Department of our hospital on the same day.
Fig. 1 Timeline of case management from admission to discharge from the intensive care unit
During admission, the patient was awake and alert; however, she could open her mouth only to the width of a single finger. In addition, she was unable to flex her neck due to involuntary overextension and pain in the posterior cervical muscles. Her blood pressure was 155/109 mmHg, heart rate was 120 beats/min, respiratory rate was 16 breaths/min, body temperature (axillary) was 36.4 °C, and SpO2 was 99% (room air). After excluding other conditions that could account for the presenting symptoms, the patient was diagnosed with tetanus.
Advanced breast cancer in the precordial region was suspected to account for the presence of a large tumor and skin ulcer (Fig. 2). Blood tests revealed a mild increase in the levels of inflammatory reaction parameters, likely occurring due to the skin ulcer. Computed tomography revealed no obvious cranial abnormalities; however, it showed that the precordial tumor had invaded the rib cage. Contralateral axillary lymph node metastasis was also observed; however, there was no evidence of distant organ metastases (Fig. 3). Since there was no history of minor or major trauma during 1 month prior to symptom onset, the skin ulcer was considered the most likely site of infection. As the patient reported being an avid gardener, she was at high risk of exposure to tetanus bacteria that may be present in the soil. The skin ulcer was extensive in width and depth; thus, highly invasive thoracoplasty was considered required to achieve sufficient debridement. However, progressing tetanus could cause postoperative complications such as flap necrosis. As the patient refused to consent to surgery, we did not perform surgical debridement but simply provided medical treatment.
Fig. 2 Front view of the breast cancer skin ulcer on Day 4 of hospitalization. The tumor was approximately 20 × 20 cm in size with extensive necrosis. The image is anonymized to protect the patient’s privacy
Fig. 3 Computed tomography performed on the day of admission showing that the tumor had invaded the rib cage
On the first day of hospitalization, the patient received an intramuscular injection of tetanus toxoid and an intravenous injection of tetanus immunoglobulin at a dose of 4500 U. After the patient was admitted to the intensive care unit (ICU), tracheal intubation and deep sedation were performed; in addition, artificial respiration management was performed in a room that was sound- and light-shielded. Concurrently, the patient received an infusion of metronidazole at a dose of 500 mg every 8 h. Fentanyl and dexmedetomidine were administered by continuous intravenous infusion for analgesia and sedation. Magnesium sulfate was intravenously injected at 2 g/day to control muscle rigidity and convulsions.
On Day 7, the patient presented with mild opisthotonus. However, there was no significant change in the autonomic nervous system function to suggest autonomic hyperactivity.
We assessed the severity of her tetanus using the Ablett classification [22]; all symptoms were in the moderate category.
On Day 16, no sign of opisthotonus was observed, suggesting that the patient had entered a recovery period. Tracheotomy was performed on Day 19 to relieve the remaining grinding trismus. On Day 20, sound insulation and shading and sedation management were completed. Oral intake and rehabilitation commenced on Day 22. The patient was discharged from the ICU on Day 25. On Day 33, the tracheal cannula was removed, and the tracheostomy was closed.
Wound treatment consisted of daily cleaning with soap and application of the petroleum jelly Vaseline. A wound care specialist nurse instructed the patient on wound care.
On Day 45 post-tetanus onset, the patient received a second dose of tetanus toxoid. The patient was discharged on Day 54. Three years after she left the hospital, she underwent an excision of a breast cancer skin ulcer. At present, 5 years post-discharge, the patient resides at home and has shown no evidence of tetanus recurrence or long-term adverse events. At the time of writing (July 2020), the patient continues to receive chemotherapy.
Discussion and conclusion
C. tetani grow and germinate in an anaerobic environment (necrotic tissue) and produce toxins. Although antibacterial agents tend to be effective in killing germinated tetanus bacteria, their effectiveness in killing these bacteria in the spore state is reduced; thus, treatment of tetanus in the necrotic tissue requires an approach that includes elements other than an antibacterial agent alone. An ulcer resulting from advanced breast cancer tends to move toward the surface of the body, exposing the chest wall in the process. This lesion is associated with anaerobic infection;
cases of tetanus infection from a breast cancer skin ulcer have been reported among other types of anaerobic infection.
The spore-forming C. tetani are resilient and can survive for a long time in an environment that is unsuitable for their activity. However, when the environment does become favorable, the host develops tetanus due to bacterial germination and the production of C. tetani toxins. Furthermore, a previous experimental study examining the impact of inoculating cancer-bearing animals showed that C. tetani spores that invade through a fresh wound can quickly migrate to and colonize necrotic tissues of cancer, leading to the development of tetanus [19]. In essence, a breast cancer skin ulcer functions as a reservoir of C. tetani toxins, even if they originally developed elsewhere.
Chronic wounds other than breast cancer skin ulcers can also be an entry point for tetanus bacteria. Barogui et al. reported a case of tetanus infection from a Bruli ulcer, which is an endemic disease in the tropics. The patient was cured of tetanus via debridement performed for the treatment of a Bruli ulcer [23]. Evidence suggests that active debridement of the infection site is important for the treatment of tetanus [1, 3, 19–21].
Recent studies have reported 15 cases of tetanus in patients with breast cancer skin ulcer (Table 1) [4–17]. Twelve of these cases (A-L) underwent surgical debridement. Two cases (C, I) died of tetanus after debridement was performed. One case (G) recovered from tetanus, but the patient died of sequela. Overall, this evidence suggests that tetanus originating from breast cancer skin ulcers is associated with a high risk of death and recurrence. As in the present case, debridement itself can be life threatening, resulting in patients refusing consent to surgery. In such cases, alternatives to debridement should be considered to help achieve good patient outcomes.
Table 1 Summary of previously reported cases of tetanus associated with breast cancer-related skin ulcer. No previous studies reported long-term antimicrobial therapy for the prevention of tetanus recurrence
Case Age Debridement Antibiotics Tetanus immunoglobulin Toxoid (after tetanus infection) Autonomic hyperactivity Recurrence Outcome Reference number
A 62 Yes Penicillin and metronidazole N/A One time N/A N/A Survival [4]
B 55 Yes Yes (specifics unknown) Yes N/A No No Survival [5]a
C 53 Yes Penicillin, ceftazidime, imipenem, and gentamycin Yes One time Yes No Deceased [6]
D 46 Yes Penicillin Yes N/A Yes N/A Survival [7]
E 59 Yes Penicillin Yes One time N/A N/A Survival [8]
F 75 Yes Piperacillin Yes N/A Yes N/A Survival [9]
G 56 Yes N/A Yes N/A N/A N/A Deceased [10]
H 55 Yes Penicillin Yes N/A Yes N/A Survival [11]
I 60 Yes N/A N/A N/A Yes No Deceased [12]
J 60 Yes Penicillin Yes Two times Yes N/A Survival [13]
K 67 Yes Penicillin Yes One time Yes No Survival [14]
L 65 Yes Penicillin, metronidazole, and cefepime Yes One time Yes No Survival [15]
M 50s No Meropenem Yes No Yes No Deceased [16]a
N 40 No Metronidazole Yes One time Yes Yes Deceased [17]
O 54 No Metronidazole, piperacillin/tazobactam, and ceftriaxone Yes One time No Yes Survival [17]
aWe contacted the authors of these papers directly and included the information they provided in this table
Three cases (M-O) of skin ulcer-related tetanus treated without debridement were previously reported. Among them, one patient (M) died as a result of tetanus, while the remaining two patients (N, O) achieved remission. However, both patients experienced recurrence: one patient (N) died of recurrent tetanus and the other patient (O) experienced tetanus remission and recurrence at least twice, but the patient’s subsequent course is unknown. Autonomic hyperactivity due to tetanus was not seen in the first remission of either case (N, O). At the time of recurrence, one of the patients (N) died due to autonomic hyperactivity, whereas the other patient (O), whose tetanus was localized, subsequently went into remission.
The severity of tetanus depends on the amount of bacterial toxin present. The most serious cases of tetanus show autonomic symptoms [24].
Severe tetanus is associated with poor prognosis compared to that associated its mild form [1, 24]. Although toxin levels may determine patient prognosis, no previous study has examined this association.
The amount of toxins present in the body is associated with the severity of tetanus and the amount of time that passes between bacterial invasion and treatment commencement. In the present case, we observed rapid remission with no recurrence. There are two reasons that may account for this finding. First, the administration of metronidazole might have killed all the tetanus bacteria before they were able to sporulate further. Concurrently, the administration of antitoxin antibodies might have neutralized the activity of the remaining toxin. However, as similar cases (M, N) have previously shown, tetanus bacillus can remain latent in the body and may cause tetanus recurrence. In animal studies in which tetanus bacteria were inoculated into cancer-bearing rats, tetanus bacteria were established in the tumor within 48 h [19]. In the present case, the patient presented more than a week after the onset of disease; the delay made it difficult to eliminate all tetanus bacteria and toxins with the use of antimicrobials and antitoxin antibodies. Second, the present patient may have acquired active immunity through two vaccinations, which may in turn have inhibited the recurrence of tetanus. The present case differs from cases N and O in that there has been no recurrence for at least 3 years after remission. Our patient had a booster shot before discharge from our hospital, while cases N and O received toxoid only once at the time of admission. Antibody titers rarely rise sufficiently with a single inoculation of toxoid. In fact, some cases of tetanus that recurred after vaccination involved antibody titers below the onset arrest concentration of 0.01 IU/ml [2, 25, 26].
Surgical resection of chronic wounds is the most reliable method of reducing the risk of tetanus recurrence. In cases where surgery cannot be performed, active immunity is required to suppress recurrence. The present patient did not experience tetanus recurrence for 3 years since the completion of treatment likely due to acquired active immunity. Tetanus can be a life-threatening disease whose occurrence can be prevented by vaccination. Cancer patients with lesions susceptible to tetanus should be actively vaccinated [3].
Nevertheless, a case of malignant tumor-associated tetanus, in which three inoculations of toxoid failed to activate immunity, likely due to the effect of cancer-induced immunodeficiency, has been reported [27]. At present, these is no clear evidence on how many toxoid inoculations should be given to cancer-bearing patients. Therefore, tetanus antibody titers should be measured in conjunction with vaccination administration to ensure that adequate antibody titers are maintained.
The tetanus antibody titer value required to prevent tetanus or maintain its remission in cancer patients remains unclear. In fact, no previous study has investigated the optimum dose, frequency, or duration of toxoid inoculation required for such patients. Further research is required to elucidate these parameters.
In summary, tetanus with chronic skin ulcer without autonomic hyperactivity can be ameliorated without debridement. However, as tetanus is prone to recurrence, the acquisition of active immunity is essential to prevent recurrence after remission. Multiple doses of vaccination may be required to ensure adequate antibody titers and immunity to tetanus are achieved in cancer patients [17, 25–27].
Abbreviation
ICUIntensive care unit
Publisher’s Note
Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
All authors express their deep gratitude to the paramedical staff for their professional and devoted service.
Authors’ contributions
KN (corresponding author) wrote the entire manuscript and performed the literature review. ES compiled the patient’s medical history and laboratory data. AY, WA, ES, SS, HO, YT, SU, and EN contributed to the interpretation of the clinical manifestations and revised the manuscript for critical intellectual content. All authors have read and approved the manuscript.
Funding
This study received no specific funding.
Availability of data and materials
The datasets used and/or analyzed during the current study available from the corresponding author on reasonable request.
Ethics approval and consent to participate
Not applicable.
Consent for publication
Written consent to publish our case was obtained from the patient. A copy of the written consent is available to be reviewed by the editorial committee of this journal.
Competing interests
The authors declare that they have no competing interests. | Intravenous (not otherwise specified) | DrugAdministrationRoute | CC BY | 33413196 | 18,794,500 | 2021-01-07 |
What was the administration route of drug 'HUMAN CLOSTRIDIUM TETANI TOXOID IMMUNE GLOBULIN'? | Non-surgical treatment of tetanus infection associated with breast cancer skin ulcer: a case report and literature review.
BACKGROUND
Previous studies have reported poor prognosis in cases of tetanus that develops after bacteria enters via breast cancer-related skin ulcers that are not treated with surgical debridement. Herein, we review the literature concerning this presentation and report the first case of complete remission from tetanus without surgical debridement of the skin ulcer.
METHODS
An Asian woman aged over 60 years had a history of skin ulcer caused by breast cancer. She was diagnosed with tetanus due to trismus and opisthotonus. Based on the suspicion that the skin ulcer was the portal of entry for tetanus bacteria, we considered several debridement and thoracic surgical options for tetanus treatment. However, debridement was not performed as the surgery was considered high risk and the patient did not consent to it. The patient received treatment with anti-tetanus globulin and metronidazole; sound insulation and shielding were also performed in a dark room. Subsequently, the patient's symptoms improved, and sound insulation and deep sedation management were completed on 19th day of hospitalization. With no symptom recurrence, the patient was discharged on Day 54. To date, over 3 years after treatment, no evidence of tetanus recurrence has been observed. The case was characterized by a lack of autonomic hyperactivity. The tetanus severity was likely representative of the low amount of toxin that the patient was exposed to.
CONCLUSIONS
This case involved moderate severity tetanus originating from a chronic skin ulcer related to breast cancer. The patient survived without undergoing extensive debridement. No evidence of tetanus relapse was observed during the follow-up period, likely due to vaccination that might have restored the patient's active immunity. Debridement is not always necessary for tetanus complicated by breast cancer skin ulcers. Furthermore, appropriate toxoid vaccination is critical for preventing the onset and recurrence of tetanus in these patients.
Background
Tetanus is caused by Clostridium tetani, an obligate anaerobic bacterium, that enters the body and releases toxins. The tetanus toxin causes severe spastic paralysis and autonomic hyperactivity, which may lead to death [1, 2]. Patients with chronic wounds such as skin ulcer are at a high risk of tetanus as these wounds provide an entry route for tetanus bacteria [3]. In fact, previous studies have shown that patients with skin ulcer due to advanced breast cancer are at a particularly high risk of developing tetanus and that removing the ulcer is the only effective treatment in such cases [4–17]. A cancerous skin ulcer contains necrotic tissue, which constitutes anaerobic environment that is conducive to the growth of tetanus bacteria and the production of toxins [3, 18, 19]. As blood flow to necrotic tissues is restricted, treatment with antibiotics tends to be ineffective in such cases due to the body’s inability to deliver the treatment to the site of infection. In addition, tetanus bacteria can form spores, which may reduce the effectiveness of antibacterial drugs. As a result, in cases of tetanus associated with chronic wounds, debridement of the wound has been considered an essential element of treatment [1, 3, 19–21]. Herein, we report about a patient with tetanus due to skin ulcer associated with breast cancer who was treated without debridement and who presented with no sign of recurrence 3 years after treatment completion.
Case presentation
An Asian woman aged over 60 years had a history of left-sided breast cancer (Fig. 1). She had received two tetanus vaccinations: first as an infant and second at around 10 years of age. She underwent cancer resection in her 40s; however, the cancer recurred and was initially treated with chemotherapy until the patient declined further treatment and stopped attending her hospital appointments. After several years, as she was no longer a patient, her medical records were discarded, leading to the loss of clinical data, including her breast cancer histopathological findings and information on disease stage and treatment. At the time of recurrence, the patient presented with an untreated breast cancer that had invaded the skin and formed a sizable tumor and ulcer in the precordial region. The patient attempted to treat her own wounds without visiting a hospital. Approximately a week before hospitalization, the patient presented with trismus. As trismus progressed, she visited a dental clinic, where the severity of her trismus precluded treatment. The patient had no disease that caused dental trismus but a cervical flexion disorder and was therefore suspected of having tetanus and subsequently referred to the Emergency Department of our hospital on the same day.
Fig. 1 Timeline of case management from admission to discharge from the intensive care unit
During admission, the patient was awake and alert; however, she could open her mouth only to the width of a single finger. In addition, she was unable to flex her neck due to involuntary overextension and pain in the posterior cervical muscles. Her blood pressure was 155/109 mmHg, heart rate was 120 beats/min, respiratory rate was 16 breaths/min, body temperature (axillary) was 36.4 °C, and SpO2 was 99% (room air). After excluding other conditions that could account for the presenting symptoms, the patient was diagnosed with tetanus.
Advanced breast cancer in the precordial region was suspected to account for the presence of a large tumor and skin ulcer (Fig. 2). Blood tests revealed a mild increase in the levels of inflammatory reaction parameters, likely occurring due to the skin ulcer. Computed tomography revealed no obvious cranial abnormalities; however, it showed that the precordial tumor had invaded the rib cage. Contralateral axillary lymph node metastasis was also observed; however, there was no evidence of distant organ metastases (Fig. 3). Since there was no history of minor or major trauma during 1 month prior to symptom onset, the skin ulcer was considered the most likely site of infection. As the patient reported being an avid gardener, she was at high risk of exposure to tetanus bacteria that may be present in the soil. The skin ulcer was extensive in width and depth; thus, highly invasive thoracoplasty was considered required to achieve sufficient debridement. However, progressing tetanus could cause postoperative complications such as flap necrosis. As the patient refused to consent to surgery, we did not perform surgical debridement but simply provided medical treatment.
Fig. 2 Front view of the breast cancer skin ulcer on Day 4 of hospitalization. The tumor was approximately 20 × 20 cm in size with extensive necrosis. The image is anonymized to protect the patient’s privacy
Fig. 3 Computed tomography performed on the day of admission showing that the tumor had invaded the rib cage
On the first day of hospitalization, the patient received an intramuscular injection of tetanus toxoid and an intravenous injection of tetanus immunoglobulin at a dose of 4500 U. After the patient was admitted to the intensive care unit (ICU), tracheal intubation and deep sedation were performed; in addition, artificial respiration management was performed in a room that was sound- and light-shielded. Concurrently, the patient received an infusion of metronidazole at a dose of 500 mg every 8 h. Fentanyl and dexmedetomidine were administered by continuous intravenous infusion for analgesia and sedation. Magnesium sulfate was intravenously injected at 2 g/day to control muscle rigidity and convulsions.
On Day 7, the patient presented with mild opisthotonus. However, there was no significant change in the autonomic nervous system function to suggest autonomic hyperactivity.
We assessed the severity of her tetanus using the Ablett classification [22]; all symptoms were in the moderate category.
On Day 16, no sign of opisthotonus was observed, suggesting that the patient had entered a recovery period. Tracheotomy was performed on Day 19 to relieve the remaining grinding trismus. On Day 20, sound insulation and shading and sedation management were completed. Oral intake and rehabilitation commenced on Day 22. The patient was discharged from the ICU on Day 25. On Day 33, the tracheal cannula was removed, and the tracheostomy was closed.
Wound treatment consisted of daily cleaning with soap and application of the petroleum jelly Vaseline. A wound care specialist nurse instructed the patient on wound care.
On Day 45 post-tetanus onset, the patient received a second dose of tetanus toxoid. The patient was discharged on Day 54. Three years after she left the hospital, she underwent an excision of a breast cancer skin ulcer. At present, 5 years post-discharge, the patient resides at home and has shown no evidence of tetanus recurrence or long-term adverse events. At the time of writing (July 2020), the patient continues to receive chemotherapy.
Discussion and conclusion
C. tetani grow and germinate in an anaerobic environment (necrotic tissue) and produce toxins. Although antibacterial agents tend to be effective in killing germinated tetanus bacteria, their effectiveness in killing these bacteria in the spore state is reduced; thus, treatment of tetanus in the necrotic tissue requires an approach that includes elements other than an antibacterial agent alone. An ulcer resulting from advanced breast cancer tends to move toward the surface of the body, exposing the chest wall in the process. This lesion is associated with anaerobic infection;
cases of tetanus infection from a breast cancer skin ulcer have been reported among other types of anaerobic infection.
The spore-forming C. tetani are resilient and can survive for a long time in an environment that is unsuitable for their activity. However, when the environment does become favorable, the host develops tetanus due to bacterial germination and the production of C. tetani toxins. Furthermore, a previous experimental study examining the impact of inoculating cancer-bearing animals showed that C. tetani spores that invade through a fresh wound can quickly migrate to and colonize necrotic tissues of cancer, leading to the development of tetanus [19]. In essence, a breast cancer skin ulcer functions as a reservoir of C. tetani toxins, even if they originally developed elsewhere.
Chronic wounds other than breast cancer skin ulcers can also be an entry point for tetanus bacteria. Barogui et al. reported a case of tetanus infection from a Bruli ulcer, which is an endemic disease in the tropics. The patient was cured of tetanus via debridement performed for the treatment of a Bruli ulcer [23]. Evidence suggests that active debridement of the infection site is important for the treatment of tetanus [1, 3, 19–21].
Recent studies have reported 15 cases of tetanus in patients with breast cancer skin ulcer (Table 1) [4–17]. Twelve of these cases (A-L) underwent surgical debridement. Two cases (C, I) died of tetanus after debridement was performed. One case (G) recovered from tetanus, but the patient died of sequela. Overall, this evidence suggests that tetanus originating from breast cancer skin ulcers is associated with a high risk of death and recurrence. As in the present case, debridement itself can be life threatening, resulting in patients refusing consent to surgery. In such cases, alternatives to debridement should be considered to help achieve good patient outcomes.
Table 1 Summary of previously reported cases of tetanus associated with breast cancer-related skin ulcer. No previous studies reported long-term antimicrobial therapy for the prevention of tetanus recurrence
Case Age Debridement Antibiotics Tetanus immunoglobulin Toxoid (after tetanus infection) Autonomic hyperactivity Recurrence Outcome Reference number
A 62 Yes Penicillin and metronidazole N/A One time N/A N/A Survival [4]
B 55 Yes Yes (specifics unknown) Yes N/A No No Survival [5]a
C 53 Yes Penicillin, ceftazidime, imipenem, and gentamycin Yes One time Yes No Deceased [6]
D 46 Yes Penicillin Yes N/A Yes N/A Survival [7]
E 59 Yes Penicillin Yes One time N/A N/A Survival [8]
F 75 Yes Piperacillin Yes N/A Yes N/A Survival [9]
G 56 Yes N/A Yes N/A N/A N/A Deceased [10]
H 55 Yes Penicillin Yes N/A Yes N/A Survival [11]
I 60 Yes N/A N/A N/A Yes No Deceased [12]
J 60 Yes Penicillin Yes Two times Yes N/A Survival [13]
K 67 Yes Penicillin Yes One time Yes No Survival [14]
L 65 Yes Penicillin, metronidazole, and cefepime Yes One time Yes No Survival [15]
M 50s No Meropenem Yes No Yes No Deceased [16]a
N 40 No Metronidazole Yes One time Yes Yes Deceased [17]
O 54 No Metronidazole, piperacillin/tazobactam, and ceftriaxone Yes One time No Yes Survival [17]
aWe contacted the authors of these papers directly and included the information they provided in this table
Three cases (M-O) of skin ulcer-related tetanus treated without debridement were previously reported. Among them, one patient (M) died as a result of tetanus, while the remaining two patients (N, O) achieved remission. However, both patients experienced recurrence: one patient (N) died of recurrent tetanus and the other patient (O) experienced tetanus remission and recurrence at least twice, but the patient’s subsequent course is unknown. Autonomic hyperactivity due to tetanus was not seen in the first remission of either case (N, O). At the time of recurrence, one of the patients (N) died due to autonomic hyperactivity, whereas the other patient (O), whose tetanus was localized, subsequently went into remission.
The severity of tetanus depends on the amount of bacterial toxin present. The most serious cases of tetanus show autonomic symptoms [24].
Severe tetanus is associated with poor prognosis compared to that associated its mild form [1, 24]. Although toxin levels may determine patient prognosis, no previous study has examined this association.
The amount of toxins present in the body is associated with the severity of tetanus and the amount of time that passes between bacterial invasion and treatment commencement. In the present case, we observed rapid remission with no recurrence. There are two reasons that may account for this finding. First, the administration of metronidazole might have killed all the tetanus bacteria before they were able to sporulate further. Concurrently, the administration of antitoxin antibodies might have neutralized the activity of the remaining toxin. However, as similar cases (M, N) have previously shown, tetanus bacillus can remain latent in the body and may cause tetanus recurrence. In animal studies in which tetanus bacteria were inoculated into cancer-bearing rats, tetanus bacteria were established in the tumor within 48 h [19]. In the present case, the patient presented more than a week after the onset of disease; the delay made it difficult to eliminate all tetanus bacteria and toxins with the use of antimicrobials and antitoxin antibodies. Second, the present patient may have acquired active immunity through two vaccinations, which may in turn have inhibited the recurrence of tetanus. The present case differs from cases N and O in that there has been no recurrence for at least 3 years after remission. Our patient had a booster shot before discharge from our hospital, while cases N and O received toxoid only once at the time of admission. Antibody titers rarely rise sufficiently with a single inoculation of toxoid. In fact, some cases of tetanus that recurred after vaccination involved antibody titers below the onset arrest concentration of 0.01 IU/ml [2, 25, 26].
Surgical resection of chronic wounds is the most reliable method of reducing the risk of tetanus recurrence. In cases where surgery cannot be performed, active immunity is required to suppress recurrence. The present patient did not experience tetanus recurrence for 3 years since the completion of treatment likely due to acquired active immunity. Tetanus can be a life-threatening disease whose occurrence can be prevented by vaccination. Cancer patients with lesions susceptible to tetanus should be actively vaccinated [3].
Nevertheless, a case of malignant tumor-associated tetanus, in which three inoculations of toxoid failed to activate immunity, likely due to the effect of cancer-induced immunodeficiency, has been reported [27]. At present, these is no clear evidence on how many toxoid inoculations should be given to cancer-bearing patients. Therefore, tetanus antibody titers should be measured in conjunction with vaccination administration to ensure that adequate antibody titers are maintained.
The tetanus antibody titer value required to prevent tetanus or maintain its remission in cancer patients remains unclear. In fact, no previous study has investigated the optimum dose, frequency, or duration of toxoid inoculation required for such patients. Further research is required to elucidate these parameters.
In summary, tetanus with chronic skin ulcer without autonomic hyperactivity can be ameliorated without debridement. However, as tetanus is prone to recurrence, the acquisition of active immunity is essential to prevent recurrence after remission. Multiple doses of vaccination may be required to ensure adequate antibody titers and immunity to tetanus are achieved in cancer patients [17, 25–27].
Abbreviation
ICUIntensive care unit
Publisher’s Note
Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
All authors express their deep gratitude to the paramedical staff for their professional and devoted service.
Authors’ contributions
KN (corresponding author) wrote the entire manuscript and performed the literature review. ES compiled the patient’s medical history and laboratory data. AY, WA, ES, SS, HO, YT, SU, and EN contributed to the interpretation of the clinical manifestations and revised the manuscript for critical intellectual content. All authors have read and approved the manuscript.
Funding
This study received no specific funding.
Availability of data and materials
The datasets used and/or analyzed during the current study available from the corresponding author on reasonable request.
Ethics approval and consent to participate
Not applicable.
Consent for publication
Written consent to publish our case was obtained from the patient. A copy of the written consent is available to be reviewed by the editorial committee of this journal.
Competing interests
The authors declare that they have no competing interests. | Intravenous (not otherwise specified) | DrugAdministrationRoute | CC BY | 33413196 | 18,794,500 | 2021-01-07 |
What was the administration route of drug 'MAGNESIUM SULFATE'? | Non-surgical treatment of tetanus infection associated with breast cancer skin ulcer: a case report and literature review.
BACKGROUND
Previous studies have reported poor prognosis in cases of tetanus that develops after bacteria enters via breast cancer-related skin ulcers that are not treated with surgical debridement. Herein, we review the literature concerning this presentation and report the first case of complete remission from tetanus without surgical debridement of the skin ulcer.
METHODS
An Asian woman aged over 60 years had a history of skin ulcer caused by breast cancer. She was diagnosed with tetanus due to trismus and opisthotonus. Based on the suspicion that the skin ulcer was the portal of entry for tetanus bacteria, we considered several debridement and thoracic surgical options for tetanus treatment. However, debridement was not performed as the surgery was considered high risk and the patient did not consent to it. The patient received treatment with anti-tetanus globulin and metronidazole; sound insulation and shielding were also performed in a dark room. Subsequently, the patient's symptoms improved, and sound insulation and deep sedation management were completed on 19th day of hospitalization. With no symptom recurrence, the patient was discharged on Day 54. To date, over 3 years after treatment, no evidence of tetanus recurrence has been observed. The case was characterized by a lack of autonomic hyperactivity. The tetanus severity was likely representative of the low amount of toxin that the patient was exposed to.
CONCLUSIONS
This case involved moderate severity tetanus originating from a chronic skin ulcer related to breast cancer. The patient survived without undergoing extensive debridement. No evidence of tetanus relapse was observed during the follow-up period, likely due to vaccination that might have restored the patient's active immunity. Debridement is not always necessary for tetanus complicated by breast cancer skin ulcers. Furthermore, appropriate toxoid vaccination is critical for preventing the onset and recurrence of tetanus in these patients.
Background
Tetanus is caused by Clostridium tetani, an obligate anaerobic bacterium, that enters the body and releases toxins. The tetanus toxin causes severe spastic paralysis and autonomic hyperactivity, which may lead to death [1, 2]. Patients with chronic wounds such as skin ulcer are at a high risk of tetanus as these wounds provide an entry route for tetanus bacteria [3]. In fact, previous studies have shown that patients with skin ulcer due to advanced breast cancer are at a particularly high risk of developing tetanus and that removing the ulcer is the only effective treatment in such cases [4–17]. A cancerous skin ulcer contains necrotic tissue, which constitutes anaerobic environment that is conducive to the growth of tetanus bacteria and the production of toxins [3, 18, 19]. As blood flow to necrotic tissues is restricted, treatment with antibiotics tends to be ineffective in such cases due to the body’s inability to deliver the treatment to the site of infection. In addition, tetanus bacteria can form spores, which may reduce the effectiveness of antibacterial drugs. As a result, in cases of tetanus associated with chronic wounds, debridement of the wound has been considered an essential element of treatment [1, 3, 19–21]. Herein, we report about a patient with tetanus due to skin ulcer associated with breast cancer who was treated without debridement and who presented with no sign of recurrence 3 years after treatment completion.
Case presentation
An Asian woman aged over 60 years had a history of left-sided breast cancer (Fig. 1). She had received two tetanus vaccinations: first as an infant and second at around 10 years of age. She underwent cancer resection in her 40s; however, the cancer recurred and was initially treated with chemotherapy until the patient declined further treatment and stopped attending her hospital appointments. After several years, as she was no longer a patient, her medical records were discarded, leading to the loss of clinical data, including her breast cancer histopathological findings and information on disease stage and treatment. At the time of recurrence, the patient presented with an untreated breast cancer that had invaded the skin and formed a sizable tumor and ulcer in the precordial region. The patient attempted to treat her own wounds without visiting a hospital. Approximately a week before hospitalization, the patient presented with trismus. As trismus progressed, she visited a dental clinic, where the severity of her trismus precluded treatment. The patient had no disease that caused dental trismus but a cervical flexion disorder and was therefore suspected of having tetanus and subsequently referred to the Emergency Department of our hospital on the same day.
Fig. 1 Timeline of case management from admission to discharge from the intensive care unit
During admission, the patient was awake and alert; however, she could open her mouth only to the width of a single finger. In addition, she was unable to flex her neck due to involuntary overextension and pain in the posterior cervical muscles. Her blood pressure was 155/109 mmHg, heart rate was 120 beats/min, respiratory rate was 16 breaths/min, body temperature (axillary) was 36.4 °C, and SpO2 was 99% (room air). After excluding other conditions that could account for the presenting symptoms, the patient was diagnosed with tetanus.
Advanced breast cancer in the precordial region was suspected to account for the presence of a large tumor and skin ulcer (Fig. 2). Blood tests revealed a mild increase in the levels of inflammatory reaction parameters, likely occurring due to the skin ulcer. Computed tomography revealed no obvious cranial abnormalities; however, it showed that the precordial tumor had invaded the rib cage. Contralateral axillary lymph node metastasis was also observed; however, there was no evidence of distant organ metastases (Fig. 3). Since there was no history of minor or major trauma during 1 month prior to symptom onset, the skin ulcer was considered the most likely site of infection. As the patient reported being an avid gardener, she was at high risk of exposure to tetanus bacteria that may be present in the soil. The skin ulcer was extensive in width and depth; thus, highly invasive thoracoplasty was considered required to achieve sufficient debridement. However, progressing tetanus could cause postoperative complications such as flap necrosis. As the patient refused to consent to surgery, we did not perform surgical debridement but simply provided medical treatment.
Fig. 2 Front view of the breast cancer skin ulcer on Day 4 of hospitalization. The tumor was approximately 20 × 20 cm in size with extensive necrosis. The image is anonymized to protect the patient’s privacy
Fig. 3 Computed tomography performed on the day of admission showing that the tumor had invaded the rib cage
On the first day of hospitalization, the patient received an intramuscular injection of tetanus toxoid and an intravenous injection of tetanus immunoglobulin at a dose of 4500 U. After the patient was admitted to the intensive care unit (ICU), tracheal intubation and deep sedation were performed; in addition, artificial respiration management was performed in a room that was sound- and light-shielded. Concurrently, the patient received an infusion of metronidazole at a dose of 500 mg every 8 h. Fentanyl and dexmedetomidine were administered by continuous intravenous infusion for analgesia and sedation. Magnesium sulfate was intravenously injected at 2 g/day to control muscle rigidity and convulsions.
On Day 7, the patient presented with mild opisthotonus. However, there was no significant change in the autonomic nervous system function to suggest autonomic hyperactivity.
We assessed the severity of her tetanus using the Ablett classification [22]; all symptoms were in the moderate category.
On Day 16, no sign of opisthotonus was observed, suggesting that the patient had entered a recovery period. Tracheotomy was performed on Day 19 to relieve the remaining grinding trismus. On Day 20, sound insulation and shading and sedation management were completed. Oral intake and rehabilitation commenced on Day 22. The patient was discharged from the ICU on Day 25. On Day 33, the tracheal cannula was removed, and the tracheostomy was closed.
Wound treatment consisted of daily cleaning with soap and application of the petroleum jelly Vaseline. A wound care specialist nurse instructed the patient on wound care.
On Day 45 post-tetanus onset, the patient received a second dose of tetanus toxoid. The patient was discharged on Day 54. Three years after she left the hospital, she underwent an excision of a breast cancer skin ulcer. At present, 5 years post-discharge, the patient resides at home and has shown no evidence of tetanus recurrence or long-term adverse events. At the time of writing (July 2020), the patient continues to receive chemotherapy.
Discussion and conclusion
C. tetani grow and germinate in an anaerobic environment (necrotic tissue) and produce toxins. Although antibacterial agents tend to be effective in killing germinated tetanus bacteria, their effectiveness in killing these bacteria in the spore state is reduced; thus, treatment of tetanus in the necrotic tissue requires an approach that includes elements other than an antibacterial agent alone. An ulcer resulting from advanced breast cancer tends to move toward the surface of the body, exposing the chest wall in the process. This lesion is associated with anaerobic infection;
cases of tetanus infection from a breast cancer skin ulcer have been reported among other types of anaerobic infection.
The spore-forming C. tetani are resilient and can survive for a long time in an environment that is unsuitable for their activity. However, when the environment does become favorable, the host develops tetanus due to bacterial germination and the production of C. tetani toxins. Furthermore, a previous experimental study examining the impact of inoculating cancer-bearing animals showed that C. tetani spores that invade through a fresh wound can quickly migrate to and colonize necrotic tissues of cancer, leading to the development of tetanus [19]. In essence, a breast cancer skin ulcer functions as a reservoir of C. tetani toxins, even if they originally developed elsewhere.
Chronic wounds other than breast cancer skin ulcers can also be an entry point for tetanus bacteria. Barogui et al. reported a case of tetanus infection from a Bruli ulcer, which is an endemic disease in the tropics. The patient was cured of tetanus via debridement performed for the treatment of a Bruli ulcer [23]. Evidence suggests that active debridement of the infection site is important for the treatment of tetanus [1, 3, 19–21].
Recent studies have reported 15 cases of tetanus in patients with breast cancer skin ulcer (Table 1) [4–17]. Twelve of these cases (A-L) underwent surgical debridement. Two cases (C, I) died of tetanus after debridement was performed. One case (G) recovered from tetanus, but the patient died of sequela. Overall, this evidence suggests that tetanus originating from breast cancer skin ulcers is associated with a high risk of death and recurrence. As in the present case, debridement itself can be life threatening, resulting in patients refusing consent to surgery. In such cases, alternatives to debridement should be considered to help achieve good patient outcomes.
Table 1 Summary of previously reported cases of tetanus associated with breast cancer-related skin ulcer. No previous studies reported long-term antimicrobial therapy for the prevention of tetanus recurrence
Case Age Debridement Antibiotics Tetanus immunoglobulin Toxoid (after tetanus infection) Autonomic hyperactivity Recurrence Outcome Reference number
A 62 Yes Penicillin and metronidazole N/A One time N/A N/A Survival [4]
B 55 Yes Yes (specifics unknown) Yes N/A No No Survival [5]a
C 53 Yes Penicillin, ceftazidime, imipenem, and gentamycin Yes One time Yes No Deceased [6]
D 46 Yes Penicillin Yes N/A Yes N/A Survival [7]
E 59 Yes Penicillin Yes One time N/A N/A Survival [8]
F 75 Yes Piperacillin Yes N/A Yes N/A Survival [9]
G 56 Yes N/A Yes N/A N/A N/A Deceased [10]
H 55 Yes Penicillin Yes N/A Yes N/A Survival [11]
I 60 Yes N/A N/A N/A Yes No Deceased [12]
J 60 Yes Penicillin Yes Two times Yes N/A Survival [13]
K 67 Yes Penicillin Yes One time Yes No Survival [14]
L 65 Yes Penicillin, metronidazole, and cefepime Yes One time Yes No Survival [15]
M 50s No Meropenem Yes No Yes No Deceased [16]a
N 40 No Metronidazole Yes One time Yes Yes Deceased [17]
O 54 No Metronidazole, piperacillin/tazobactam, and ceftriaxone Yes One time No Yes Survival [17]
aWe contacted the authors of these papers directly and included the information they provided in this table
Three cases (M-O) of skin ulcer-related tetanus treated without debridement were previously reported. Among them, one patient (M) died as a result of tetanus, while the remaining two patients (N, O) achieved remission. However, both patients experienced recurrence: one patient (N) died of recurrent tetanus and the other patient (O) experienced tetanus remission and recurrence at least twice, but the patient’s subsequent course is unknown. Autonomic hyperactivity due to tetanus was not seen in the first remission of either case (N, O). At the time of recurrence, one of the patients (N) died due to autonomic hyperactivity, whereas the other patient (O), whose tetanus was localized, subsequently went into remission.
The severity of tetanus depends on the amount of bacterial toxin present. The most serious cases of tetanus show autonomic symptoms [24].
Severe tetanus is associated with poor prognosis compared to that associated its mild form [1, 24]. Although toxin levels may determine patient prognosis, no previous study has examined this association.
The amount of toxins present in the body is associated with the severity of tetanus and the amount of time that passes between bacterial invasion and treatment commencement. In the present case, we observed rapid remission with no recurrence. There are two reasons that may account for this finding. First, the administration of metronidazole might have killed all the tetanus bacteria before they were able to sporulate further. Concurrently, the administration of antitoxin antibodies might have neutralized the activity of the remaining toxin. However, as similar cases (M, N) have previously shown, tetanus bacillus can remain latent in the body and may cause tetanus recurrence. In animal studies in which tetanus bacteria were inoculated into cancer-bearing rats, tetanus bacteria were established in the tumor within 48 h [19]. In the present case, the patient presented more than a week after the onset of disease; the delay made it difficult to eliminate all tetanus bacteria and toxins with the use of antimicrobials and antitoxin antibodies. Second, the present patient may have acquired active immunity through two vaccinations, which may in turn have inhibited the recurrence of tetanus. The present case differs from cases N and O in that there has been no recurrence for at least 3 years after remission. Our patient had a booster shot before discharge from our hospital, while cases N and O received toxoid only once at the time of admission. Antibody titers rarely rise sufficiently with a single inoculation of toxoid. In fact, some cases of tetanus that recurred after vaccination involved antibody titers below the onset arrest concentration of 0.01 IU/ml [2, 25, 26].
Surgical resection of chronic wounds is the most reliable method of reducing the risk of tetanus recurrence. In cases where surgery cannot be performed, active immunity is required to suppress recurrence. The present patient did not experience tetanus recurrence for 3 years since the completion of treatment likely due to acquired active immunity. Tetanus can be a life-threatening disease whose occurrence can be prevented by vaccination. Cancer patients with lesions susceptible to tetanus should be actively vaccinated [3].
Nevertheless, a case of malignant tumor-associated tetanus, in which three inoculations of toxoid failed to activate immunity, likely due to the effect of cancer-induced immunodeficiency, has been reported [27]. At present, these is no clear evidence on how many toxoid inoculations should be given to cancer-bearing patients. Therefore, tetanus antibody titers should be measured in conjunction with vaccination administration to ensure that adequate antibody titers are maintained.
The tetanus antibody titer value required to prevent tetanus or maintain its remission in cancer patients remains unclear. In fact, no previous study has investigated the optimum dose, frequency, or duration of toxoid inoculation required for such patients. Further research is required to elucidate these parameters.
In summary, tetanus with chronic skin ulcer without autonomic hyperactivity can be ameliorated without debridement. However, as tetanus is prone to recurrence, the acquisition of active immunity is essential to prevent recurrence after remission. Multiple doses of vaccination may be required to ensure adequate antibody titers and immunity to tetanus are achieved in cancer patients [17, 25–27].
Abbreviation
ICUIntensive care unit
Publisher’s Note
Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
All authors express their deep gratitude to the paramedical staff for their professional and devoted service.
Authors’ contributions
KN (corresponding author) wrote the entire manuscript and performed the literature review. ES compiled the patient’s medical history and laboratory data. AY, WA, ES, SS, HO, YT, SU, and EN contributed to the interpretation of the clinical manifestations and revised the manuscript for critical intellectual content. All authors have read and approved the manuscript.
Funding
This study received no specific funding.
Availability of data and materials
The datasets used and/or analyzed during the current study available from the corresponding author on reasonable request.
Ethics approval and consent to participate
Not applicable.
Consent for publication
Written consent to publish our case was obtained from the patient. A copy of the written consent is available to be reviewed by the editorial committee of this journal.
Competing interests
The authors declare that they have no competing interests. | Intravenous (not otherwise specified) | DrugAdministrationRoute | CC BY | 33413196 | 18,794,500 | 2021-01-07 |
What was the administration route of drug 'TETANUS TOXOIDS'? | Non-surgical treatment of tetanus infection associated with breast cancer skin ulcer: a case report and literature review.
BACKGROUND
Previous studies have reported poor prognosis in cases of tetanus that develops after bacteria enters via breast cancer-related skin ulcers that are not treated with surgical debridement. Herein, we review the literature concerning this presentation and report the first case of complete remission from tetanus without surgical debridement of the skin ulcer.
METHODS
An Asian woman aged over 60 years had a history of skin ulcer caused by breast cancer. She was diagnosed with tetanus due to trismus and opisthotonus. Based on the suspicion that the skin ulcer was the portal of entry for tetanus bacteria, we considered several debridement and thoracic surgical options for tetanus treatment. However, debridement was not performed as the surgery was considered high risk and the patient did not consent to it. The patient received treatment with anti-tetanus globulin and metronidazole; sound insulation and shielding were also performed in a dark room. Subsequently, the patient's symptoms improved, and sound insulation and deep sedation management were completed on 19th day of hospitalization. With no symptom recurrence, the patient was discharged on Day 54. To date, over 3 years after treatment, no evidence of tetanus recurrence has been observed. The case was characterized by a lack of autonomic hyperactivity. The tetanus severity was likely representative of the low amount of toxin that the patient was exposed to.
CONCLUSIONS
This case involved moderate severity tetanus originating from a chronic skin ulcer related to breast cancer. The patient survived without undergoing extensive debridement. No evidence of tetanus relapse was observed during the follow-up period, likely due to vaccination that might have restored the patient's active immunity. Debridement is not always necessary for tetanus complicated by breast cancer skin ulcers. Furthermore, appropriate toxoid vaccination is critical for preventing the onset and recurrence of tetanus in these patients.
Background
Tetanus is caused by Clostridium tetani, an obligate anaerobic bacterium, that enters the body and releases toxins. The tetanus toxin causes severe spastic paralysis and autonomic hyperactivity, which may lead to death [1, 2]. Patients with chronic wounds such as skin ulcer are at a high risk of tetanus as these wounds provide an entry route for tetanus bacteria [3]. In fact, previous studies have shown that patients with skin ulcer due to advanced breast cancer are at a particularly high risk of developing tetanus and that removing the ulcer is the only effective treatment in such cases [4–17]. A cancerous skin ulcer contains necrotic tissue, which constitutes anaerobic environment that is conducive to the growth of tetanus bacteria and the production of toxins [3, 18, 19]. As blood flow to necrotic tissues is restricted, treatment with antibiotics tends to be ineffective in such cases due to the body’s inability to deliver the treatment to the site of infection. In addition, tetanus bacteria can form spores, which may reduce the effectiveness of antibacterial drugs. As a result, in cases of tetanus associated with chronic wounds, debridement of the wound has been considered an essential element of treatment [1, 3, 19–21]. Herein, we report about a patient with tetanus due to skin ulcer associated with breast cancer who was treated without debridement and who presented with no sign of recurrence 3 years after treatment completion.
Case presentation
An Asian woman aged over 60 years had a history of left-sided breast cancer (Fig. 1). She had received two tetanus vaccinations: first as an infant and second at around 10 years of age. She underwent cancer resection in her 40s; however, the cancer recurred and was initially treated with chemotherapy until the patient declined further treatment and stopped attending her hospital appointments. After several years, as she was no longer a patient, her medical records were discarded, leading to the loss of clinical data, including her breast cancer histopathological findings and information on disease stage and treatment. At the time of recurrence, the patient presented with an untreated breast cancer that had invaded the skin and formed a sizable tumor and ulcer in the precordial region. The patient attempted to treat her own wounds without visiting a hospital. Approximately a week before hospitalization, the patient presented with trismus. As trismus progressed, she visited a dental clinic, where the severity of her trismus precluded treatment. The patient had no disease that caused dental trismus but a cervical flexion disorder and was therefore suspected of having tetanus and subsequently referred to the Emergency Department of our hospital on the same day.
Fig. 1 Timeline of case management from admission to discharge from the intensive care unit
During admission, the patient was awake and alert; however, she could open her mouth only to the width of a single finger. In addition, she was unable to flex her neck due to involuntary overextension and pain in the posterior cervical muscles. Her blood pressure was 155/109 mmHg, heart rate was 120 beats/min, respiratory rate was 16 breaths/min, body temperature (axillary) was 36.4 °C, and SpO2 was 99% (room air). After excluding other conditions that could account for the presenting symptoms, the patient was diagnosed with tetanus.
Advanced breast cancer in the precordial region was suspected to account for the presence of a large tumor and skin ulcer (Fig. 2). Blood tests revealed a mild increase in the levels of inflammatory reaction parameters, likely occurring due to the skin ulcer. Computed tomography revealed no obvious cranial abnormalities; however, it showed that the precordial tumor had invaded the rib cage. Contralateral axillary lymph node metastasis was also observed; however, there was no evidence of distant organ metastases (Fig. 3). Since there was no history of minor or major trauma during 1 month prior to symptom onset, the skin ulcer was considered the most likely site of infection. As the patient reported being an avid gardener, she was at high risk of exposure to tetanus bacteria that may be present in the soil. The skin ulcer was extensive in width and depth; thus, highly invasive thoracoplasty was considered required to achieve sufficient debridement. However, progressing tetanus could cause postoperative complications such as flap necrosis. As the patient refused to consent to surgery, we did not perform surgical debridement but simply provided medical treatment.
Fig. 2 Front view of the breast cancer skin ulcer on Day 4 of hospitalization. The tumor was approximately 20 × 20 cm in size with extensive necrosis. The image is anonymized to protect the patient’s privacy
Fig. 3 Computed tomography performed on the day of admission showing that the tumor had invaded the rib cage
On the first day of hospitalization, the patient received an intramuscular injection of tetanus toxoid and an intravenous injection of tetanus immunoglobulin at a dose of 4500 U. After the patient was admitted to the intensive care unit (ICU), tracheal intubation and deep sedation were performed; in addition, artificial respiration management was performed in a room that was sound- and light-shielded. Concurrently, the patient received an infusion of metronidazole at a dose of 500 mg every 8 h. Fentanyl and dexmedetomidine were administered by continuous intravenous infusion for analgesia and sedation. Magnesium sulfate was intravenously injected at 2 g/day to control muscle rigidity and convulsions.
On Day 7, the patient presented with mild opisthotonus. However, there was no significant change in the autonomic nervous system function to suggest autonomic hyperactivity.
We assessed the severity of her tetanus using the Ablett classification [22]; all symptoms were in the moderate category.
On Day 16, no sign of opisthotonus was observed, suggesting that the patient had entered a recovery period. Tracheotomy was performed on Day 19 to relieve the remaining grinding trismus. On Day 20, sound insulation and shading and sedation management were completed. Oral intake and rehabilitation commenced on Day 22. The patient was discharged from the ICU on Day 25. On Day 33, the tracheal cannula was removed, and the tracheostomy was closed.
Wound treatment consisted of daily cleaning with soap and application of the petroleum jelly Vaseline. A wound care specialist nurse instructed the patient on wound care.
On Day 45 post-tetanus onset, the patient received a second dose of tetanus toxoid. The patient was discharged on Day 54. Three years after she left the hospital, she underwent an excision of a breast cancer skin ulcer. At present, 5 years post-discharge, the patient resides at home and has shown no evidence of tetanus recurrence or long-term adverse events. At the time of writing (July 2020), the patient continues to receive chemotherapy.
Discussion and conclusion
C. tetani grow and germinate in an anaerobic environment (necrotic tissue) and produce toxins. Although antibacterial agents tend to be effective in killing germinated tetanus bacteria, their effectiveness in killing these bacteria in the spore state is reduced; thus, treatment of tetanus in the necrotic tissue requires an approach that includes elements other than an antibacterial agent alone. An ulcer resulting from advanced breast cancer tends to move toward the surface of the body, exposing the chest wall in the process. This lesion is associated with anaerobic infection;
cases of tetanus infection from a breast cancer skin ulcer have been reported among other types of anaerobic infection.
The spore-forming C. tetani are resilient and can survive for a long time in an environment that is unsuitable for their activity. However, when the environment does become favorable, the host develops tetanus due to bacterial germination and the production of C. tetani toxins. Furthermore, a previous experimental study examining the impact of inoculating cancer-bearing animals showed that C. tetani spores that invade through a fresh wound can quickly migrate to and colonize necrotic tissues of cancer, leading to the development of tetanus [19]. In essence, a breast cancer skin ulcer functions as a reservoir of C. tetani toxins, even if they originally developed elsewhere.
Chronic wounds other than breast cancer skin ulcers can also be an entry point for tetanus bacteria. Barogui et al. reported a case of tetanus infection from a Bruli ulcer, which is an endemic disease in the tropics. The patient was cured of tetanus via debridement performed for the treatment of a Bruli ulcer [23]. Evidence suggests that active debridement of the infection site is important for the treatment of tetanus [1, 3, 19–21].
Recent studies have reported 15 cases of tetanus in patients with breast cancer skin ulcer (Table 1) [4–17]. Twelve of these cases (A-L) underwent surgical debridement. Two cases (C, I) died of tetanus after debridement was performed. One case (G) recovered from tetanus, but the patient died of sequela. Overall, this evidence suggests that tetanus originating from breast cancer skin ulcers is associated with a high risk of death and recurrence. As in the present case, debridement itself can be life threatening, resulting in patients refusing consent to surgery. In such cases, alternatives to debridement should be considered to help achieve good patient outcomes.
Table 1 Summary of previously reported cases of tetanus associated with breast cancer-related skin ulcer. No previous studies reported long-term antimicrobial therapy for the prevention of tetanus recurrence
Case Age Debridement Antibiotics Tetanus immunoglobulin Toxoid (after tetanus infection) Autonomic hyperactivity Recurrence Outcome Reference number
A 62 Yes Penicillin and metronidazole N/A One time N/A N/A Survival [4]
B 55 Yes Yes (specifics unknown) Yes N/A No No Survival [5]a
C 53 Yes Penicillin, ceftazidime, imipenem, and gentamycin Yes One time Yes No Deceased [6]
D 46 Yes Penicillin Yes N/A Yes N/A Survival [7]
E 59 Yes Penicillin Yes One time N/A N/A Survival [8]
F 75 Yes Piperacillin Yes N/A Yes N/A Survival [9]
G 56 Yes N/A Yes N/A N/A N/A Deceased [10]
H 55 Yes Penicillin Yes N/A Yes N/A Survival [11]
I 60 Yes N/A N/A N/A Yes No Deceased [12]
J 60 Yes Penicillin Yes Two times Yes N/A Survival [13]
K 67 Yes Penicillin Yes One time Yes No Survival [14]
L 65 Yes Penicillin, metronidazole, and cefepime Yes One time Yes No Survival [15]
M 50s No Meropenem Yes No Yes No Deceased [16]a
N 40 No Metronidazole Yes One time Yes Yes Deceased [17]
O 54 No Metronidazole, piperacillin/tazobactam, and ceftriaxone Yes One time No Yes Survival [17]
aWe contacted the authors of these papers directly and included the information they provided in this table
Three cases (M-O) of skin ulcer-related tetanus treated without debridement were previously reported. Among them, one patient (M) died as a result of tetanus, while the remaining two patients (N, O) achieved remission. However, both patients experienced recurrence: one patient (N) died of recurrent tetanus and the other patient (O) experienced tetanus remission and recurrence at least twice, but the patient’s subsequent course is unknown. Autonomic hyperactivity due to tetanus was not seen in the first remission of either case (N, O). At the time of recurrence, one of the patients (N) died due to autonomic hyperactivity, whereas the other patient (O), whose tetanus was localized, subsequently went into remission.
The severity of tetanus depends on the amount of bacterial toxin present. The most serious cases of tetanus show autonomic symptoms [24].
Severe tetanus is associated with poor prognosis compared to that associated its mild form [1, 24]. Although toxin levels may determine patient prognosis, no previous study has examined this association.
The amount of toxins present in the body is associated with the severity of tetanus and the amount of time that passes between bacterial invasion and treatment commencement. In the present case, we observed rapid remission with no recurrence. There are two reasons that may account for this finding. First, the administration of metronidazole might have killed all the tetanus bacteria before they were able to sporulate further. Concurrently, the administration of antitoxin antibodies might have neutralized the activity of the remaining toxin. However, as similar cases (M, N) have previously shown, tetanus bacillus can remain latent in the body and may cause tetanus recurrence. In animal studies in which tetanus bacteria were inoculated into cancer-bearing rats, tetanus bacteria were established in the tumor within 48 h [19]. In the present case, the patient presented more than a week after the onset of disease; the delay made it difficult to eliminate all tetanus bacteria and toxins with the use of antimicrobials and antitoxin antibodies. Second, the present patient may have acquired active immunity through two vaccinations, which may in turn have inhibited the recurrence of tetanus. The present case differs from cases N and O in that there has been no recurrence for at least 3 years after remission. Our patient had a booster shot before discharge from our hospital, while cases N and O received toxoid only once at the time of admission. Antibody titers rarely rise sufficiently with a single inoculation of toxoid. In fact, some cases of tetanus that recurred after vaccination involved antibody titers below the onset arrest concentration of 0.01 IU/ml [2, 25, 26].
Surgical resection of chronic wounds is the most reliable method of reducing the risk of tetanus recurrence. In cases where surgery cannot be performed, active immunity is required to suppress recurrence. The present patient did not experience tetanus recurrence for 3 years since the completion of treatment likely due to acquired active immunity. Tetanus can be a life-threatening disease whose occurrence can be prevented by vaccination. Cancer patients with lesions susceptible to tetanus should be actively vaccinated [3].
Nevertheless, a case of malignant tumor-associated tetanus, in which three inoculations of toxoid failed to activate immunity, likely due to the effect of cancer-induced immunodeficiency, has been reported [27]. At present, these is no clear evidence on how many toxoid inoculations should be given to cancer-bearing patients. Therefore, tetanus antibody titers should be measured in conjunction with vaccination administration to ensure that adequate antibody titers are maintained.
The tetanus antibody titer value required to prevent tetanus or maintain its remission in cancer patients remains unclear. In fact, no previous study has investigated the optimum dose, frequency, or duration of toxoid inoculation required for such patients. Further research is required to elucidate these parameters.
In summary, tetanus with chronic skin ulcer without autonomic hyperactivity can be ameliorated without debridement. However, as tetanus is prone to recurrence, the acquisition of active immunity is essential to prevent recurrence after remission. Multiple doses of vaccination may be required to ensure adequate antibody titers and immunity to tetanus are achieved in cancer patients [17, 25–27].
Abbreviation
ICUIntensive care unit
Publisher’s Note
Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
All authors express their deep gratitude to the paramedical staff for their professional and devoted service.
Authors’ contributions
KN (corresponding author) wrote the entire manuscript and performed the literature review. ES compiled the patient’s medical history and laboratory data. AY, WA, ES, SS, HO, YT, SU, and EN contributed to the interpretation of the clinical manifestations and revised the manuscript for critical intellectual content. All authors have read and approved the manuscript.
Funding
This study received no specific funding.
Availability of data and materials
The datasets used and/or analyzed during the current study available from the corresponding author on reasonable request.
Ethics approval and consent to participate
Not applicable.
Consent for publication
Written consent to publish our case was obtained from the patient. A copy of the written consent is available to be reviewed by the editorial committee of this journal.
Competing interests
The authors declare that they have no competing interests. | Intramuscular | DrugAdministrationRoute | CC BY | 33413196 | 18,794,500 | 2021-01-07 |
What was the dosage of drug 'HUMAN CLOSTRIDIUM TETANI TOXOID IMMUNE GLOBULIN'? | Non-surgical treatment of tetanus infection associated with breast cancer skin ulcer: a case report and literature review.
BACKGROUND
Previous studies have reported poor prognosis in cases of tetanus that develops after bacteria enters via breast cancer-related skin ulcers that are not treated with surgical debridement. Herein, we review the literature concerning this presentation and report the first case of complete remission from tetanus without surgical debridement of the skin ulcer.
METHODS
An Asian woman aged over 60 years had a history of skin ulcer caused by breast cancer. She was diagnosed with tetanus due to trismus and opisthotonus. Based on the suspicion that the skin ulcer was the portal of entry for tetanus bacteria, we considered several debridement and thoracic surgical options for tetanus treatment. However, debridement was not performed as the surgery was considered high risk and the patient did not consent to it. The patient received treatment with anti-tetanus globulin and metronidazole; sound insulation and shielding were also performed in a dark room. Subsequently, the patient's symptoms improved, and sound insulation and deep sedation management were completed on 19th day of hospitalization. With no symptom recurrence, the patient was discharged on Day 54. To date, over 3 years after treatment, no evidence of tetanus recurrence has been observed. The case was characterized by a lack of autonomic hyperactivity. The tetanus severity was likely representative of the low amount of toxin that the patient was exposed to.
CONCLUSIONS
This case involved moderate severity tetanus originating from a chronic skin ulcer related to breast cancer. The patient survived without undergoing extensive debridement. No evidence of tetanus relapse was observed during the follow-up period, likely due to vaccination that might have restored the patient's active immunity. Debridement is not always necessary for tetanus complicated by breast cancer skin ulcers. Furthermore, appropriate toxoid vaccination is critical for preventing the onset and recurrence of tetanus in these patients.
Background
Tetanus is caused by Clostridium tetani, an obligate anaerobic bacterium, that enters the body and releases toxins. The tetanus toxin causes severe spastic paralysis and autonomic hyperactivity, which may lead to death [1, 2]. Patients with chronic wounds such as skin ulcer are at a high risk of tetanus as these wounds provide an entry route for tetanus bacteria [3]. In fact, previous studies have shown that patients with skin ulcer due to advanced breast cancer are at a particularly high risk of developing tetanus and that removing the ulcer is the only effective treatment in such cases [4–17]. A cancerous skin ulcer contains necrotic tissue, which constitutes anaerobic environment that is conducive to the growth of tetanus bacteria and the production of toxins [3, 18, 19]. As blood flow to necrotic tissues is restricted, treatment with antibiotics tends to be ineffective in such cases due to the body’s inability to deliver the treatment to the site of infection. In addition, tetanus bacteria can form spores, which may reduce the effectiveness of antibacterial drugs. As a result, in cases of tetanus associated with chronic wounds, debridement of the wound has been considered an essential element of treatment [1, 3, 19–21]. Herein, we report about a patient with tetanus due to skin ulcer associated with breast cancer who was treated without debridement and who presented with no sign of recurrence 3 years after treatment completion.
Case presentation
An Asian woman aged over 60 years had a history of left-sided breast cancer (Fig. 1). She had received two tetanus vaccinations: first as an infant and second at around 10 years of age. She underwent cancer resection in her 40s; however, the cancer recurred and was initially treated with chemotherapy until the patient declined further treatment and stopped attending her hospital appointments. After several years, as she was no longer a patient, her medical records were discarded, leading to the loss of clinical data, including her breast cancer histopathological findings and information on disease stage and treatment. At the time of recurrence, the patient presented with an untreated breast cancer that had invaded the skin and formed a sizable tumor and ulcer in the precordial region. The patient attempted to treat her own wounds without visiting a hospital. Approximately a week before hospitalization, the patient presented with trismus. As trismus progressed, she visited a dental clinic, where the severity of her trismus precluded treatment. The patient had no disease that caused dental trismus but a cervical flexion disorder and was therefore suspected of having tetanus and subsequently referred to the Emergency Department of our hospital on the same day.
Fig. 1 Timeline of case management from admission to discharge from the intensive care unit
During admission, the patient was awake and alert; however, she could open her mouth only to the width of a single finger. In addition, she was unable to flex her neck due to involuntary overextension and pain in the posterior cervical muscles. Her blood pressure was 155/109 mmHg, heart rate was 120 beats/min, respiratory rate was 16 breaths/min, body temperature (axillary) was 36.4 °C, and SpO2 was 99% (room air). After excluding other conditions that could account for the presenting symptoms, the patient was diagnosed with tetanus.
Advanced breast cancer in the precordial region was suspected to account for the presence of a large tumor and skin ulcer (Fig. 2). Blood tests revealed a mild increase in the levels of inflammatory reaction parameters, likely occurring due to the skin ulcer. Computed tomography revealed no obvious cranial abnormalities; however, it showed that the precordial tumor had invaded the rib cage. Contralateral axillary lymph node metastasis was also observed; however, there was no evidence of distant organ metastases (Fig. 3). Since there was no history of minor or major trauma during 1 month prior to symptom onset, the skin ulcer was considered the most likely site of infection. As the patient reported being an avid gardener, she was at high risk of exposure to tetanus bacteria that may be present in the soil. The skin ulcer was extensive in width and depth; thus, highly invasive thoracoplasty was considered required to achieve sufficient debridement. However, progressing tetanus could cause postoperative complications such as flap necrosis. As the patient refused to consent to surgery, we did not perform surgical debridement but simply provided medical treatment.
Fig. 2 Front view of the breast cancer skin ulcer on Day 4 of hospitalization. The tumor was approximately 20 × 20 cm in size with extensive necrosis. The image is anonymized to protect the patient’s privacy
Fig. 3 Computed tomography performed on the day of admission showing that the tumor had invaded the rib cage
On the first day of hospitalization, the patient received an intramuscular injection of tetanus toxoid and an intravenous injection of tetanus immunoglobulin at a dose of 4500 U. After the patient was admitted to the intensive care unit (ICU), tracheal intubation and deep sedation were performed; in addition, artificial respiration management was performed in a room that was sound- and light-shielded. Concurrently, the patient received an infusion of metronidazole at a dose of 500 mg every 8 h. Fentanyl and dexmedetomidine were administered by continuous intravenous infusion for analgesia and sedation. Magnesium sulfate was intravenously injected at 2 g/day to control muscle rigidity and convulsions.
On Day 7, the patient presented with mild opisthotonus. However, there was no significant change in the autonomic nervous system function to suggest autonomic hyperactivity.
We assessed the severity of her tetanus using the Ablett classification [22]; all symptoms were in the moderate category.
On Day 16, no sign of opisthotonus was observed, suggesting that the patient had entered a recovery period. Tracheotomy was performed on Day 19 to relieve the remaining grinding trismus. On Day 20, sound insulation and shading and sedation management were completed. Oral intake and rehabilitation commenced on Day 22. The patient was discharged from the ICU on Day 25. On Day 33, the tracheal cannula was removed, and the tracheostomy was closed.
Wound treatment consisted of daily cleaning with soap and application of the petroleum jelly Vaseline. A wound care specialist nurse instructed the patient on wound care.
On Day 45 post-tetanus onset, the patient received a second dose of tetanus toxoid. The patient was discharged on Day 54. Three years after she left the hospital, she underwent an excision of a breast cancer skin ulcer. At present, 5 years post-discharge, the patient resides at home and has shown no evidence of tetanus recurrence or long-term adverse events. At the time of writing (July 2020), the patient continues to receive chemotherapy.
Discussion and conclusion
C. tetani grow and germinate in an anaerobic environment (necrotic tissue) and produce toxins. Although antibacterial agents tend to be effective in killing germinated tetanus bacteria, their effectiveness in killing these bacteria in the spore state is reduced; thus, treatment of tetanus in the necrotic tissue requires an approach that includes elements other than an antibacterial agent alone. An ulcer resulting from advanced breast cancer tends to move toward the surface of the body, exposing the chest wall in the process. This lesion is associated with anaerobic infection;
cases of tetanus infection from a breast cancer skin ulcer have been reported among other types of anaerobic infection.
The spore-forming C. tetani are resilient and can survive for a long time in an environment that is unsuitable for their activity. However, when the environment does become favorable, the host develops tetanus due to bacterial germination and the production of C. tetani toxins. Furthermore, a previous experimental study examining the impact of inoculating cancer-bearing animals showed that C. tetani spores that invade through a fresh wound can quickly migrate to and colonize necrotic tissues of cancer, leading to the development of tetanus [19]. In essence, a breast cancer skin ulcer functions as a reservoir of C. tetani toxins, even if they originally developed elsewhere.
Chronic wounds other than breast cancer skin ulcers can also be an entry point for tetanus bacteria. Barogui et al. reported a case of tetanus infection from a Bruli ulcer, which is an endemic disease in the tropics. The patient was cured of tetanus via debridement performed for the treatment of a Bruli ulcer [23]. Evidence suggests that active debridement of the infection site is important for the treatment of tetanus [1, 3, 19–21].
Recent studies have reported 15 cases of tetanus in patients with breast cancer skin ulcer (Table 1) [4–17]. Twelve of these cases (A-L) underwent surgical debridement. Two cases (C, I) died of tetanus after debridement was performed. One case (G) recovered from tetanus, but the patient died of sequela. Overall, this evidence suggests that tetanus originating from breast cancer skin ulcers is associated with a high risk of death and recurrence. As in the present case, debridement itself can be life threatening, resulting in patients refusing consent to surgery. In such cases, alternatives to debridement should be considered to help achieve good patient outcomes.
Table 1 Summary of previously reported cases of tetanus associated with breast cancer-related skin ulcer. No previous studies reported long-term antimicrobial therapy for the prevention of tetanus recurrence
Case Age Debridement Antibiotics Tetanus immunoglobulin Toxoid (after tetanus infection) Autonomic hyperactivity Recurrence Outcome Reference number
A 62 Yes Penicillin and metronidazole N/A One time N/A N/A Survival [4]
B 55 Yes Yes (specifics unknown) Yes N/A No No Survival [5]a
C 53 Yes Penicillin, ceftazidime, imipenem, and gentamycin Yes One time Yes No Deceased [6]
D 46 Yes Penicillin Yes N/A Yes N/A Survival [7]
E 59 Yes Penicillin Yes One time N/A N/A Survival [8]
F 75 Yes Piperacillin Yes N/A Yes N/A Survival [9]
G 56 Yes N/A Yes N/A N/A N/A Deceased [10]
H 55 Yes Penicillin Yes N/A Yes N/A Survival [11]
I 60 Yes N/A N/A N/A Yes No Deceased [12]
J 60 Yes Penicillin Yes Two times Yes N/A Survival [13]
K 67 Yes Penicillin Yes One time Yes No Survival [14]
L 65 Yes Penicillin, metronidazole, and cefepime Yes One time Yes No Survival [15]
M 50s No Meropenem Yes No Yes No Deceased [16]a
N 40 No Metronidazole Yes One time Yes Yes Deceased [17]
O 54 No Metronidazole, piperacillin/tazobactam, and ceftriaxone Yes One time No Yes Survival [17]
aWe contacted the authors of these papers directly and included the information they provided in this table
Three cases (M-O) of skin ulcer-related tetanus treated without debridement were previously reported. Among them, one patient (M) died as a result of tetanus, while the remaining two patients (N, O) achieved remission. However, both patients experienced recurrence: one patient (N) died of recurrent tetanus and the other patient (O) experienced tetanus remission and recurrence at least twice, but the patient’s subsequent course is unknown. Autonomic hyperactivity due to tetanus was not seen in the first remission of either case (N, O). At the time of recurrence, one of the patients (N) died due to autonomic hyperactivity, whereas the other patient (O), whose tetanus was localized, subsequently went into remission.
The severity of tetanus depends on the amount of bacterial toxin present. The most serious cases of tetanus show autonomic symptoms [24].
Severe tetanus is associated with poor prognosis compared to that associated its mild form [1, 24]. Although toxin levels may determine patient prognosis, no previous study has examined this association.
The amount of toxins present in the body is associated with the severity of tetanus and the amount of time that passes between bacterial invasion and treatment commencement. In the present case, we observed rapid remission with no recurrence. There are two reasons that may account for this finding. First, the administration of metronidazole might have killed all the tetanus bacteria before they were able to sporulate further. Concurrently, the administration of antitoxin antibodies might have neutralized the activity of the remaining toxin. However, as similar cases (M, N) have previously shown, tetanus bacillus can remain latent in the body and may cause tetanus recurrence. In animal studies in which tetanus bacteria were inoculated into cancer-bearing rats, tetanus bacteria were established in the tumor within 48 h [19]. In the present case, the patient presented more than a week after the onset of disease; the delay made it difficult to eliminate all tetanus bacteria and toxins with the use of antimicrobials and antitoxin antibodies. Second, the present patient may have acquired active immunity through two vaccinations, which may in turn have inhibited the recurrence of tetanus. The present case differs from cases N and O in that there has been no recurrence for at least 3 years after remission. Our patient had a booster shot before discharge from our hospital, while cases N and O received toxoid only once at the time of admission. Antibody titers rarely rise sufficiently with a single inoculation of toxoid. In fact, some cases of tetanus that recurred after vaccination involved antibody titers below the onset arrest concentration of 0.01 IU/ml [2, 25, 26].
Surgical resection of chronic wounds is the most reliable method of reducing the risk of tetanus recurrence. In cases where surgery cannot be performed, active immunity is required to suppress recurrence. The present patient did not experience tetanus recurrence for 3 years since the completion of treatment likely due to acquired active immunity. Tetanus can be a life-threatening disease whose occurrence can be prevented by vaccination. Cancer patients with lesions susceptible to tetanus should be actively vaccinated [3].
Nevertheless, a case of malignant tumor-associated tetanus, in which three inoculations of toxoid failed to activate immunity, likely due to the effect of cancer-induced immunodeficiency, has been reported [27]. At present, these is no clear evidence on how many toxoid inoculations should be given to cancer-bearing patients. Therefore, tetanus antibody titers should be measured in conjunction with vaccination administration to ensure that adequate antibody titers are maintained.
The tetanus antibody titer value required to prevent tetanus or maintain its remission in cancer patients remains unclear. In fact, no previous study has investigated the optimum dose, frequency, or duration of toxoid inoculation required for such patients. Further research is required to elucidate these parameters.
In summary, tetanus with chronic skin ulcer without autonomic hyperactivity can be ameliorated without debridement. However, as tetanus is prone to recurrence, the acquisition of active immunity is essential to prevent recurrence after remission. Multiple doses of vaccination may be required to ensure adequate antibody titers and immunity to tetanus are achieved in cancer patients [17, 25–27].
Abbreviation
ICUIntensive care unit
Publisher’s Note
Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
All authors express their deep gratitude to the paramedical staff for their professional and devoted service.
Authors’ contributions
KN (corresponding author) wrote the entire manuscript and performed the literature review. ES compiled the patient’s medical history and laboratory data. AY, WA, ES, SS, HO, YT, SU, and EN contributed to the interpretation of the clinical manifestations and revised the manuscript for critical intellectual content. All authors have read and approved the manuscript.
Funding
This study received no specific funding.
Availability of data and materials
The datasets used and/or analyzed during the current study available from the corresponding author on reasonable request.
Ethics approval and consent to participate
Not applicable.
Consent for publication
Written consent to publish our case was obtained from the patient. A copy of the written consent is available to be reviewed by the editorial committee of this journal.
Competing interests
The authors declare that they have no competing interests. | 4500 INTERNATIONAL UNIT | DrugDosageText | CC BY | 33413196 | 18,794,500 | 2021-01-07 |
What was the dosage of drug 'MAGNESIUM SULFATE'? | Non-surgical treatment of tetanus infection associated with breast cancer skin ulcer: a case report and literature review.
BACKGROUND
Previous studies have reported poor prognosis in cases of tetanus that develops after bacteria enters via breast cancer-related skin ulcers that are not treated with surgical debridement. Herein, we review the literature concerning this presentation and report the first case of complete remission from tetanus without surgical debridement of the skin ulcer.
METHODS
An Asian woman aged over 60 years had a history of skin ulcer caused by breast cancer. She was diagnosed with tetanus due to trismus and opisthotonus. Based on the suspicion that the skin ulcer was the portal of entry for tetanus bacteria, we considered several debridement and thoracic surgical options for tetanus treatment. However, debridement was not performed as the surgery was considered high risk and the patient did not consent to it. The patient received treatment with anti-tetanus globulin and metronidazole; sound insulation and shielding were also performed in a dark room. Subsequently, the patient's symptoms improved, and sound insulation and deep sedation management were completed on 19th day of hospitalization. With no symptom recurrence, the patient was discharged on Day 54. To date, over 3 years after treatment, no evidence of tetanus recurrence has been observed. The case was characterized by a lack of autonomic hyperactivity. The tetanus severity was likely representative of the low amount of toxin that the patient was exposed to.
CONCLUSIONS
This case involved moderate severity tetanus originating from a chronic skin ulcer related to breast cancer. The patient survived without undergoing extensive debridement. No evidence of tetanus relapse was observed during the follow-up period, likely due to vaccination that might have restored the patient's active immunity. Debridement is not always necessary for tetanus complicated by breast cancer skin ulcers. Furthermore, appropriate toxoid vaccination is critical for preventing the onset and recurrence of tetanus in these patients.
Background
Tetanus is caused by Clostridium tetani, an obligate anaerobic bacterium, that enters the body and releases toxins. The tetanus toxin causes severe spastic paralysis and autonomic hyperactivity, which may lead to death [1, 2]. Patients with chronic wounds such as skin ulcer are at a high risk of tetanus as these wounds provide an entry route for tetanus bacteria [3]. In fact, previous studies have shown that patients with skin ulcer due to advanced breast cancer are at a particularly high risk of developing tetanus and that removing the ulcer is the only effective treatment in such cases [4–17]. A cancerous skin ulcer contains necrotic tissue, which constitutes anaerobic environment that is conducive to the growth of tetanus bacteria and the production of toxins [3, 18, 19]. As blood flow to necrotic tissues is restricted, treatment with antibiotics tends to be ineffective in such cases due to the body’s inability to deliver the treatment to the site of infection. In addition, tetanus bacteria can form spores, which may reduce the effectiveness of antibacterial drugs. As a result, in cases of tetanus associated with chronic wounds, debridement of the wound has been considered an essential element of treatment [1, 3, 19–21]. Herein, we report about a patient with tetanus due to skin ulcer associated with breast cancer who was treated without debridement and who presented with no sign of recurrence 3 years after treatment completion.
Case presentation
An Asian woman aged over 60 years had a history of left-sided breast cancer (Fig. 1). She had received two tetanus vaccinations: first as an infant and second at around 10 years of age. She underwent cancer resection in her 40s; however, the cancer recurred and was initially treated with chemotherapy until the patient declined further treatment and stopped attending her hospital appointments. After several years, as she was no longer a patient, her medical records were discarded, leading to the loss of clinical data, including her breast cancer histopathological findings and information on disease stage and treatment. At the time of recurrence, the patient presented with an untreated breast cancer that had invaded the skin and formed a sizable tumor and ulcer in the precordial region. The patient attempted to treat her own wounds without visiting a hospital. Approximately a week before hospitalization, the patient presented with trismus. As trismus progressed, she visited a dental clinic, where the severity of her trismus precluded treatment. The patient had no disease that caused dental trismus but a cervical flexion disorder and was therefore suspected of having tetanus and subsequently referred to the Emergency Department of our hospital on the same day.
Fig. 1 Timeline of case management from admission to discharge from the intensive care unit
During admission, the patient was awake and alert; however, she could open her mouth only to the width of a single finger. In addition, she was unable to flex her neck due to involuntary overextension and pain in the posterior cervical muscles. Her blood pressure was 155/109 mmHg, heart rate was 120 beats/min, respiratory rate was 16 breaths/min, body temperature (axillary) was 36.4 °C, and SpO2 was 99% (room air). After excluding other conditions that could account for the presenting symptoms, the patient was diagnosed with tetanus.
Advanced breast cancer in the precordial region was suspected to account for the presence of a large tumor and skin ulcer (Fig. 2). Blood tests revealed a mild increase in the levels of inflammatory reaction parameters, likely occurring due to the skin ulcer. Computed tomography revealed no obvious cranial abnormalities; however, it showed that the precordial tumor had invaded the rib cage. Contralateral axillary lymph node metastasis was also observed; however, there was no evidence of distant organ metastases (Fig. 3). Since there was no history of minor or major trauma during 1 month prior to symptom onset, the skin ulcer was considered the most likely site of infection. As the patient reported being an avid gardener, she was at high risk of exposure to tetanus bacteria that may be present in the soil. The skin ulcer was extensive in width and depth; thus, highly invasive thoracoplasty was considered required to achieve sufficient debridement. However, progressing tetanus could cause postoperative complications such as flap necrosis. As the patient refused to consent to surgery, we did not perform surgical debridement but simply provided medical treatment.
Fig. 2 Front view of the breast cancer skin ulcer on Day 4 of hospitalization. The tumor was approximately 20 × 20 cm in size with extensive necrosis. The image is anonymized to protect the patient’s privacy
Fig. 3 Computed tomography performed on the day of admission showing that the tumor had invaded the rib cage
On the first day of hospitalization, the patient received an intramuscular injection of tetanus toxoid and an intravenous injection of tetanus immunoglobulin at a dose of 4500 U. After the patient was admitted to the intensive care unit (ICU), tracheal intubation and deep sedation were performed; in addition, artificial respiration management was performed in a room that was sound- and light-shielded. Concurrently, the patient received an infusion of metronidazole at a dose of 500 mg every 8 h. Fentanyl and dexmedetomidine were administered by continuous intravenous infusion for analgesia and sedation. Magnesium sulfate was intravenously injected at 2 g/day to control muscle rigidity and convulsions.
On Day 7, the patient presented with mild opisthotonus. However, there was no significant change in the autonomic nervous system function to suggest autonomic hyperactivity.
We assessed the severity of her tetanus using the Ablett classification [22]; all symptoms were in the moderate category.
On Day 16, no sign of opisthotonus was observed, suggesting that the patient had entered a recovery period. Tracheotomy was performed on Day 19 to relieve the remaining grinding trismus. On Day 20, sound insulation and shading and sedation management were completed. Oral intake and rehabilitation commenced on Day 22. The patient was discharged from the ICU on Day 25. On Day 33, the tracheal cannula was removed, and the tracheostomy was closed.
Wound treatment consisted of daily cleaning with soap and application of the petroleum jelly Vaseline. A wound care specialist nurse instructed the patient on wound care.
On Day 45 post-tetanus onset, the patient received a second dose of tetanus toxoid. The patient was discharged on Day 54. Three years after she left the hospital, she underwent an excision of a breast cancer skin ulcer. At present, 5 years post-discharge, the patient resides at home and has shown no evidence of tetanus recurrence or long-term adverse events. At the time of writing (July 2020), the patient continues to receive chemotherapy.
Discussion and conclusion
C. tetani grow and germinate in an anaerobic environment (necrotic tissue) and produce toxins. Although antibacterial agents tend to be effective in killing germinated tetanus bacteria, their effectiveness in killing these bacteria in the spore state is reduced; thus, treatment of tetanus in the necrotic tissue requires an approach that includes elements other than an antibacterial agent alone. An ulcer resulting from advanced breast cancer tends to move toward the surface of the body, exposing the chest wall in the process. This lesion is associated with anaerobic infection;
cases of tetanus infection from a breast cancer skin ulcer have been reported among other types of anaerobic infection.
The spore-forming C. tetani are resilient and can survive for a long time in an environment that is unsuitable for their activity. However, when the environment does become favorable, the host develops tetanus due to bacterial germination and the production of C. tetani toxins. Furthermore, a previous experimental study examining the impact of inoculating cancer-bearing animals showed that C. tetani spores that invade through a fresh wound can quickly migrate to and colonize necrotic tissues of cancer, leading to the development of tetanus [19]. In essence, a breast cancer skin ulcer functions as a reservoir of C. tetani toxins, even if they originally developed elsewhere.
Chronic wounds other than breast cancer skin ulcers can also be an entry point for tetanus bacteria. Barogui et al. reported a case of tetanus infection from a Bruli ulcer, which is an endemic disease in the tropics. The patient was cured of tetanus via debridement performed for the treatment of a Bruli ulcer [23]. Evidence suggests that active debridement of the infection site is important for the treatment of tetanus [1, 3, 19–21].
Recent studies have reported 15 cases of tetanus in patients with breast cancer skin ulcer (Table 1) [4–17]. Twelve of these cases (A-L) underwent surgical debridement. Two cases (C, I) died of tetanus after debridement was performed. One case (G) recovered from tetanus, but the patient died of sequela. Overall, this evidence suggests that tetanus originating from breast cancer skin ulcers is associated with a high risk of death and recurrence. As in the present case, debridement itself can be life threatening, resulting in patients refusing consent to surgery. In such cases, alternatives to debridement should be considered to help achieve good patient outcomes.
Table 1 Summary of previously reported cases of tetanus associated with breast cancer-related skin ulcer. No previous studies reported long-term antimicrobial therapy for the prevention of tetanus recurrence
Case Age Debridement Antibiotics Tetanus immunoglobulin Toxoid (after tetanus infection) Autonomic hyperactivity Recurrence Outcome Reference number
A 62 Yes Penicillin and metronidazole N/A One time N/A N/A Survival [4]
B 55 Yes Yes (specifics unknown) Yes N/A No No Survival [5]a
C 53 Yes Penicillin, ceftazidime, imipenem, and gentamycin Yes One time Yes No Deceased [6]
D 46 Yes Penicillin Yes N/A Yes N/A Survival [7]
E 59 Yes Penicillin Yes One time N/A N/A Survival [8]
F 75 Yes Piperacillin Yes N/A Yes N/A Survival [9]
G 56 Yes N/A Yes N/A N/A N/A Deceased [10]
H 55 Yes Penicillin Yes N/A Yes N/A Survival [11]
I 60 Yes N/A N/A N/A Yes No Deceased [12]
J 60 Yes Penicillin Yes Two times Yes N/A Survival [13]
K 67 Yes Penicillin Yes One time Yes No Survival [14]
L 65 Yes Penicillin, metronidazole, and cefepime Yes One time Yes No Survival [15]
M 50s No Meropenem Yes No Yes No Deceased [16]a
N 40 No Metronidazole Yes One time Yes Yes Deceased [17]
O 54 No Metronidazole, piperacillin/tazobactam, and ceftriaxone Yes One time No Yes Survival [17]
aWe contacted the authors of these papers directly and included the information they provided in this table
Three cases (M-O) of skin ulcer-related tetanus treated without debridement were previously reported. Among them, one patient (M) died as a result of tetanus, while the remaining two patients (N, O) achieved remission. However, both patients experienced recurrence: one patient (N) died of recurrent tetanus and the other patient (O) experienced tetanus remission and recurrence at least twice, but the patient’s subsequent course is unknown. Autonomic hyperactivity due to tetanus was not seen in the first remission of either case (N, O). At the time of recurrence, one of the patients (N) died due to autonomic hyperactivity, whereas the other patient (O), whose tetanus was localized, subsequently went into remission.
The severity of tetanus depends on the amount of bacterial toxin present. The most serious cases of tetanus show autonomic symptoms [24].
Severe tetanus is associated with poor prognosis compared to that associated its mild form [1, 24]. Although toxin levels may determine patient prognosis, no previous study has examined this association.
The amount of toxins present in the body is associated with the severity of tetanus and the amount of time that passes between bacterial invasion and treatment commencement. In the present case, we observed rapid remission with no recurrence. There are two reasons that may account for this finding. First, the administration of metronidazole might have killed all the tetanus bacteria before they were able to sporulate further. Concurrently, the administration of antitoxin antibodies might have neutralized the activity of the remaining toxin. However, as similar cases (M, N) have previously shown, tetanus bacillus can remain latent in the body and may cause tetanus recurrence. In animal studies in which tetanus bacteria were inoculated into cancer-bearing rats, tetanus bacteria were established in the tumor within 48 h [19]. In the present case, the patient presented more than a week after the onset of disease; the delay made it difficult to eliminate all tetanus bacteria and toxins with the use of antimicrobials and antitoxin antibodies. Second, the present patient may have acquired active immunity through two vaccinations, which may in turn have inhibited the recurrence of tetanus. The present case differs from cases N and O in that there has been no recurrence for at least 3 years after remission. Our patient had a booster shot before discharge from our hospital, while cases N and O received toxoid only once at the time of admission. Antibody titers rarely rise sufficiently with a single inoculation of toxoid. In fact, some cases of tetanus that recurred after vaccination involved antibody titers below the onset arrest concentration of 0.01 IU/ml [2, 25, 26].
Surgical resection of chronic wounds is the most reliable method of reducing the risk of tetanus recurrence. In cases where surgery cannot be performed, active immunity is required to suppress recurrence. The present patient did not experience tetanus recurrence for 3 years since the completion of treatment likely due to acquired active immunity. Tetanus can be a life-threatening disease whose occurrence can be prevented by vaccination. Cancer patients with lesions susceptible to tetanus should be actively vaccinated [3].
Nevertheless, a case of malignant tumor-associated tetanus, in which three inoculations of toxoid failed to activate immunity, likely due to the effect of cancer-induced immunodeficiency, has been reported [27]. At present, these is no clear evidence on how many toxoid inoculations should be given to cancer-bearing patients. Therefore, tetanus antibody titers should be measured in conjunction with vaccination administration to ensure that adequate antibody titers are maintained.
The tetanus antibody titer value required to prevent tetanus or maintain its remission in cancer patients remains unclear. In fact, no previous study has investigated the optimum dose, frequency, or duration of toxoid inoculation required for such patients. Further research is required to elucidate these parameters.
In summary, tetanus with chronic skin ulcer without autonomic hyperactivity can be ameliorated without debridement. However, as tetanus is prone to recurrence, the acquisition of active immunity is essential to prevent recurrence after remission. Multiple doses of vaccination may be required to ensure adequate antibody titers and immunity to tetanus are achieved in cancer patients [17, 25–27].
Abbreviation
ICUIntensive care unit
Publisher’s Note
Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
All authors express their deep gratitude to the paramedical staff for their professional and devoted service.
Authors’ contributions
KN (corresponding author) wrote the entire manuscript and performed the literature review. ES compiled the patient’s medical history and laboratory data. AY, WA, ES, SS, HO, YT, SU, and EN contributed to the interpretation of the clinical manifestations and revised the manuscript for critical intellectual content. All authors have read and approved the manuscript.
Funding
This study received no specific funding.
Availability of data and materials
The datasets used and/or analyzed during the current study available from the corresponding author on reasonable request.
Ethics approval and consent to participate
Not applicable.
Consent for publication
Written consent to publish our case was obtained from the patient. A copy of the written consent is available to be reviewed by the editorial committee of this journal.
Competing interests
The authors declare that they have no competing interests. | 2 GRAM, QD | DrugDosageText | CC BY | 33413196 | 18,794,500 | 2021-01-07 |
What was the dosage of drug 'METRONIDAZOLE'? | Non-surgical treatment of tetanus infection associated with breast cancer skin ulcer: a case report and literature review.
BACKGROUND
Previous studies have reported poor prognosis in cases of tetanus that develops after bacteria enters via breast cancer-related skin ulcers that are not treated with surgical debridement. Herein, we review the literature concerning this presentation and report the first case of complete remission from tetanus without surgical debridement of the skin ulcer.
METHODS
An Asian woman aged over 60 years had a history of skin ulcer caused by breast cancer. She was diagnosed with tetanus due to trismus and opisthotonus. Based on the suspicion that the skin ulcer was the portal of entry for tetanus bacteria, we considered several debridement and thoracic surgical options for tetanus treatment. However, debridement was not performed as the surgery was considered high risk and the patient did not consent to it. The patient received treatment with anti-tetanus globulin and metronidazole; sound insulation and shielding were also performed in a dark room. Subsequently, the patient's symptoms improved, and sound insulation and deep sedation management were completed on 19th day of hospitalization. With no symptom recurrence, the patient was discharged on Day 54. To date, over 3 years after treatment, no evidence of tetanus recurrence has been observed. The case was characterized by a lack of autonomic hyperactivity. The tetanus severity was likely representative of the low amount of toxin that the patient was exposed to.
CONCLUSIONS
This case involved moderate severity tetanus originating from a chronic skin ulcer related to breast cancer. The patient survived without undergoing extensive debridement. No evidence of tetanus relapse was observed during the follow-up period, likely due to vaccination that might have restored the patient's active immunity. Debridement is not always necessary for tetanus complicated by breast cancer skin ulcers. Furthermore, appropriate toxoid vaccination is critical for preventing the onset and recurrence of tetanus in these patients.
Background
Tetanus is caused by Clostridium tetani, an obligate anaerobic bacterium, that enters the body and releases toxins. The tetanus toxin causes severe spastic paralysis and autonomic hyperactivity, which may lead to death [1, 2]. Patients with chronic wounds such as skin ulcer are at a high risk of tetanus as these wounds provide an entry route for tetanus bacteria [3]. In fact, previous studies have shown that patients with skin ulcer due to advanced breast cancer are at a particularly high risk of developing tetanus and that removing the ulcer is the only effective treatment in such cases [4–17]. A cancerous skin ulcer contains necrotic tissue, which constitutes anaerobic environment that is conducive to the growth of tetanus bacteria and the production of toxins [3, 18, 19]. As blood flow to necrotic tissues is restricted, treatment with antibiotics tends to be ineffective in such cases due to the body’s inability to deliver the treatment to the site of infection. In addition, tetanus bacteria can form spores, which may reduce the effectiveness of antibacterial drugs. As a result, in cases of tetanus associated with chronic wounds, debridement of the wound has been considered an essential element of treatment [1, 3, 19–21]. Herein, we report about a patient with tetanus due to skin ulcer associated with breast cancer who was treated without debridement and who presented with no sign of recurrence 3 years after treatment completion.
Case presentation
An Asian woman aged over 60 years had a history of left-sided breast cancer (Fig. 1). She had received two tetanus vaccinations: first as an infant and second at around 10 years of age. She underwent cancer resection in her 40s; however, the cancer recurred and was initially treated with chemotherapy until the patient declined further treatment and stopped attending her hospital appointments. After several years, as she was no longer a patient, her medical records were discarded, leading to the loss of clinical data, including her breast cancer histopathological findings and information on disease stage and treatment. At the time of recurrence, the patient presented with an untreated breast cancer that had invaded the skin and formed a sizable tumor and ulcer in the precordial region. The patient attempted to treat her own wounds without visiting a hospital. Approximately a week before hospitalization, the patient presented with trismus. As trismus progressed, she visited a dental clinic, where the severity of her trismus precluded treatment. The patient had no disease that caused dental trismus but a cervical flexion disorder and was therefore suspected of having tetanus and subsequently referred to the Emergency Department of our hospital on the same day.
Fig. 1 Timeline of case management from admission to discharge from the intensive care unit
During admission, the patient was awake and alert; however, she could open her mouth only to the width of a single finger. In addition, she was unable to flex her neck due to involuntary overextension and pain in the posterior cervical muscles. Her blood pressure was 155/109 mmHg, heart rate was 120 beats/min, respiratory rate was 16 breaths/min, body temperature (axillary) was 36.4 °C, and SpO2 was 99% (room air). After excluding other conditions that could account for the presenting symptoms, the patient was diagnosed with tetanus.
Advanced breast cancer in the precordial region was suspected to account for the presence of a large tumor and skin ulcer (Fig. 2). Blood tests revealed a mild increase in the levels of inflammatory reaction parameters, likely occurring due to the skin ulcer. Computed tomography revealed no obvious cranial abnormalities; however, it showed that the precordial tumor had invaded the rib cage. Contralateral axillary lymph node metastasis was also observed; however, there was no evidence of distant organ metastases (Fig. 3). Since there was no history of minor or major trauma during 1 month prior to symptom onset, the skin ulcer was considered the most likely site of infection. As the patient reported being an avid gardener, she was at high risk of exposure to tetanus bacteria that may be present in the soil. The skin ulcer was extensive in width and depth; thus, highly invasive thoracoplasty was considered required to achieve sufficient debridement. However, progressing tetanus could cause postoperative complications such as flap necrosis. As the patient refused to consent to surgery, we did not perform surgical debridement but simply provided medical treatment.
Fig. 2 Front view of the breast cancer skin ulcer on Day 4 of hospitalization. The tumor was approximately 20 × 20 cm in size with extensive necrosis. The image is anonymized to protect the patient’s privacy
Fig. 3 Computed tomography performed on the day of admission showing that the tumor had invaded the rib cage
On the first day of hospitalization, the patient received an intramuscular injection of tetanus toxoid and an intravenous injection of tetanus immunoglobulin at a dose of 4500 U. After the patient was admitted to the intensive care unit (ICU), tracheal intubation and deep sedation were performed; in addition, artificial respiration management was performed in a room that was sound- and light-shielded. Concurrently, the patient received an infusion of metronidazole at a dose of 500 mg every 8 h. Fentanyl and dexmedetomidine were administered by continuous intravenous infusion for analgesia and sedation. Magnesium sulfate was intravenously injected at 2 g/day to control muscle rigidity and convulsions.
On Day 7, the patient presented with mild opisthotonus. However, there was no significant change in the autonomic nervous system function to suggest autonomic hyperactivity.
We assessed the severity of her tetanus using the Ablett classification [22]; all symptoms were in the moderate category.
On Day 16, no sign of opisthotonus was observed, suggesting that the patient had entered a recovery period. Tracheotomy was performed on Day 19 to relieve the remaining grinding trismus. On Day 20, sound insulation and shading and sedation management were completed. Oral intake and rehabilitation commenced on Day 22. The patient was discharged from the ICU on Day 25. On Day 33, the tracheal cannula was removed, and the tracheostomy was closed.
Wound treatment consisted of daily cleaning with soap and application of the petroleum jelly Vaseline. A wound care specialist nurse instructed the patient on wound care.
On Day 45 post-tetanus onset, the patient received a second dose of tetanus toxoid. The patient was discharged on Day 54. Three years after she left the hospital, she underwent an excision of a breast cancer skin ulcer. At present, 5 years post-discharge, the patient resides at home and has shown no evidence of tetanus recurrence or long-term adverse events. At the time of writing (July 2020), the patient continues to receive chemotherapy.
Discussion and conclusion
C. tetani grow and germinate in an anaerobic environment (necrotic tissue) and produce toxins. Although antibacterial agents tend to be effective in killing germinated tetanus bacteria, their effectiveness in killing these bacteria in the spore state is reduced; thus, treatment of tetanus in the necrotic tissue requires an approach that includes elements other than an antibacterial agent alone. An ulcer resulting from advanced breast cancer tends to move toward the surface of the body, exposing the chest wall in the process. This lesion is associated with anaerobic infection;
cases of tetanus infection from a breast cancer skin ulcer have been reported among other types of anaerobic infection.
The spore-forming C. tetani are resilient and can survive for a long time in an environment that is unsuitable for their activity. However, when the environment does become favorable, the host develops tetanus due to bacterial germination and the production of C. tetani toxins. Furthermore, a previous experimental study examining the impact of inoculating cancer-bearing animals showed that C. tetani spores that invade through a fresh wound can quickly migrate to and colonize necrotic tissues of cancer, leading to the development of tetanus [19]. In essence, a breast cancer skin ulcer functions as a reservoir of C. tetani toxins, even if they originally developed elsewhere.
Chronic wounds other than breast cancer skin ulcers can also be an entry point for tetanus bacteria. Barogui et al. reported a case of tetanus infection from a Bruli ulcer, which is an endemic disease in the tropics. The patient was cured of tetanus via debridement performed for the treatment of a Bruli ulcer [23]. Evidence suggests that active debridement of the infection site is important for the treatment of tetanus [1, 3, 19–21].
Recent studies have reported 15 cases of tetanus in patients with breast cancer skin ulcer (Table 1) [4–17]. Twelve of these cases (A-L) underwent surgical debridement. Two cases (C, I) died of tetanus after debridement was performed. One case (G) recovered from tetanus, but the patient died of sequela. Overall, this evidence suggests that tetanus originating from breast cancer skin ulcers is associated with a high risk of death and recurrence. As in the present case, debridement itself can be life threatening, resulting in patients refusing consent to surgery. In such cases, alternatives to debridement should be considered to help achieve good patient outcomes.
Table 1 Summary of previously reported cases of tetanus associated with breast cancer-related skin ulcer. No previous studies reported long-term antimicrobial therapy for the prevention of tetanus recurrence
Case Age Debridement Antibiotics Tetanus immunoglobulin Toxoid (after tetanus infection) Autonomic hyperactivity Recurrence Outcome Reference number
A 62 Yes Penicillin and metronidazole N/A One time N/A N/A Survival [4]
B 55 Yes Yes (specifics unknown) Yes N/A No No Survival [5]a
C 53 Yes Penicillin, ceftazidime, imipenem, and gentamycin Yes One time Yes No Deceased [6]
D 46 Yes Penicillin Yes N/A Yes N/A Survival [7]
E 59 Yes Penicillin Yes One time N/A N/A Survival [8]
F 75 Yes Piperacillin Yes N/A Yes N/A Survival [9]
G 56 Yes N/A Yes N/A N/A N/A Deceased [10]
H 55 Yes Penicillin Yes N/A Yes N/A Survival [11]
I 60 Yes N/A N/A N/A Yes No Deceased [12]
J 60 Yes Penicillin Yes Two times Yes N/A Survival [13]
K 67 Yes Penicillin Yes One time Yes No Survival [14]
L 65 Yes Penicillin, metronidazole, and cefepime Yes One time Yes No Survival [15]
M 50s No Meropenem Yes No Yes No Deceased [16]a
N 40 No Metronidazole Yes One time Yes Yes Deceased [17]
O 54 No Metronidazole, piperacillin/tazobactam, and ceftriaxone Yes One time No Yes Survival [17]
aWe contacted the authors of these papers directly and included the information they provided in this table
Three cases (M-O) of skin ulcer-related tetanus treated without debridement were previously reported. Among them, one patient (M) died as a result of tetanus, while the remaining two patients (N, O) achieved remission. However, both patients experienced recurrence: one patient (N) died of recurrent tetanus and the other patient (O) experienced tetanus remission and recurrence at least twice, but the patient’s subsequent course is unknown. Autonomic hyperactivity due to tetanus was not seen in the first remission of either case (N, O). At the time of recurrence, one of the patients (N) died due to autonomic hyperactivity, whereas the other patient (O), whose tetanus was localized, subsequently went into remission.
The severity of tetanus depends on the amount of bacterial toxin present. The most serious cases of tetanus show autonomic symptoms [24].
Severe tetanus is associated with poor prognosis compared to that associated its mild form [1, 24]. Although toxin levels may determine patient prognosis, no previous study has examined this association.
The amount of toxins present in the body is associated with the severity of tetanus and the amount of time that passes between bacterial invasion and treatment commencement. In the present case, we observed rapid remission with no recurrence. There are two reasons that may account for this finding. First, the administration of metronidazole might have killed all the tetanus bacteria before they were able to sporulate further. Concurrently, the administration of antitoxin antibodies might have neutralized the activity of the remaining toxin. However, as similar cases (M, N) have previously shown, tetanus bacillus can remain latent in the body and may cause tetanus recurrence. In animal studies in which tetanus bacteria were inoculated into cancer-bearing rats, tetanus bacteria were established in the tumor within 48 h [19]. In the present case, the patient presented more than a week after the onset of disease; the delay made it difficult to eliminate all tetanus bacteria and toxins with the use of antimicrobials and antitoxin antibodies. Second, the present patient may have acquired active immunity through two vaccinations, which may in turn have inhibited the recurrence of tetanus. The present case differs from cases N and O in that there has been no recurrence for at least 3 years after remission. Our patient had a booster shot before discharge from our hospital, while cases N and O received toxoid only once at the time of admission. Antibody titers rarely rise sufficiently with a single inoculation of toxoid. In fact, some cases of tetanus that recurred after vaccination involved antibody titers below the onset arrest concentration of 0.01 IU/ml [2, 25, 26].
Surgical resection of chronic wounds is the most reliable method of reducing the risk of tetanus recurrence. In cases where surgery cannot be performed, active immunity is required to suppress recurrence. The present patient did not experience tetanus recurrence for 3 years since the completion of treatment likely due to acquired active immunity. Tetanus can be a life-threatening disease whose occurrence can be prevented by vaccination. Cancer patients with lesions susceptible to tetanus should be actively vaccinated [3].
Nevertheless, a case of malignant tumor-associated tetanus, in which three inoculations of toxoid failed to activate immunity, likely due to the effect of cancer-induced immunodeficiency, has been reported [27]. At present, these is no clear evidence on how many toxoid inoculations should be given to cancer-bearing patients. Therefore, tetanus antibody titers should be measured in conjunction with vaccination administration to ensure that adequate antibody titers are maintained.
The tetanus antibody titer value required to prevent tetanus or maintain its remission in cancer patients remains unclear. In fact, no previous study has investigated the optimum dose, frequency, or duration of toxoid inoculation required for such patients. Further research is required to elucidate these parameters.
In summary, tetanus with chronic skin ulcer without autonomic hyperactivity can be ameliorated without debridement. However, as tetanus is prone to recurrence, the acquisition of active immunity is essential to prevent recurrence after remission. Multiple doses of vaccination may be required to ensure adequate antibody titers and immunity to tetanus are achieved in cancer patients [17, 25–27].
Abbreviation
ICUIntensive care unit
Publisher’s Note
Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
All authors express their deep gratitude to the paramedical staff for their professional and devoted service.
Authors’ contributions
KN (corresponding author) wrote the entire manuscript and performed the literature review. ES compiled the patient’s medical history and laboratory data. AY, WA, ES, SS, HO, YT, SU, and EN contributed to the interpretation of the clinical manifestations and revised the manuscript for critical intellectual content. All authors have read and approved the manuscript.
Funding
This study received no specific funding.
Availability of data and materials
The datasets used and/or analyzed during the current study available from the corresponding author on reasonable request.
Ethics approval and consent to participate
Not applicable.
Consent for publication
Written consent to publish our case was obtained from the patient. A copy of the written consent is available to be reviewed by the editorial committee of this journal.
Competing interests
The authors declare that they have no competing interests. | 500 MG, Q 8 HR | DrugDosageText | CC BY | 33413196 | 18,794,500 | 2021-01-07 |
What was the outcome of reaction 'Opisthotonus'? | Non-surgical treatment of tetanus infection associated with breast cancer skin ulcer: a case report and literature review.
BACKGROUND
Previous studies have reported poor prognosis in cases of tetanus that develops after bacteria enters via breast cancer-related skin ulcers that are not treated with surgical debridement. Herein, we review the literature concerning this presentation and report the first case of complete remission from tetanus without surgical debridement of the skin ulcer.
METHODS
An Asian woman aged over 60 years had a history of skin ulcer caused by breast cancer. She was diagnosed with tetanus due to trismus and opisthotonus. Based on the suspicion that the skin ulcer was the portal of entry for tetanus bacteria, we considered several debridement and thoracic surgical options for tetanus treatment. However, debridement was not performed as the surgery was considered high risk and the patient did not consent to it. The patient received treatment with anti-tetanus globulin and metronidazole; sound insulation and shielding were also performed in a dark room. Subsequently, the patient's symptoms improved, and sound insulation and deep sedation management were completed on 19th day of hospitalization. With no symptom recurrence, the patient was discharged on Day 54. To date, over 3 years after treatment, no evidence of tetanus recurrence has been observed. The case was characterized by a lack of autonomic hyperactivity. The tetanus severity was likely representative of the low amount of toxin that the patient was exposed to.
CONCLUSIONS
This case involved moderate severity tetanus originating from a chronic skin ulcer related to breast cancer. The patient survived without undergoing extensive debridement. No evidence of tetanus relapse was observed during the follow-up period, likely due to vaccination that might have restored the patient's active immunity. Debridement is not always necessary for tetanus complicated by breast cancer skin ulcers. Furthermore, appropriate toxoid vaccination is critical for preventing the onset and recurrence of tetanus in these patients.
Background
Tetanus is caused by Clostridium tetani, an obligate anaerobic bacterium, that enters the body and releases toxins. The tetanus toxin causes severe spastic paralysis and autonomic hyperactivity, which may lead to death [1, 2]. Patients with chronic wounds such as skin ulcer are at a high risk of tetanus as these wounds provide an entry route for tetanus bacteria [3]. In fact, previous studies have shown that patients with skin ulcer due to advanced breast cancer are at a particularly high risk of developing tetanus and that removing the ulcer is the only effective treatment in such cases [4–17]. A cancerous skin ulcer contains necrotic tissue, which constitutes anaerobic environment that is conducive to the growth of tetanus bacteria and the production of toxins [3, 18, 19]. As blood flow to necrotic tissues is restricted, treatment with antibiotics tends to be ineffective in such cases due to the body’s inability to deliver the treatment to the site of infection. In addition, tetanus bacteria can form spores, which may reduce the effectiveness of antibacterial drugs. As a result, in cases of tetanus associated with chronic wounds, debridement of the wound has been considered an essential element of treatment [1, 3, 19–21]. Herein, we report about a patient with tetanus due to skin ulcer associated with breast cancer who was treated without debridement and who presented with no sign of recurrence 3 years after treatment completion.
Case presentation
An Asian woman aged over 60 years had a history of left-sided breast cancer (Fig. 1). She had received two tetanus vaccinations: first as an infant and second at around 10 years of age. She underwent cancer resection in her 40s; however, the cancer recurred and was initially treated with chemotherapy until the patient declined further treatment and stopped attending her hospital appointments. After several years, as she was no longer a patient, her medical records were discarded, leading to the loss of clinical data, including her breast cancer histopathological findings and information on disease stage and treatment. At the time of recurrence, the patient presented with an untreated breast cancer that had invaded the skin and formed a sizable tumor and ulcer in the precordial region. The patient attempted to treat her own wounds without visiting a hospital. Approximately a week before hospitalization, the patient presented with trismus. As trismus progressed, she visited a dental clinic, where the severity of her trismus precluded treatment. The patient had no disease that caused dental trismus but a cervical flexion disorder and was therefore suspected of having tetanus and subsequently referred to the Emergency Department of our hospital on the same day.
Fig. 1 Timeline of case management from admission to discharge from the intensive care unit
During admission, the patient was awake and alert; however, she could open her mouth only to the width of a single finger. In addition, she was unable to flex her neck due to involuntary overextension and pain in the posterior cervical muscles. Her blood pressure was 155/109 mmHg, heart rate was 120 beats/min, respiratory rate was 16 breaths/min, body temperature (axillary) was 36.4 °C, and SpO2 was 99% (room air). After excluding other conditions that could account for the presenting symptoms, the patient was diagnosed with tetanus.
Advanced breast cancer in the precordial region was suspected to account for the presence of a large tumor and skin ulcer (Fig. 2). Blood tests revealed a mild increase in the levels of inflammatory reaction parameters, likely occurring due to the skin ulcer. Computed tomography revealed no obvious cranial abnormalities; however, it showed that the precordial tumor had invaded the rib cage. Contralateral axillary lymph node metastasis was also observed; however, there was no evidence of distant organ metastases (Fig. 3). Since there was no history of minor or major trauma during 1 month prior to symptom onset, the skin ulcer was considered the most likely site of infection. As the patient reported being an avid gardener, she was at high risk of exposure to tetanus bacteria that may be present in the soil. The skin ulcer was extensive in width and depth; thus, highly invasive thoracoplasty was considered required to achieve sufficient debridement. However, progressing tetanus could cause postoperative complications such as flap necrosis. As the patient refused to consent to surgery, we did not perform surgical debridement but simply provided medical treatment.
Fig. 2 Front view of the breast cancer skin ulcer on Day 4 of hospitalization. The tumor was approximately 20 × 20 cm in size with extensive necrosis. The image is anonymized to protect the patient’s privacy
Fig. 3 Computed tomography performed on the day of admission showing that the tumor had invaded the rib cage
On the first day of hospitalization, the patient received an intramuscular injection of tetanus toxoid and an intravenous injection of tetanus immunoglobulin at a dose of 4500 U. After the patient was admitted to the intensive care unit (ICU), tracheal intubation and deep sedation were performed; in addition, artificial respiration management was performed in a room that was sound- and light-shielded. Concurrently, the patient received an infusion of metronidazole at a dose of 500 mg every 8 h. Fentanyl and dexmedetomidine were administered by continuous intravenous infusion for analgesia and sedation. Magnesium sulfate was intravenously injected at 2 g/day to control muscle rigidity and convulsions.
On Day 7, the patient presented with mild opisthotonus. However, there was no significant change in the autonomic nervous system function to suggest autonomic hyperactivity.
We assessed the severity of her tetanus using the Ablett classification [22]; all symptoms were in the moderate category.
On Day 16, no sign of opisthotonus was observed, suggesting that the patient had entered a recovery period. Tracheotomy was performed on Day 19 to relieve the remaining grinding trismus. On Day 20, sound insulation and shading and sedation management were completed. Oral intake and rehabilitation commenced on Day 22. The patient was discharged from the ICU on Day 25. On Day 33, the tracheal cannula was removed, and the tracheostomy was closed.
Wound treatment consisted of daily cleaning with soap and application of the petroleum jelly Vaseline. A wound care specialist nurse instructed the patient on wound care.
On Day 45 post-tetanus onset, the patient received a second dose of tetanus toxoid. The patient was discharged on Day 54. Three years after she left the hospital, she underwent an excision of a breast cancer skin ulcer. At present, 5 years post-discharge, the patient resides at home and has shown no evidence of tetanus recurrence or long-term adverse events. At the time of writing (July 2020), the patient continues to receive chemotherapy.
Discussion and conclusion
C. tetani grow and germinate in an anaerobic environment (necrotic tissue) and produce toxins. Although antibacterial agents tend to be effective in killing germinated tetanus bacteria, their effectiveness in killing these bacteria in the spore state is reduced; thus, treatment of tetanus in the necrotic tissue requires an approach that includes elements other than an antibacterial agent alone. An ulcer resulting from advanced breast cancer tends to move toward the surface of the body, exposing the chest wall in the process. This lesion is associated with anaerobic infection;
cases of tetanus infection from a breast cancer skin ulcer have been reported among other types of anaerobic infection.
The spore-forming C. tetani are resilient and can survive for a long time in an environment that is unsuitable for their activity. However, when the environment does become favorable, the host develops tetanus due to bacterial germination and the production of C. tetani toxins. Furthermore, a previous experimental study examining the impact of inoculating cancer-bearing animals showed that C. tetani spores that invade through a fresh wound can quickly migrate to and colonize necrotic tissues of cancer, leading to the development of tetanus [19]. In essence, a breast cancer skin ulcer functions as a reservoir of C. tetani toxins, even if they originally developed elsewhere.
Chronic wounds other than breast cancer skin ulcers can also be an entry point for tetanus bacteria. Barogui et al. reported a case of tetanus infection from a Bruli ulcer, which is an endemic disease in the tropics. The patient was cured of tetanus via debridement performed for the treatment of a Bruli ulcer [23]. Evidence suggests that active debridement of the infection site is important for the treatment of tetanus [1, 3, 19–21].
Recent studies have reported 15 cases of tetanus in patients with breast cancer skin ulcer (Table 1) [4–17]. Twelve of these cases (A-L) underwent surgical debridement. Two cases (C, I) died of tetanus after debridement was performed. One case (G) recovered from tetanus, but the patient died of sequela. Overall, this evidence suggests that tetanus originating from breast cancer skin ulcers is associated with a high risk of death and recurrence. As in the present case, debridement itself can be life threatening, resulting in patients refusing consent to surgery. In such cases, alternatives to debridement should be considered to help achieve good patient outcomes.
Table 1 Summary of previously reported cases of tetanus associated with breast cancer-related skin ulcer. No previous studies reported long-term antimicrobial therapy for the prevention of tetanus recurrence
Case Age Debridement Antibiotics Tetanus immunoglobulin Toxoid (after tetanus infection) Autonomic hyperactivity Recurrence Outcome Reference number
A 62 Yes Penicillin and metronidazole N/A One time N/A N/A Survival [4]
B 55 Yes Yes (specifics unknown) Yes N/A No No Survival [5]a
C 53 Yes Penicillin, ceftazidime, imipenem, and gentamycin Yes One time Yes No Deceased [6]
D 46 Yes Penicillin Yes N/A Yes N/A Survival [7]
E 59 Yes Penicillin Yes One time N/A N/A Survival [8]
F 75 Yes Piperacillin Yes N/A Yes N/A Survival [9]
G 56 Yes N/A Yes N/A N/A N/A Deceased [10]
H 55 Yes Penicillin Yes N/A Yes N/A Survival [11]
I 60 Yes N/A N/A N/A Yes No Deceased [12]
J 60 Yes Penicillin Yes Two times Yes N/A Survival [13]
K 67 Yes Penicillin Yes One time Yes No Survival [14]
L 65 Yes Penicillin, metronidazole, and cefepime Yes One time Yes No Survival [15]
M 50s No Meropenem Yes No Yes No Deceased [16]a
N 40 No Metronidazole Yes One time Yes Yes Deceased [17]
O 54 No Metronidazole, piperacillin/tazobactam, and ceftriaxone Yes One time No Yes Survival [17]
aWe contacted the authors of these papers directly and included the information they provided in this table
Three cases (M-O) of skin ulcer-related tetanus treated without debridement were previously reported. Among them, one patient (M) died as a result of tetanus, while the remaining two patients (N, O) achieved remission. However, both patients experienced recurrence: one patient (N) died of recurrent tetanus and the other patient (O) experienced tetanus remission and recurrence at least twice, but the patient’s subsequent course is unknown. Autonomic hyperactivity due to tetanus was not seen in the first remission of either case (N, O). At the time of recurrence, one of the patients (N) died due to autonomic hyperactivity, whereas the other patient (O), whose tetanus was localized, subsequently went into remission.
The severity of tetanus depends on the amount of bacterial toxin present. The most serious cases of tetanus show autonomic symptoms [24].
Severe tetanus is associated with poor prognosis compared to that associated its mild form [1, 24]. Although toxin levels may determine patient prognosis, no previous study has examined this association.
The amount of toxins present in the body is associated with the severity of tetanus and the amount of time that passes between bacterial invasion and treatment commencement. In the present case, we observed rapid remission with no recurrence. There are two reasons that may account for this finding. First, the administration of metronidazole might have killed all the tetanus bacteria before they were able to sporulate further. Concurrently, the administration of antitoxin antibodies might have neutralized the activity of the remaining toxin. However, as similar cases (M, N) have previously shown, tetanus bacillus can remain latent in the body and may cause tetanus recurrence. In animal studies in which tetanus bacteria were inoculated into cancer-bearing rats, tetanus bacteria were established in the tumor within 48 h [19]. In the present case, the patient presented more than a week after the onset of disease; the delay made it difficult to eliminate all tetanus bacteria and toxins with the use of antimicrobials and antitoxin antibodies. Second, the present patient may have acquired active immunity through two vaccinations, which may in turn have inhibited the recurrence of tetanus. The present case differs from cases N and O in that there has been no recurrence for at least 3 years after remission. Our patient had a booster shot before discharge from our hospital, while cases N and O received toxoid only once at the time of admission. Antibody titers rarely rise sufficiently with a single inoculation of toxoid. In fact, some cases of tetanus that recurred after vaccination involved antibody titers below the onset arrest concentration of 0.01 IU/ml [2, 25, 26].
Surgical resection of chronic wounds is the most reliable method of reducing the risk of tetanus recurrence. In cases where surgery cannot be performed, active immunity is required to suppress recurrence. The present patient did not experience tetanus recurrence for 3 years since the completion of treatment likely due to acquired active immunity. Tetanus can be a life-threatening disease whose occurrence can be prevented by vaccination. Cancer patients with lesions susceptible to tetanus should be actively vaccinated [3].
Nevertheless, a case of malignant tumor-associated tetanus, in which three inoculations of toxoid failed to activate immunity, likely due to the effect of cancer-induced immunodeficiency, has been reported [27]. At present, these is no clear evidence on how many toxoid inoculations should be given to cancer-bearing patients. Therefore, tetanus antibody titers should be measured in conjunction with vaccination administration to ensure that adequate antibody titers are maintained.
The tetanus antibody titer value required to prevent tetanus or maintain its remission in cancer patients remains unclear. In fact, no previous study has investigated the optimum dose, frequency, or duration of toxoid inoculation required for such patients. Further research is required to elucidate these parameters.
In summary, tetanus with chronic skin ulcer without autonomic hyperactivity can be ameliorated without debridement. However, as tetanus is prone to recurrence, the acquisition of active immunity is essential to prevent recurrence after remission. Multiple doses of vaccination may be required to ensure adequate antibody titers and immunity to tetanus are achieved in cancer patients [17, 25–27].
Abbreviation
ICUIntensive care unit
Publisher’s Note
Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
All authors express their deep gratitude to the paramedical staff for their professional and devoted service.
Authors’ contributions
KN (corresponding author) wrote the entire manuscript and performed the literature review. ES compiled the patient’s medical history and laboratory data. AY, WA, ES, SS, HO, YT, SU, and EN contributed to the interpretation of the clinical manifestations and revised the manuscript for critical intellectual content. All authors have read and approved the manuscript.
Funding
This study received no specific funding.
Availability of data and materials
The datasets used and/or analyzed during the current study available from the corresponding author on reasonable request.
Ethics approval and consent to participate
Not applicable.
Consent for publication
Written consent to publish our case was obtained from the patient. A copy of the written consent is available to be reviewed by the editorial committee of this journal.
Competing interests
The authors declare that they have no competing interests. | Recovered | ReactionOutcome | CC BY | 33413196 | 18,794,500 | 2021-01-07 |
Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Malaise'. | Dermatomyositis associated with prostate adenocarcinoma with neuroendocrine differentiation.
BACKGROUND
Although it is known that malignancies can be associated with dermatomyositis, there are few reports on dermatomyositis associated with prostate cancer with neuroendocrine differentiation.
METHODS
A 63-year-old man visited our hospital due to pollakiuria. High levels of PSA and NSE were observed, and prostate biopsy revealed an adenocarcinoma with neuroendocrine differentiation. Multiple metastases to the lymph nodes, bones, and liver were identified, and androgen deprivation therapy (ADT) was started immediately. Following 2 weeks of treatment, erythema on the skin, and muscle weakness with severe dysphagia appeared. The patient was diagnosed with dermatomyositis, and high-dose glucocorticoid therapy was initiated. ADT and subsequent chemotherapy with etoposide and cisplatin (EP) were performed for prostate cancer, which resulted in decreased PSA and NSE and reduction of all metastases. After the initiation of EP therapy, dermatomyositis improved, and the patient regained oral intake function. Although EP therapy was replaced by docetaxel, abiraterone, and enzalutamide because of adverse events, no cancer progression was consistently observed. Dermatomyositis worsened temporarily during the administration of abiraterone, but it improved upon switching from abiraterone to enzalutamide and dose escalation of glucocorticoid.
CONCLUSIONS
We successfully treated a rare case of dermatomyositis associated with prostate adenocarcinoma with neuroendocrine differentiation.
Background
Approximately 20% of all dermatomyositis cases are accompanied by malignancies [1–3]. Furthermore, among patients with dermatomyositis, those with malignancies have a poor prognosis [1, 2]. Although there are several reports of prostate cancer with dermatomyositis [1, 3, 4], we are aware of only one case of neuroendocrine prostate cancer with dermatomyositis [5], who responded poorly to treatment and died within 4 months after initiation of treatment. Here, we report a case of long-term survival of dermatomyositis with severe dysphagia which was associated with prostate adenocarcinoma with neuroendocrine differentiation.
Case presentation
A 63-year-old man visited our hospital complaining of frequent urination and hesitancy, which had worsened a year prior to the visit. He also complained of muscle weakness and pain in the upper arms. Blood tests revealed abnormally high PSA (147.7 ng/mL), NSE (60.9 ng/mL), and CK (647 IU/L) (Fig. 1). Prostate biopsy revealed adenocarcinoma with Gleason score 4 + 5 accompanied by neuroendocrine differentiation, which was positive for PSA, synaptophysin, and NCAM1/CD56 by immunohistochemistry (Fig. 2). Contrast-enhanced computed tomography (CT) revealed prostate cancer which showed invasion to the bladder, seminal vesicles, and rectum. Multiple metastases to the liver (Fig. 3a), pelvic lymph nodes, and bone were observed. The patient was diagnosed with prostate adenocarcinoma with neuroendocrine differentiation, cT4N1M1. At the time of diagnosis, the use of abiraterone and docetaxel for high-risk metastatic hormone-sensitive prostate cancer (HSPC) was not yet approved in medical insurance in Japan. Therefore, combined androgen blockade (CAB) therapy with surgical castration and bicalutamide was initiated as the most intense treatment available in Japan at that time for high-risk metastatic HSPC. Chemotherapy with etoposide and cisplatin (EP) was not performed at this time because pure adenocarcinoma components dominated, few with neuroendocrine differentiation in the prostate biopsy.Fig. 1 Temporal changes in PSA, NSE and CK. The treatments performed are indicated above the graph
Fig. 2 Immunohistochemical findings of prostate biopsy; hematoxylin and eosin (a, b), PSA (c, d), synaptophysin (e), and NCAM1/CD56 (f). Hematoxylin and eosin staining reveals adenocarcinoma with Gleason score 4 + 5 (a) and components of neuroendocrine differentiation (b). The components of typical adenocarcinoma (c) and neuroendocrine differentiation (d) are highly and weakly positive for PSA, respectively. The components of neuroendocrine differentiation are positive for synaptophysin (e) and NCAM1/CD56 (f). The bar indicates 100 μm
Fig. 3 CT findings of liver metastases before ADT (a), before EP therapy (b), and after 4 courses of EP therapy (c)
Two weeks later, dysphagia, edema of both upper limbs, and erythema on the skin were identified. Bicalutamide was discontinued and high-dose glucocorticoid therapy with methylprednisolone (mPSL) was initiated at a dose of 125 mg/day intravenously (IV) for the first 3 days, 80 mg/day IV for the next 3 days, and 40 mg/day IV for the next 3 days. At this time, the symptoms were suspected to be bicalutamide-induced adverse events. One week after the initiation of mPSL, dysphagia and erythema of the skin and muscle weakness of both arms did not improve. Physical examination revealed erythema on the back of the finger joints (Gottron’s sign) (Fig. 4a), from the shoulder to the upper back (shawl sign) (Fig. 4b) and around the neck (V-neck sign) (Fig. 4c), and edematous erythema on the bilateral eyelids (heliotrope rash) (Fig. 4d). Blood tests revealed abnormally high values of CK (1727 IU/L, Fig. 1), aldolase (14.5 U/L), and myoglobin (435.8 ng/mL). Anti-nuclear antibody was positive at titers of 1:640, anti-ARS antibody was negative, and anti-TIF1-γ antibody was positive. Based on these findings, the patient was diagnosed with malignancy-associated dermatomyositis. He was presented with dysphagia, which was severe and required temporary fasting and central parenteral nutrition. Glucocorticoid administration was changed from mPSL to prednisolone (PSL) at a dose of 60 mg/day IV.Fig. 4 Various skin symptoms observed in the patient. Erythema on the back of the finger joint (Gottron’s sign) (a), erythema from shoulder to upper back (shawl sign) (b), erythema around the neck (V-neck sign) (c), and edematous erythema on the bilateral eyelids (heliotrope rash) (d)
Four weeks after the start of androgen deprivation therapy (ADT), CT showed residual multiple liver metastases (Fig. 3b), although PSA and NSE decreased to 7.0 ng/mL and 21.9 ng/mL, respectively (Fig. 1). Then, EP therapy (etoposide 100 mg/m2 and cisplatin 20 mg/m2, every 3 weeks) was commenced, resulting in a rapid decrease of PSA and NSE to < 1 ng/mL and < 13 ng/mL, respectively (Fig. 1). Two weeks after EP therapy started, swallowing function improved with a decrease in CK (Fig. 1) and oral intake became possible. PSL administration was gradually tapered to 5 mg/day.
After 4 courses of EP therapy, CT showed marked reduction of the primary tumor and all metastases including those in the liver (Fig. 3c), but EP therapy was discontinued due to grade 3 malaise. Although the metastases had shrunk, they did not disappear, and we supposed that a small amount of cancer progression could lead to a relapse of dermatomyositis. The patient was therefore switched to docetaxel therapy (70 mg/m2, every 3 weeks). After 4 courses, docetaxel was also discontinued due to grade 3 malaise, and abiraterone acetate treatment was initiated. Abiraterone acetate treatment was ceased after one month because erythema on his face and extremities and serum CK level worsened (246 IU/L). Enzalutamide treatment and dose escalation of PSL to 30 mg/day were started, and dermatomyositis improved. PSA and NSE were consistently low, and no progressions were observed during the administration of docetaxel, abiraterone, and enzalutamide. At present, 31 months after the start of enzalutamide administration, no cancer progression has been observed. Dermatomyositis is in remission, and the patient is on PSL at 10 mg/day.
Discussion and conclusions
It is difficult to obtain a good therapeutic effect in patients with dermatomyositis complicated by malignant tumors, as long as the tumor is present; conversely, radical treatment of malignancy may improve muscle and skin symptoms. Therefore, treatment of malignancy is prioritized in order to improve dermatomyositis [3]. In the present case, dermatomyositis was improved by treatment for prostate cancer in addition to high-dose glucocorticoid therapy. ADT was initially performed to treat prostate cancer with neuroendocrine differentiation and the treatment had limited effects on dermatomyositis, and dysphagia became apparent. Although dermatomyositis tends to improve with high-dose glucocorticoid therapy, oral intake was possible after EP therapy was commenced. These findings suggest that EP therapy was required to address the component of neuroendocrine differentiation.
Pure neuroendocrine prostate cancer (including small cell carcinoma and large cell carcinoma) has a poor prognosis. However, it is controversial whether neuroendocrine differentiation in adenocarcinomas worsens the prognosis [6, 7]. In the present case, multiple liver metastases were observed from the first visit, suggesting that the cancer was aggressive. ADT was followed by EP therapy and other strong treatments with docetaxel, abiraterone, and enzalutamide before the onset of castration resistance. We believe that the ability to control aggressive cancers with these treatments may have led to an improvement in disease activity of dermatomyositis.
In conclusion, we encountered a rare case of dermatomyositis associated with prostate adenocarcinoma with neuroendocrine differentiation. The patient was successfully treated with ADT and subsequent EP therapy for prostate cancer and high-dose glucocorticoid therapy for dermatomyositis.
Abbreviations
PSAProstate specific antigen
NSENeuron specific enolase
CKCreatinine kinase
NCAM1Neural cell adhesion molecule 1
Publisher's Note
Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
Acknowledgements
Not applicable.
Authors’ contributions
HM collected data and wrote the manuscripts. TK contributed to concept of this paper, interpreted the data, and prepared the manuscripts. AM, KM, and YS contributed to concept of this paper. KN, MT, and NT collected data regarding the dermatomyositis, and reviewed the manuscripts. EI performed the histological examination. YY, MN, DY, MS, TM, and HK reviewed the manuscripts. All authors read and approved the final manuscript.
Funding
No funding.
Availability of data and materials
All data generated or analyzed during this study are included in this published article and available from the corresponding author on reasonable request.
Ethics approval and consent to participate
This report was approved by the Ethics Committee at the Ome Municipal General Hospital (Approval number: 54). Informed consent to participate was obtained from the patient.
Consent for publication
Written informed consent for publication of their clinical details and/or clinical images was obtained from the patient. A copy of the consent form is available for review by the Editor of this journal.
Competing interests
The authors declare that they have no competing interests. | CISPLATIN, DOCETAXEL, ETOPOSIDE, PREDNISOLONE | DrugsGivenReaction | CC BY | 33413292 | 18,769,778 | 2021-01-07 |
What was the administration route of drug 'PREDNISOLONE'? | Dermatomyositis associated with prostate adenocarcinoma with neuroendocrine differentiation.
BACKGROUND
Although it is known that malignancies can be associated with dermatomyositis, there are few reports on dermatomyositis associated with prostate cancer with neuroendocrine differentiation.
METHODS
A 63-year-old man visited our hospital due to pollakiuria. High levels of PSA and NSE were observed, and prostate biopsy revealed an adenocarcinoma with neuroendocrine differentiation. Multiple metastases to the lymph nodes, bones, and liver were identified, and androgen deprivation therapy (ADT) was started immediately. Following 2 weeks of treatment, erythema on the skin, and muscle weakness with severe dysphagia appeared. The patient was diagnosed with dermatomyositis, and high-dose glucocorticoid therapy was initiated. ADT and subsequent chemotherapy with etoposide and cisplatin (EP) were performed for prostate cancer, which resulted in decreased PSA and NSE and reduction of all metastases. After the initiation of EP therapy, dermatomyositis improved, and the patient regained oral intake function. Although EP therapy was replaced by docetaxel, abiraterone, and enzalutamide because of adverse events, no cancer progression was consistently observed. Dermatomyositis worsened temporarily during the administration of abiraterone, but it improved upon switching from abiraterone to enzalutamide and dose escalation of glucocorticoid.
CONCLUSIONS
We successfully treated a rare case of dermatomyositis associated with prostate adenocarcinoma with neuroendocrine differentiation.
Background
Approximately 20% of all dermatomyositis cases are accompanied by malignancies [1–3]. Furthermore, among patients with dermatomyositis, those with malignancies have a poor prognosis [1, 2]. Although there are several reports of prostate cancer with dermatomyositis [1, 3, 4], we are aware of only one case of neuroendocrine prostate cancer with dermatomyositis [5], who responded poorly to treatment and died within 4 months after initiation of treatment. Here, we report a case of long-term survival of dermatomyositis with severe dysphagia which was associated with prostate adenocarcinoma with neuroendocrine differentiation.
Case presentation
A 63-year-old man visited our hospital complaining of frequent urination and hesitancy, which had worsened a year prior to the visit. He also complained of muscle weakness and pain in the upper arms. Blood tests revealed abnormally high PSA (147.7 ng/mL), NSE (60.9 ng/mL), and CK (647 IU/L) (Fig. 1). Prostate biopsy revealed adenocarcinoma with Gleason score 4 + 5 accompanied by neuroendocrine differentiation, which was positive for PSA, synaptophysin, and NCAM1/CD56 by immunohistochemistry (Fig. 2). Contrast-enhanced computed tomography (CT) revealed prostate cancer which showed invasion to the bladder, seminal vesicles, and rectum. Multiple metastases to the liver (Fig. 3a), pelvic lymph nodes, and bone were observed. The patient was diagnosed with prostate adenocarcinoma with neuroendocrine differentiation, cT4N1M1. At the time of diagnosis, the use of abiraterone and docetaxel for high-risk metastatic hormone-sensitive prostate cancer (HSPC) was not yet approved in medical insurance in Japan. Therefore, combined androgen blockade (CAB) therapy with surgical castration and bicalutamide was initiated as the most intense treatment available in Japan at that time for high-risk metastatic HSPC. Chemotherapy with etoposide and cisplatin (EP) was not performed at this time because pure adenocarcinoma components dominated, few with neuroendocrine differentiation in the prostate biopsy.Fig. 1 Temporal changes in PSA, NSE and CK. The treatments performed are indicated above the graph
Fig. 2 Immunohistochemical findings of prostate biopsy; hematoxylin and eosin (a, b), PSA (c, d), synaptophysin (e), and NCAM1/CD56 (f). Hematoxylin and eosin staining reveals adenocarcinoma with Gleason score 4 + 5 (a) and components of neuroendocrine differentiation (b). The components of typical adenocarcinoma (c) and neuroendocrine differentiation (d) are highly and weakly positive for PSA, respectively. The components of neuroendocrine differentiation are positive for synaptophysin (e) and NCAM1/CD56 (f). The bar indicates 100 μm
Fig. 3 CT findings of liver metastases before ADT (a), before EP therapy (b), and after 4 courses of EP therapy (c)
Two weeks later, dysphagia, edema of both upper limbs, and erythema on the skin were identified. Bicalutamide was discontinued and high-dose glucocorticoid therapy with methylprednisolone (mPSL) was initiated at a dose of 125 mg/day intravenously (IV) for the first 3 days, 80 mg/day IV for the next 3 days, and 40 mg/day IV for the next 3 days. At this time, the symptoms were suspected to be bicalutamide-induced adverse events. One week after the initiation of mPSL, dysphagia and erythema of the skin and muscle weakness of both arms did not improve. Physical examination revealed erythema on the back of the finger joints (Gottron’s sign) (Fig. 4a), from the shoulder to the upper back (shawl sign) (Fig. 4b) and around the neck (V-neck sign) (Fig. 4c), and edematous erythema on the bilateral eyelids (heliotrope rash) (Fig. 4d). Blood tests revealed abnormally high values of CK (1727 IU/L, Fig. 1), aldolase (14.5 U/L), and myoglobin (435.8 ng/mL). Anti-nuclear antibody was positive at titers of 1:640, anti-ARS antibody was negative, and anti-TIF1-γ antibody was positive. Based on these findings, the patient was diagnosed with malignancy-associated dermatomyositis. He was presented with dysphagia, which was severe and required temporary fasting and central parenteral nutrition. Glucocorticoid administration was changed from mPSL to prednisolone (PSL) at a dose of 60 mg/day IV.Fig. 4 Various skin symptoms observed in the patient. Erythema on the back of the finger joint (Gottron’s sign) (a), erythema from shoulder to upper back (shawl sign) (b), erythema around the neck (V-neck sign) (c), and edematous erythema on the bilateral eyelids (heliotrope rash) (d)
Four weeks after the start of androgen deprivation therapy (ADT), CT showed residual multiple liver metastases (Fig. 3b), although PSA and NSE decreased to 7.0 ng/mL and 21.9 ng/mL, respectively (Fig. 1). Then, EP therapy (etoposide 100 mg/m2 and cisplatin 20 mg/m2, every 3 weeks) was commenced, resulting in a rapid decrease of PSA and NSE to < 1 ng/mL and < 13 ng/mL, respectively (Fig. 1). Two weeks after EP therapy started, swallowing function improved with a decrease in CK (Fig. 1) and oral intake became possible. PSL administration was gradually tapered to 5 mg/day.
After 4 courses of EP therapy, CT showed marked reduction of the primary tumor and all metastases including those in the liver (Fig. 3c), but EP therapy was discontinued due to grade 3 malaise. Although the metastases had shrunk, they did not disappear, and we supposed that a small amount of cancer progression could lead to a relapse of dermatomyositis. The patient was therefore switched to docetaxel therapy (70 mg/m2, every 3 weeks). After 4 courses, docetaxel was also discontinued due to grade 3 malaise, and abiraterone acetate treatment was initiated. Abiraterone acetate treatment was ceased after one month because erythema on his face and extremities and serum CK level worsened (246 IU/L). Enzalutamide treatment and dose escalation of PSL to 30 mg/day were started, and dermatomyositis improved. PSA and NSE were consistently low, and no progressions were observed during the administration of docetaxel, abiraterone, and enzalutamide. At present, 31 months after the start of enzalutamide administration, no cancer progression has been observed. Dermatomyositis is in remission, and the patient is on PSL at 10 mg/day.
Discussion and conclusions
It is difficult to obtain a good therapeutic effect in patients with dermatomyositis complicated by malignant tumors, as long as the tumor is present; conversely, radical treatment of malignancy may improve muscle and skin symptoms. Therefore, treatment of malignancy is prioritized in order to improve dermatomyositis [3]. In the present case, dermatomyositis was improved by treatment for prostate cancer in addition to high-dose glucocorticoid therapy. ADT was initially performed to treat prostate cancer with neuroendocrine differentiation and the treatment had limited effects on dermatomyositis, and dysphagia became apparent. Although dermatomyositis tends to improve with high-dose glucocorticoid therapy, oral intake was possible after EP therapy was commenced. These findings suggest that EP therapy was required to address the component of neuroendocrine differentiation.
Pure neuroendocrine prostate cancer (including small cell carcinoma and large cell carcinoma) has a poor prognosis. However, it is controversial whether neuroendocrine differentiation in adenocarcinomas worsens the prognosis [6, 7]. In the present case, multiple liver metastases were observed from the first visit, suggesting that the cancer was aggressive. ADT was followed by EP therapy and other strong treatments with docetaxel, abiraterone, and enzalutamide before the onset of castration resistance. We believe that the ability to control aggressive cancers with these treatments may have led to an improvement in disease activity of dermatomyositis.
In conclusion, we encountered a rare case of dermatomyositis associated with prostate adenocarcinoma with neuroendocrine differentiation. The patient was successfully treated with ADT and subsequent EP therapy for prostate cancer and high-dose glucocorticoid therapy for dermatomyositis.
Abbreviations
PSAProstate specific antigen
NSENeuron specific enolase
CKCreatinine kinase
NCAM1Neural cell adhesion molecule 1
Publisher's Note
Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
Acknowledgements
Not applicable.
Authors’ contributions
HM collected data and wrote the manuscripts. TK contributed to concept of this paper, interpreted the data, and prepared the manuscripts. AM, KM, and YS contributed to concept of this paper. KN, MT, and NT collected data regarding the dermatomyositis, and reviewed the manuscripts. EI performed the histological examination. YY, MN, DY, MS, TM, and HK reviewed the manuscripts. All authors read and approved the final manuscript.
Funding
No funding.
Availability of data and materials
All data generated or analyzed during this study are included in this published article and available from the corresponding author on reasonable request.
Ethics approval and consent to participate
This report was approved by the Ethics Committee at the Ome Municipal General Hospital (Approval number: 54). Informed consent to participate was obtained from the patient.
Consent for publication
Written informed consent for publication of their clinical details and/or clinical images was obtained from the patient. A copy of the consent form is available for review by the Editor of this journal.
Competing interests
The authors declare that they have no competing interests. | Intravenous (not otherwise specified) | DrugAdministrationRoute | CC BY | 33413292 | 18,769,778 | 2021-01-07 |
What was the dosage of drug 'CISPLATIN'? | Dermatomyositis associated with prostate adenocarcinoma with neuroendocrine differentiation.
BACKGROUND
Although it is known that malignancies can be associated with dermatomyositis, there are few reports on dermatomyositis associated with prostate cancer with neuroendocrine differentiation.
METHODS
A 63-year-old man visited our hospital due to pollakiuria. High levels of PSA and NSE were observed, and prostate biopsy revealed an adenocarcinoma with neuroendocrine differentiation. Multiple metastases to the lymph nodes, bones, and liver were identified, and androgen deprivation therapy (ADT) was started immediately. Following 2 weeks of treatment, erythema on the skin, and muscle weakness with severe dysphagia appeared. The patient was diagnosed with dermatomyositis, and high-dose glucocorticoid therapy was initiated. ADT and subsequent chemotherapy with etoposide and cisplatin (EP) were performed for prostate cancer, which resulted in decreased PSA and NSE and reduction of all metastases. After the initiation of EP therapy, dermatomyositis improved, and the patient regained oral intake function. Although EP therapy was replaced by docetaxel, abiraterone, and enzalutamide because of adverse events, no cancer progression was consistently observed. Dermatomyositis worsened temporarily during the administration of abiraterone, but it improved upon switching from abiraterone to enzalutamide and dose escalation of glucocorticoid.
CONCLUSIONS
We successfully treated a rare case of dermatomyositis associated with prostate adenocarcinoma with neuroendocrine differentiation.
Background
Approximately 20% of all dermatomyositis cases are accompanied by malignancies [1–3]. Furthermore, among patients with dermatomyositis, those with malignancies have a poor prognosis [1, 2]. Although there are several reports of prostate cancer with dermatomyositis [1, 3, 4], we are aware of only one case of neuroendocrine prostate cancer with dermatomyositis [5], who responded poorly to treatment and died within 4 months after initiation of treatment. Here, we report a case of long-term survival of dermatomyositis with severe dysphagia which was associated with prostate adenocarcinoma with neuroendocrine differentiation.
Case presentation
A 63-year-old man visited our hospital complaining of frequent urination and hesitancy, which had worsened a year prior to the visit. He also complained of muscle weakness and pain in the upper arms. Blood tests revealed abnormally high PSA (147.7 ng/mL), NSE (60.9 ng/mL), and CK (647 IU/L) (Fig. 1). Prostate biopsy revealed adenocarcinoma with Gleason score 4 + 5 accompanied by neuroendocrine differentiation, which was positive for PSA, synaptophysin, and NCAM1/CD56 by immunohistochemistry (Fig. 2). Contrast-enhanced computed tomography (CT) revealed prostate cancer which showed invasion to the bladder, seminal vesicles, and rectum. Multiple metastases to the liver (Fig. 3a), pelvic lymph nodes, and bone were observed. The patient was diagnosed with prostate adenocarcinoma with neuroendocrine differentiation, cT4N1M1. At the time of diagnosis, the use of abiraterone and docetaxel for high-risk metastatic hormone-sensitive prostate cancer (HSPC) was not yet approved in medical insurance in Japan. Therefore, combined androgen blockade (CAB) therapy with surgical castration and bicalutamide was initiated as the most intense treatment available in Japan at that time for high-risk metastatic HSPC. Chemotherapy with etoposide and cisplatin (EP) was not performed at this time because pure adenocarcinoma components dominated, few with neuroendocrine differentiation in the prostate biopsy.Fig. 1 Temporal changes in PSA, NSE and CK. The treatments performed are indicated above the graph
Fig. 2 Immunohistochemical findings of prostate biopsy; hematoxylin and eosin (a, b), PSA (c, d), synaptophysin (e), and NCAM1/CD56 (f). Hematoxylin and eosin staining reveals adenocarcinoma with Gleason score 4 + 5 (a) and components of neuroendocrine differentiation (b). The components of typical adenocarcinoma (c) and neuroendocrine differentiation (d) are highly and weakly positive for PSA, respectively. The components of neuroendocrine differentiation are positive for synaptophysin (e) and NCAM1/CD56 (f). The bar indicates 100 μm
Fig. 3 CT findings of liver metastases before ADT (a), before EP therapy (b), and after 4 courses of EP therapy (c)
Two weeks later, dysphagia, edema of both upper limbs, and erythema on the skin were identified. Bicalutamide was discontinued and high-dose glucocorticoid therapy with methylprednisolone (mPSL) was initiated at a dose of 125 mg/day intravenously (IV) for the first 3 days, 80 mg/day IV for the next 3 days, and 40 mg/day IV for the next 3 days. At this time, the symptoms were suspected to be bicalutamide-induced adverse events. One week after the initiation of mPSL, dysphagia and erythema of the skin and muscle weakness of both arms did not improve. Physical examination revealed erythema on the back of the finger joints (Gottron’s sign) (Fig. 4a), from the shoulder to the upper back (shawl sign) (Fig. 4b) and around the neck (V-neck sign) (Fig. 4c), and edematous erythema on the bilateral eyelids (heliotrope rash) (Fig. 4d). Blood tests revealed abnormally high values of CK (1727 IU/L, Fig. 1), aldolase (14.5 U/L), and myoglobin (435.8 ng/mL). Anti-nuclear antibody was positive at titers of 1:640, anti-ARS antibody was negative, and anti-TIF1-γ antibody was positive. Based on these findings, the patient was diagnosed with malignancy-associated dermatomyositis. He was presented with dysphagia, which was severe and required temporary fasting and central parenteral nutrition. Glucocorticoid administration was changed from mPSL to prednisolone (PSL) at a dose of 60 mg/day IV.Fig. 4 Various skin symptoms observed in the patient. Erythema on the back of the finger joint (Gottron’s sign) (a), erythema from shoulder to upper back (shawl sign) (b), erythema around the neck (V-neck sign) (c), and edematous erythema on the bilateral eyelids (heliotrope rash) (d)
Four weeks after the start of androgen deprivation therapy (ADT), CT showed residual multiple liver metastases (Fig. 3b), although PSA and NSE decreased to 7.0 ng/mL and 21.9 ng/mL, respectively (Fig. 1). Then, EP therapy (etoposide 100 mg/m2 and cisplatin 20 mg/m2, every 3 weeks) was commenced, resulting in a rapid decrease of PSA and NSE to < 1 ng/mL and < 13 ng/mL, respectively (Fig. 1). Two weeks after EP therapy started, swallowing function improved with a decrease in CK (Fig. 1) and oral intake became possible. PSL administration was gradually tapered to 5 mg/day.
After 4 courses of EP therapy, CT showed marked reduction of the primary tumor and all metastases including those in the liver (Fig. 3c), but EP therapy was discontinued due to grade 3 malaise. Although the metastases had shrunk, they did not disappear, and we supposed that a small amount of cancer progression could lead to a relapse of dermatomyositis. The patient was therefore switched to docetaxel therapy (70 mg/m2, every 3 weeks). After 4 courses, docetaxel was also discontinued due to grade 3 malaise, and abiraterone acetate treatment was initiated. Abiraterone acetate treatment was ceased after one month because erythema on his face and extremities and serum CK level worsened (246 IU/L). Enzalutamide treatment and dose escalation of PSL to 30 mg/day were started, and dermatomyositis improved. PSA and NSE were consistently low, and no progressions were observed during the administration of docetaxel, abiraterone, and enzalutamide. At present, 31 months after the start of enzalutamide administration, no cancer progression has been observed. Dermatomyositis is in remission, and the patient is on PSL at 10 mg/day.
Discussion and conclusions
It is difficult to obtain a good therapeutic effect in patients with dermatomyositis complicated by malignant tumors, as long as the tumor is present; conversely, radical treatment of malignancy may improve muscle and skin symptoms. Therefore, treatment of malignancy is prioritized in order to improve dermatomyositis [3]. In the present case, dermatomyositis was improved by treatment for prostate cancer in addition to high-dose glucocorticoid therapy. ADT was initially performed to treat prostate cancer with neuroendocrine differentiation and the treatment had limited effects on dermatomyositis, and dysphagia became apparent. Although dermatomyositis tends to improve with high-dose glucocorticoid therapy, oral intake was possible after EP therapy was commenced. These findings suggest that EP therapy was required to address the component of neuroendocrine differentiation.
Pure neuroendocrine prostate cancer (including small cell carcinoma and large cell carcinoma) has a poor prognosis. However, it is controversial whether neuroendocrine differentiation in adenocarcinomas worsens the prognosis [6, 7]. In the present case, multiple liver metastases were observed from the first visit, suggesting that the cancer was aggressive. ADT was followed by EP therapy and other strong treatments with docetaxel, abiraterone, and enzalutamide before the onset of castration resistance. We believe that the ability to control aggressive cancers with these treatments may have led to an improvement in disease activity of dermatomyositis.
In conclusion, we encountered a rare case of dermatomyositis associated with prostate adenocarcinoma with neuroendocrine differentiation. The patient was successfully treated with ADT and subsequent EP therapy for prostate cancer and high-dose glucocorticoid therapy for dermatomyositis.
Abbreviations
PSAProstate specific antigen
NSENeuron specific enolase
CKCreatinine kinase
NCAM1Neural cell adhesion molecule 1
Publisher's Note
Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
Acknowledgements
Not applicable.
Authors’ contributions
HM collected data and wrote the manuscripts. TK contributed to concept of this paper, interpreted the data, and prepared the manuscripts. AM, KM, and YS contributed to concept of this paper. KN, MT, and NT collected data regarding the dermatomyositis, and reviewed the manuscripts. EI performed the histological examination. YY, MN, DY, MS, TM, and HK reviewed the manuscripts. All authors read and approved the final manuscript.
Funding
No funding.
Availability of data and materials
All data generated or analyzed during this study are included in this published article and available from the corresponding author on reasonable request.
Ethics approval and consent to participate
This report was approved by the Ethics Committee at the Ome Municipal General Hospital (Approval number: 54). Informed consent to participate was obtained from the patient.
Consent for publication
Written informed consent for publication of their clinical details and/or clinical images was obtained from the patient. A copy of the consent form is available for review by the Editor of this journal.
Competing interests
The authors declare that they have no competing interests. | 20 MG/M2, EVERY 3 WEEKS | DrugDosageText | CC BY | 33413292 | 18,769,778 | 2021-01-07 |
What was the dosage of drug 'DOCETAXEL'? | Dermatomyositis associated with prostate adenocarcinoma with neuroendocrine differentiation.
BACKGROUND
Although it is known that malignancies can be associated with dermatomyositis, there are few reports on dermatomyositis associated with prostate cancer with neuroendocrine differentiation.
METHODS
A 63-year-old man visited our hospital due to pollakiuria. High levels of PSA and NSE were observed, and prostate biopsy revealed an adenocarcinoma with neuroendocrine differentiation. Multiple metastases to the lymph nodes, bones, and liver were identified, and androgen deprivation therapy (ADT) was started immediately. Following 2 weeks of treatment, erythema on the skin, and muscle weakness with severe dysphagia appeared. The patient was diagnosed with dermatomyositis, and high-dose glucocorticoid therapy was initiated. ADT and subsequent chemotherapy with etoposide and cisplatin (EP) were performed for prostate cancer, which resulted in decreased PSA and NSE and reduction of all metastases. After the initiation of EP therapy, dermatomyositis improved, and the patient regained oral intake function. Although EP therapy was replaced by docetaxel, abiraterone, and enzalutamide because of adverse events, no cancer progression was consistently observed. Dermatomyositis worsened temporarily during the administration of abiraterone, but it improved upon switching from abiraterone to enzalutamide and dose escalation of glucocorticoid.
CONCLUSIONS
We successfully treated a rare case of dermatomyositis associated with prostate adenocarcinoma with neuroendocrine differentiation.
Background
Approximately 20% of all dermatomyositis cases are accompanied by malignancies [1–3]. Furthermore, among patients with dermatomyositis, those with malignancies have a poor prognosis [1, 2]. Although there are several reports of prostate cancer with dermatomyositis [1, 3, 4], we are aware of only one case of neuroendocrine prostate cancer with dermatomyositis [5], who responded poorly to treatment and died within 4 months after initiation of treatment. Here, we report a case of long-term survival of dermatomyositis with severe dysphagia which was associated with prostate adenocarcinoma with neuroendocrine differentiation.
Case presentation
A 63-year-old man visited our hospital complaining of frequent urination and hesitancy, which had worsened a year prior to the visit. He also complained of muscle weakness and pain in the upper arms. Blood tests revealed abnormally high PSA (147.7 ng/mL), NSE (60.9 ng/mL), and CK (647 IU/L) (Fig. 1). Prostate biopsy revealed adenocarcinoma with Gleason score 4 + 5 accompanied by neuroendocrine differentiation, which was positive for PSA, synaptophysin, and NCAM1/CD56 by immunohistochemistry (Fig. 2). Contrast-enhanced computed tomography (CT) revealed prostate cancer which showed invasion to the bladder, seminal vesicles, and rectum. Multiple metastases to the liver (Fig. 3a), pelvic lymph nodes, and bone were observed. The patient was diagnosed with prostate adenocarcinoma with neuroendocrine differentiation, cT4N1M1. At the time of diagnosis, the use of abiraterone and docetaxel for high-risk metastatic hormone-sensitive prostate cancer (HSPC) was not yet approved in medical insurance in Japan. Therefore, combined androgen blockade (CAB) therapy with surgical castration and bicalutamide was initiated as the most intense treatment available in Japan at that time for high-risk metastatic HSPC. Chemotherapy with etoposide and cisplatin (EP) was not performed at this time because pure adenocarcinoma components dominated, few with neuroendocrine differentiation in the prostate biopsy.Fig. 1 Temporal changes in PSA, NSE and CK. The treatments performed are indicated above the graph
Fig. 2 Immunohistochemical findings of prostate biopsy; hematoxylin and eosin (a, b), PSA (c, d), synaptophysin (e), and NCAM1/CD56 (f). Hematoxylin and eosin staining reveals adenocarcinoma with Gleason score 4 + 5 (a) and components of neuroendocrine differentiation (b). The components of typical adenocarcinoma (c) and neuroendocrine differentiation (d) are highly and weakly positive for PSA, respectively. The components of neuroendocrine differentiation are positive for synaptophysin (e) and NCAM1/CD56 (f). The bar indicates 100 μm
Fig. 3 CT findings of liver metastases before ADT (a), before EP therapy (b), and after 4 courses of EP therapy (c)
Two weeks later, dysphagia, edema of both upper limbs, and erythema on the skin were identified. Bicalutamide was discontinued and high-dose glucocorticoid therapy with methylprednisolone (mPSL) was initiated at a dose of 125 mg/day intravenously (IV) for the first 3 days, 80 mg/day IV for the next 3 days, and 40 mg/day IV for the next 3 days. At this time, the symptoms were suspected to be bicalutamide-induced adverse events. One week after the initiation of mPSL, dysphagia and erythema of the skin and muscle weakness of both arms did not improve. Physical examination revealed erythema on the back of the finger joints (Gottron’s sign) (Fig. 4a), from the shoulder to the upper back (shawl sign) (Fig. 4b) and around the neck (V-neck sign) (Fig. 4c), and edematous erythema on the bilateral eyelids (heliotrope rash) (Fig. 4d). Blood tests revealed abnormally high values of CK (1727 IU/L, Fig. 1), aldolase (14.5 U/L), and myoglobin (435.8 ng/mL). Anti-nuclear antibody was positive at titers of 1:640, anti-ARS antibody was negative, and anti-TIF1-γ antibody was positive. Based on these findings, the patient was diagnosed with malignancy-associated dermatomyositis. He was presented with dysphagia, which was severe and required temporary fasting and central parenteral nutrition. Glucocorticoid administration was changed from mPSL to prednisolone (PSL) at a dose of 60 mg/day IV.Fig. 4 Various skin symptoms observed in the patient. Erythema on the back of the finger joint (Gottron’s sign) (a), erythema from shoulder to upper back (shawl sign) (b), erythema around the neck (V-neck sign) (c), and edematous erythema on the bilateral eyelids (heliotrope rash) (d)
Four weeks after the start of androgen deprivation therapy (ADT), CT showed residual multiple liver metastases (Fig. 3b), although PSA and NSE decreased to 7.0 ng/mL and 21.9 ng/mL, respectively (Fig. 1). Then, EP therapy (etoposide 100 mg/m2 and cisplatin 20 mg/m2, every 3 weeks) was commenced, resulting in a rapid decrease of PSA and NSE to < 1 ng/mL and < 13 ng/mL, respectively (Fig. 1). Two weeks after EP therapy started, swallowing function improved with a decrease in CK (Fig. 1) and oral intake became possible. PSL administration was gradually tapered to 5 mg/day.
After 4 courses of EP therapy, CT showed marked reduction of the primary tumor and all metastases including those in the liver (Fig. 3c), but EP therapy was discontinued due to grade 3 malaise. Although the metastases had shrunk, they did not disappear, and we supposed that a small amount of cancer progression could lead to a relapse of dermatomyositis. The patient was therefore switched to docetaxel therapy (70 mg/m2, every 3 weeks). After 4 courses, docetaxel was also discontinued due to grade 3 malaise, and abiraterone acetate treatment was initiated. Abiraterone acetate treatment was ceased after one month because erythema on his face and extremities and serum CK level worsened (246 IU/L). Enzalutamide treatment and dose escalation of PSL to 30 mg/day were started, and dermatomyositis improved. PSA and NSE were consistently low, and no progressions were observed during the administration of docetaxel, abiraterone, and enzalutamide. At present, 31 months after the start of enzalutamide administration, no cancer progression has been observed. Dermatomyositis is in remission, and the patient is on PSL at 10 mg/day.
Discussion and conclusions
It is difficult to obtain a good therapeutic effect in patients with dermatomyositis complicated by malignant tumors, as long as the tumor is present; conversely, radical treatment of malignancy may improve muscle and skin symptoms. Therefore, treatment of malignancy is prioritized in order to improve dermatomyositis [3]. In the present case, dermatomyositis was improved by treatment for prostate cancer in addition to high-dose glucocorticoid therapy. ADT was initially performed to treat prostate cancer with neuroendocrine differentiation and the treatment had limited effects on dermatomyositis, and dysphagia became apparent. Although dermatomyositis tends to improve with high-dose glucocorticoid therapy, oral intake was possible after EP therapy was commenced. These findings suggest that EP therapy was required to address the component of neuroendocrine differentiation.
Pure neuroendocrine prostate cancer (including small cell carcinoma and large cell carcinoma) has a poor prognosis. However, it is controversial whether neuroendocrine differentiation in adenocarcinomas worsens the prognosis [6, 7]. In the present case, multiple liver metastases were observed from the first visit, suggesting that the cancer was aggressive. ADT was followed by EP therapy and other strong treatments with docetaxel, abiraterone, and enzalutamide before the onset of castration resistance. We believe that the ability to control aggressive cancers with these treatments may have led to an improvement in disease activity of dermatomyositis.
In conclusion, we encountered a rare case of dermatomyositis associated with prostate adenocarcinoma with neuroendocrine differentiation. The patient was successfully treated with ADT and subsequent EP therapy for prostate cancer and high-dose glucocorticoid therapy for dermatomyositis.
Abbreviations
PSAProstate specific antigen
NSENeuron specific enolase
CKCreatinine kinase
NCAM1Neural cell adhesion molecule 1
Publisher's Note
Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
Acknowledgements
Not applicable.
Authors’ contributions
HM collected data and wrote the manuscripts. TK contributed to concept of this paper, interpreted the data, and prepared the manuscripts. AM, KM, and YS contributed to concept of this paper. KN, MT, and NT collected data regarding the dermatomyositis, and reviewed the manuscripts. EI performed the histological examination. YY, MN, DY, MS, TM, and HK reviewed the manuscripts. All authors read and approved the final manuscript.
Funding
No funding.
Availability of data and materials
All data generated or analyzed during this study are included in this published article and available from the corresponding author on reasonable request.
Ethics approval and consent to participate
This report was approved by the Ethics Committee at the Ome Municipal General Hospital (Approval number: 54). Informed consent to participate was obtained from the patient.
Consent for publication
Written informed consent for publication of their clinical details and/or clinical images was obtained from the patient. A copy of the consent form is available for review by the Editor of this journal.
Competing interests
The authors declare that they have no competing interests. | 70 MG/M2, EVERY 3 WEEKS | DrugDosageText | CC BY | 33413292 | 18,769,778 | 2021-01-07 |
What was the dosage of drug 'ETOPOSIDE'? | Dermatomyositis associated with prostate adenocarcinoma with neuroendocrine differentiation.
BACKGROUND
Although it is known that malignancies can be associated with dermatomyositis, there are few reports on dermatomyositis associated with prostate cancer with neuroendocrine differentiation.
METHODS
A 63-year-old man visited our hospital due to pollakiuria. High levels of PSA and NSE were observed, and prostate biopsy revealed an adenocarcinoma with neuroendocrine differentiation. Multiple metastases to the lymph nodes, bones, and liver were identified, and androgen deprivation therapy (ADT) was started immediately. Following 2 weeks of treatment, erythema on the skin, and muscle weakness with severe dysphagia appeared. The patient was diagnosed with dermatomyositis, and high-dose glucocorticoid therapy was initiated. ADT and subsequent chemotherapy with etoposide and cisplatin (EP) were performed for prostate cancer, which resulted in decreased PSA and NSE and reduction of all metastases. After the initiation of EP therapy, dermatomyositis improved, and the patient regained oral intake function. Although EP therapy was replaced by docetaxel, abiraterone, and enzalutamide because of adverse events, no cancer progression was consistently observed. Dermatomyositis worsened temporarily during the administration of abiraterone, but it improved upon switching from abiraterone to enzalutamide and dose escalation of glucocorticoid.
CONCLUSIONS
We successfully treated a rare case of dermatomyositis associated with prostate adenocarcinoma with neuroendocrine differentiation.
Background
Approximately 20% of all dermatomyositis cases are accompanied by malignancies [1–3]. Furthermore, among patients with dermatomyositis, those with malignancies have a poor prognosis [1, 2]. Although there are several reports of prostate cancer with dermatomyositis [1, 3, 4], we are aware of only one case of neuroendocrine prostate cancer with dermatomyositis [5], who responded poorly to treatment and died within 4 months after initiation of treatment. Here, we report a case of long-term survival of dermatomyositis with severe dysphagia which was associated with prostate adenocarcinoma with neuroendocrine differentiation.
Case presentation
A 63-year-old man visited our hospital complaining of frequent urination and hesitancy, which had worsened a year prior to the visit. He also complained of muscle weakness and pain in the upper arms. Blood tests revealed abnormally high PSA (147.7 ng/mL), NSE (60.9 ng/mL), and CK (647 IU/L) (Fig. 1). Prostate biopsy revealed adenocarcinoma with Gleason score 4 + 5 accompanied by neuroendocrine differentiation, which was positive for PSA, synaptophysin, and NCAM1/CD56 by immunohistochemistry (Fig. 2). Contrast-enhanced computed tomography (CT) revealed prostate cancer which showed invasion to the bladder, seminal vesicles, and rectum. Multiple metastases to the liver (Fig. 3a), pelvic lymph nodes, and bone were observed. The patient was diagnosed with prostate adenocarcinoma with neuroendocrine differentiation, cT4N1M1. At the time of diagnosis, the use of abiraterone and docetaxel for high-risk metastatic hormone-sensitive prostate cancer (HSPC) was not yet approved in medical insurance in Japan. Therefore, combined androgen blockade (CAB) therapy with surgical castration and bicalutamide was initiated as the most intense treatment available in Japan at that time for high-risk metastatic HSPC. Chemotherapy with etoposide and cisplatin (EP) was not performed at this time because pure adenocarcinoma components dominated, few with neuroendocrine differentiation in the prostate biopsy.Fig. 1 Temporal changes in PSA, NSE and CK. The treatments performed are indicated above the graph
Fig. 2 Immunohistochemical findings of prostate biopsy; hematoxylin and eosin (a, b), PSA (c, d), synaptophysin (e), and NCAM1/CD56 (f). Hematoxylin and eosin staining reveals adenocarcinoma with Gleason score 4 + 5 (a) and components of neuroendocrine differentiation (b). The components of typical adenocarcinoma (c) and neuroendocrine differentiation (d) are highly and weakly positive for PSA, respectively. The components of neuroendocrine differentiation are positive for synaptophysin (e) and NCAM1/CD56 (f). The bar indicates 100 μm
Fig. 3 CT findings of liver metastases before ADT (a), before EP therapy (b), and after 4 courses of EP therapy (c)
Two weeks later, dysphagia, edema of both upper limbs, and erythema on the skin were identified. Bicalutamide was discontinued and high-dose glucocorticoid therapy with methylprednisolone (mPSL) was initiated at a dose of 125 mg/day intravenously (IV) for the first 3 days, 80 mg/day IV for the next 3 days, and 40 mg/day IV for the next 3 days. At this time, the symptoms were suspected to be bicalutamide-induced adverse events. One week after the initiation of mPSL, dysphagia and erythema of the skin and muscle weakness of both arms did not improve. Physical examination revealed erythema on the back of the finger joints (Gottron’s sign) (Fig. 4a), from the shoulder to the upper back (shawl sign) (Fig. 4b) and around the neck (V-neck sign) (Fig. 4c), and edematous erythema on the bilateral eyelids (heliotrope rash) (Fig. 4d). Blood tests revealed abnormally high values of CK (1727 IU/L, Fig. 1), aldolase (14.5 U/L), and myoglobin (435.8 ng/mL). Anti-nuclear antibody was positive at titers of 1:640, anti-ARS antibody was negative, and anti-TIF1-γ antibody was positive. Based on these findings, the patient was diagnosed with malignancy-associated dermatomyositis. He was presented with dysphagia, which was severe and required temporary fasting and central parenteral nutrition. Glucocorticoid administration was changed from mPSL to prednisolone (PSL) at a dose of 60 mg/day IV.Fig. 4 Various skin symptoms observed in the patient. Erythema on the back of the finger joint (Gottron’s sign) (a), erythema from shoulder to upper back (shawl sign) (b), erythema around the neck (V-neck sign) (c), and edematous erythema on the bilateral eyelids (heliotrope rash) (d)
Four weeks after the start of androgen deprivation therapy (ADT), CT showed residual multiple liver metastases (Fig. 3b), although PSA and NSE decreased to 7.0 ng/mL and 21.9 ng/mL, respectively (Fig. 1). Then, EP therapy (etoposide 100 mg/m2 and cisplatin 20 mg/m2, every 3 weeks) was commenced, resulting in a rapid decrease of PSA and NSE to < 1 ng/mL and < 13 ng/mL, respectively (Fig. 1). Two weeks after EP therapy started, swallowing function improved with a decrease in CK (Fig. 1) and oral intake became possible. PSL administration was gradually tapered to 5 mg/day.
After 4 courses of EP therapy, CT showed marked reduction of the primary tumor and all metastases including those in the liver (Fig. 3c), but EP therapy was discontinued due to grade 3 malaise. Although the metastases had shrunk, they did not disappear, and we supposed that a small amount of cancer progression could lead to a relapse of dermatomyositis. The patient was therefore switched to docetaxel therapy (70 mg/m2, every 3 weeks). After 4 courses, docetaxel was also discontinued due to grade 3 malaise, and abiraterone acetate treatment was initiated. Abiraterone acetate treatment was ceased after one month because erythema on his face and extremities and serum CK level worsened (246 IU/L). Enzalutamide treatment and dose escalation of PSL to 30 mg/day were started, and dermatomyositis improved. PSA and NSE were consistently low, and no progressions were observed during the administration of docetaxel, abiraterone, and enzalutamide. At present, 31 months after the start of enzalutamide administration, no cancer progression has been observed. Dermatomyositis is in remission, and the patient is on PSL at 10 mg/day.
Discussion and conclusions
It is difficult to obtain a good therapeutic effect in patients with dermatomyositis complicated by malignant tumors, as long as the tumor is present; conversely, radical treatment of malignancy may improve muscle and skin symptoms. Therefore, treatment of malignancy is prioritized in order to improve dermatomyositis [3]. In the present case, dermatomyositis was improved by treatment for prostate cancer in addition to high-dose glucocorticoid therapy. ADT was initially performed to treat prostate cancer with neuroendocrine differentiation and the treatment had limited effects on dermatomyositis, and dysphagia became apparent. Although dermatomyositis tends to improve with high-dose glucocorticoid therapy, oral intake was possible after EP therapy was commenced. These findings suggest that EP therapy was required to address the component of neuroendocrine differentiation.
Pure neuroendocrine prostate cancer (including small cell carcinoma and large cell carcinoma) has a poor prognosis. However, it is controversial whether neuroendocrine differentiation in adenocarcinomas worsens the prognosis [6, 7]. In the present case, multiple liver metastases were observed from the first visit, suggesting that the cancer was aggressive. ADT was followed by EP therapy and other strong treatments with docetaxel, abiraterone, and enzalutamide before the onset of castration resistance. We believe that the ability to control aggressive cancers with these treatments may have led to an improvement in disease activity of dermatomyositis.
In conclusion, we encountered a rare case of dermatomyositis associated with prostate adenocarcinoma with neuroendocrine differentiation. The patient was successfully treated with ADT and subsequent EP therapy for prostate cancer and high-dose glucocorticoid therapy for dermatomyositis.
Abbreviations
PSAProstate specific antigen
NSENeuron specific enolase
CKCreatinine kinase
NCAM1Neural cell adhesion molecule 1
Publisher's Note
Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
Acknowledgements
Not applicable.
Authors’ contributions
HM collected data and wrote the manuscripts. TK contributed to concept of this paper, interpreted the data, and prepared the manuscripts. AM, KM, and YS contributed to concept of this paper. KN, MT, and NT collected data regarding the dermatomyositis, and reviewed the manuscripts. EI performed the histological examination. YY, MN, DY, MS, TM, and HK reviewed the manuscripts. All authors read and approved the final manuscript.
Funding
No funding.
Availability of data and materials
All data generated or analyzed during this study are included in this published article and available from the corresponding author on reasonable request.
Ethics approval and consent to participate
This report was approved by the Ethics Committee at the Ome Municipal General Hospital (Approval number: 54). Informed consent to participate was obtained from the patient.
Consent for publication
Written informed consent for publication of their clinical details and/or clinical images was obtained from the patient. A copy of the consent form is available for review by the Editor of this journal.
Competing interests
The authors declare that they have no competing interests. | 100 MG/M2, EVERY 3 WEEKS | DrugDosageText | CC BY | 33413292 | 18,769,778 | 2021-01-07 |
Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Drug ineffective'. | Severe orthostatic hypotension in otherwise uncomplicated Plasmodium vivax infection.
Impaired autonomic control of postural homeostasis resulting in orthostatic hypotension has been described in falciparum malaria. However, severe orthostatic intolerance in Plasmodium vivax has been rarely reported. A case of non-immune previously healthy Thai woman presenting with P. vivax infection with well-documented orthostatic hypotension is described. In addition to oral chloroquine and intravenous artesunate, the patient was treated with fluid resuscitation and norepinephrine. During hospitalization, her haemodynamic profile revealed orthostatic hypotension persisting for another three days after microscopic and polymerase chain reaction confirmed parasite clearance. Potential causes are discussed.
Background
Impaired autonomic control of postural homeostasis resulting in orthostatic hypotension has been described in falciparum malaria, but severe orthostatic intolerance in Plasmodium vivax has been rarely reported [1–3]. Orthostatic hypotension is defined as a decrease in systolic blood pressure of 20 mmHg or a decrease in diastolic blood pressure of 10 mmHg within 3 min after a change from a reclining to upright posture, together with associated symptoms [4]. It can be a debilitating symptom in conditions characterized by autonomous nervous system dysfunction [5]. Symptoms are caused by decreased cerebral perfusion, including blurred vision, fatigue, dizziness, and, in the most extreme cases, syncope [6]. On standing, the gravitational volume shift causes a redistribution of circulating blood, with pooling in the capacitance vessels below the diaphragm [7]. A normal compensatory haemodynamic response to changes in posture requires normal function of the cardiovascular, endocrine, and autonomic nervous systems [4]. Preservation of an adequate blood pressure is ensured by a prompt rise in cardiac output, mainly through an increase in heart rate, and an increase in vascular resistance favoring the cerebral blood circulation [8]. In dysautonomic states, this response to circulatory redistribution is impaired, which may lead to a compromised cerebral blood flow. Orthostatic hypotension in acute Plasmodium falciparum infection has been well described and is related to a combination of persisting relative bradycardia and insufficient peripheral vasoconstriction [9]. A case of severe orthostatic hypotension in a patient with a P. vivax infection, mimicking severe malaria is described. Haemodynamic profiles and possible pathophysiological features are discussed.
Case presentation
Patient is a 32-year old previously healthy Thai female without a history of malaria and not taking any medication before the disease episode. Two weeks prior to admission she had travelled to a malaria endemic forested area in Kanchanaburi Province, Thailand for camping and hiking with friends and her 6-year-old son. Eight days prior to admission she developed a high-grade fever with headache and chills without localizing symptoms. She had a history of poor appetite, nausea and reduced oral intake without vomiting or diarrhoea. On admission, she had a fever of 39.8 °C, a pulse rate of 78 beats per minute and a blood pressure of 90/60 mmHg. Her weight was 49 kg which were 1 kg lower from her base line of 50 kg. Her consciousness was normal, conjunctivae were not pale and sclerae were not icteric. She had no cold or clammy skin and her capillary refill time was less than 2 s. The liver span was 10 cm in the mid-clavicular line and the spleen was normal in size on palpitation.
Initial complete blood count revealed anaemia with 31% haematocrit, as well as thrombocytopenia of 74,000/µL. Liver function tests revealed mild elevated aspartate aminotransferase and alanine aminotransferase of 60 U/L and 86 U/L, respectively. Blood sugar, creatinine, glucose-6-phosphate dehydrogenase (G6PD) enzyme activity and urinary analysis were normal. Microscopic examination of a peripheral blood film showed an asexual stage P. vivax parasitaemia of 69,800 parasites/µL and the diagnosis was confirmed by a positive polymerase chain reaction (PCR) for P. vivax. In patients breathing spontaneously, inferior vena cava (IVC) collapsibility index measured by transthoracic echocardiogram is a predictor of fluid responsiveness when the value was more than 42% [10]. In this patient, IVC collapsibility index was 46%, which is predictive of a positive fluid responsiveness. She was admitted to the Hospital for Tropical Diseases and given 600 mg chloroquine orally and started on 5% dextrose in 0.9% Sodium Chloride infusion at a rate of 80 mL/h. After 10 h and infusion of 800 mL fluids, the patient complained of postural faintness while getting out of bed. At that moment, she had an upright blood pressure of 77/46 mmHg and a pulse rate of 103 beats/min which increased to 90/50 mmHg in the supine position. Her urine output was 0.5 to 1 mL/kg per an hour. After lying down, she had good consciousness, warm extremities and capillary refill less than 2 s. Her IVC collapsibility index was 31%. Twelve-lead electrocardiogram showed sinus tachycardia with a normal QTc interval.
She was initially diagnosed with severe Plasmodium vivax and given intravenous artesunate 2.4 mg/kg promptly followed by intravenous artesunate in the same dose after 12 h, which was repeated every 24 h for 5 days. Intravenous ceftriaxone was also started to cover potential concomitant bacterial septic shock awaiting blood culture results. Blood cultures obtained before start of antibiotics, however, remained without growth after which antibiotic therapy was discontinued on the 3rd day of admission. After transferring the patient to the intensive care unit, 400 mL normal saline was given over 1 h. After the fluid bolus, her blood pressure was 88/56 mmHg and her pulse rate was 74 beats/min in the supine position with falling to 77/50 mmHg and 72 beats/min while standing, and IVC collapsibility index of 16%, compatible with non-responsiveness to fluid resuscitation. Table 1 details her haemodynamic profiles during hospital admission. This prompted the start of intravenous norepinephrine at a dose of 0.13 µg/kg/min to maintain a blood pressure of 90/50 mmHg in an upright position. Her plasma lactate assessed at that moment was 1.8 mmol/L (normal value: < 2 mmol/L). Her morning serum cortisol on the next day was 32 µg/dL (normal level: > 6 µg/dL) making a diagnosis of primary or secondary adrenal insufficiency unlikely, and corticosteroids were not started. Haemodynamic monitoring by an ultrasound cardiac output monitor (USCOM) in the supine and upright position before receiving norepinephrine showed a marked drop in cardiac index from 3 L/min/m2 in the supine position to 1.9 L/min/m2 after standing for 3 min, despite adequate hydration. The upright positional drop in cardiac output in the upright position was explained by an absence of an increase in stroke volume, and an insufficient increase in heart rate (Table 1). This orthostatic hypotension persisted until 3 days after microscopically confirmed parasite clearance, necessitating continued vasopressor support with norepinephrine (Table 1) (Figs. 1, 2, 3, 4, 5 and 6). Orthostatic intolerance only resolved completely at the 12th day of follow up. After recovery, the patient received radical treatment with a 14-day course of (0.25 mg/kg daily) primaquine.Table 1 Daily clinical data, laboratories and haemodynamic profiles
Day of admission Admission Day 01 Day 02 Day 03 Day 04 Day 05 Day 06 Day 12
Position Supine Supine Standing 3 min Supine Standing 3 min Supine Standing 3 min Supine Standing 3 min Supine Standing 3 min Supine Standing 3 min Supine Standing 3 min
Temperature (°C) 39.8 39.4 38 36.8 36.5 36.8 37 36.8
Malaria
Microscopic exam (parasites/µL) 430 155 62 Negative Negative Negative Negative Negative
PCR Plasmodium vivax N/A N/A N/A Negative for malaria N/A N/A N/A
Norepinephrine dose (µg/kg/min) 0 0.13 0.08 0.04 0.03 – – –
Hemodynamic parameters
IVC maximum (cm) 1.23 1.72 N/A 1.57 N/A 1.73 N/A 1.38 N/A 1.13 N/A 1.23 N/A 1.5 N/A
IVC minimum (cm) 0.66 1.18 N/A 1.23 N/A 1.38 N/A 1.03 N/A 0.84 N/A 1.08 N/A 0.98 N/A
IVC collapsibility (%) 46.34 31.39 N/A 21.7 N/A 20.23 N/A 25.36 N/A 25.66 N/A 12.2 N/A 34.67 N/A
Stroke volume index (mL/m²) 36 46 27 54 32 46 29 45 25 44 30 42 40 37 39
Cardiac index (L/min/m²) 2.7 3 1.9 3.2 2.3 3 2.4 3 2.3 3.4 2.6 3.2 3 2.5 2.8
Laboratories
Hematocrit (%) 31.2 26.3 26.9 27.2 28.9 – 30
Platelet (/µL) 74,000 68,000 117,000 158,000 213,000 – 240,000
AST/ALT (U/L) 60/86 40/62 105/160 – 80/154 – 24/42
Lactate (mmol/L) 1.8 1.3 0.99 – – – –
Intake/output 1,584/1,100 3248/1618 2761/3630 1593/2335 1387/1860 – –
PCR polymerase chain reaction, IVC inferior vena cava, AST aspartate aminotransferase, ALT alanine aminotransferase, N/A not available
IVC collapsibility = (maximum diameter − minimum diameter)/(maximum diameter) × 100
Fig. 1 Daily heart rate in supine and standing for 3 min position
Fig. 2 Daily systolic blood pressure and diastolic blood pressure in supine position and standing for 3 min position
Fig. 3 Daily pulse pressure in supine position and standing for 3 min position
Fig. 4 Daily mean arterial pressure in supine position and standing for 3 min position
Fig. 5 Daily cardiac index in supine position and standing for 3 min position
Fig. 6 Daily stroke volume index in supine position and standing for 3 min position
Discussion
Hypotension meeting World Health Organization criteria for severe malaria has been reported in several case series of adult vivax malaria [11–14]. However, orthostatic hypotension which has been previously well documented during an acute P. falciparum infection [9] has been rarely described in P. vivax [1–3]. This case report describes a 5-day episode of orthostatic hypotension in a non-immune Thai woman with vivax malaria after start of treatment with chloroquine and after adequate fluid resuscitation. Her orthostatic intolerance was unlikely to be caused by an underlying disease or medication. Blood cultures have a low sensitivity for detecting bacteraemia, which might not exclude concurrent bacterial sepsis. Gram negative/Salmonella coinfection has been previously reported in vivax malaria [15]. However, the observed hypotension was not considered as a feature of septic shock from bacterial infection or severe malaria, since there were no signs of tissue hypoperfusion, with a normal plasma lactate concentration and normal capillary refill time, and no other indications of organ failure. She did receive low-dose vasopressor therapy, mainly to maintain an adequate blood pressure in an upright position. In falciparum malaria three potential mechanisms of orthostatic intolerance have been proposed. The first mechanism is autonomic dysfunction causing relative bradycardia and impaired capacity to increase vascular resistance in the upright position, which will cause a drop in mainly the diastolic blood pressure in the upright position, as also observed in the presented case.
In healthy young adults, the immediate response to a change in position from supine to upright is characterized by a prompt rise in heart rate of about 15 to 30%, and in total vascular resistance of 30 to 40% [8]. The main sensory receptors involved in the orthostatic neural reflex adjustment are the arterial mechanoreceptors (baroreceptors) located in the aortic arch and carotid sinuses and mechanoreceptors located in the heart and lungs (cardiopulmonary receptors). The cardiopulmonary receptors act in concert with the arterial baroreceptors to affect the necessary adjustment in sympathetic nerve action [16]. In patients with falciparum malaria, autonomic dysfunction causing an impaired neural reflex with insufficient compensatory tachycardia and arteriolar vasoconstriction is thought to be the primary cause of orthostatic hypotension in these patients [17], and the subsequent increased subdiaphragmatic pooling of venous blood will subsequently cause a reduction in venous return resulting in a further reduction in stroke volume and thus cardiac output, exaggerating the orthostatic fall in blood pressure.
A second mechanism is blood flow redistribution due to venous vasodilation caused by fever and other factors [18], with larger proportions of blood going to skin and muscle and decreased proportions to liver and kidney [19]. Combined with autonomic failure, this can further reduce venous return and thus cardiac output. Intravascular hypovolaemia can also contribute. Dehydration is common in patients with (falciparum) malaria, as illustrated by the frequently observed increase in the urea/creatinine ratio, increased plasma osmolarity and decreased fractional excretion of sodium, in the presence of an adequate antidiuretic hormone response [20]. Dehydration in patients with malaria is usually caused by transpiration, vomiting or diarrhea, and inadequate fluid intake because of the acute illness. In our case, however, the patient had been adequately rehydrated, as illustrated by the normal IVC collapsibility index after fluid administration.
Chloroquine has also been described to cause hypotension [21, 22] and negative chronotropic effect [23]. Chloroquine decreases vascular resistance [24] through veno-vasodilation via the release of endothelial nitric oxide in the venous circulation [25]. Through vasodilatation, chloroquine may thus reduce both cardiac preload and afterload causing hypotension. Chloroquine also impairs adaptation of the heart rate via reduction in the firing of the spontaneous action potential of the so-called ‘funny current, causing bradycardia [23]. The oral administration of chloroquine could also have triggered an initial vasovagal reaction, but this would not explain the persisting orthostatic symptoms in this patient. Since her orthostatic symptoms persisted after parasite clearance, it is likely that chloroquine therapy contributed to the orthostatic hypotension in our patient, since chloroquine has a long plasma half-life, with an initial t1/2 between 150 and 290 h [26]. In the acute phase of her illness, the described factors which have been identified contributing to orthostatic hypotension in falciparum malaria could have played a role, but this is difficult to substantiate.
In conclusion, this case report shows that orthostatic hypotension may occur in patients with uncomplicated P. vivax infection. This could result from chloroquine therapy, whereas P. vivax induced autonomic dysfunction may also contribute.
Abbreviations
G6PDGlucose-6-phosphate dehydrogenase
PCRPolymerase chain reaction
IVCInferior vena cava
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Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
Acknowledgements
The authors would like to express gratitude to the patient and the staff of Hospital for Tropical Diseases, Faculty of Tropical Medicine, Mahidol University, Bangkok, Thailand and Miss Chatnapa Duangdee for diagnostic laboratory for malaria.
Authors’ contributions
CS, PW, AD and MS drafted the manuscript. CS and SK contributed in patient care. TT, KK contributed to facilitate in laboratory investigations. All authors contributed to revise the manuscript. All authors read and approved the final manuscript.
Funding
The publication of this work was granted by Faculty of Tropical Medicine, Mahidol University, Bangkok, Thailand.
Availability of data and materials
The data that support the findings of this study are available from Hospital for Tropical Diseases, but restrictions apply to the availability of these data and so are not publicly available. However, data are available from the authors upon reasonable request and with the permission of the institution.
Ethics approval and consent to participate
Exemption from obtaining ethics approval was granted due to a single case study and the patient was consented to participated in this study.
Consent for publication
Not applicable.
Conflict of interests
The authors declare that they have no competing interests. | ARTESUNATE, CEFTRIAXONE, CHLOROQUINE, NOREPINEPHRINE, SODIUM CHLORIDE | DrugsGivenReaction | CC BY | 33413379 | 18,897,227 | 2021-01-07 |
What was the administration route of drug 'ARTESUNATE'? | Severe orthostatic hypotension in otherwise uncomplicated Plasmodium vivax infection.
Impaired autonomic control of postural homeostasis resulting in orthostatic hypotension has been described in falciparum malaria. However, severe orthostatic intolerance in Plasmodium vivax has been rarely reported. A case of non-immune previously healthy Thai woman presenting with P. vivax infection with well-documented orthostatic hypotension is described. In addition to oral chloroquine and intravenous artesunate, the patient was treated with fluid resuscitation and norepinephrine. During hospitalization, her haemodynamic profile revealed orthostatic hypotension persisting for another three days after microscopic and polymerase chain reaction confirmed parasite clearance. Potential causes are discussed.
Background
Impaired autonomic control of postural homeostasis resulting in orthostatic hypotension has been described in falciparum malaria, but severe orthostatic intolerance in Plasmodium vivax has been rarely reported [1–3]. Orthostatic hypotension is defined as a decrease in systolic blood pressure of 20 mmHg or a decrease in diastolic blood pressure of 10 mmHg within 3 min after a change from a reclining to upright posture, together with associated symptoms [4]. It can be a debilitating symptom in conditions characterized by autonomous nervous system dysfunction [5]. Symptoms are caused by decreased cerebral perfusion, including blurred vision, fatigue, dizziness, and, in the most extreme cases, syncope [6]. On standing, the gravitational volume shift causes a redistribution of circulating blood, with pooling in the capacitance vessels below the diaphragm [7]. A normal compensatory haemodynamic response to changes in posture requires normal function of the cardiovascular, endocrine, and autonomic nervous systems [4]. Preservation of an adequate blood pressure is ensured by a prompt rise in cardiac output, mainly through an increase in heart rate, and an increase in vascular resistance favoring the cerebral blood circulation [8]. In dysautonomic states, this response to circulatory redistribution is impaired, which may lead to a compromised cerebral blood flow. Orthostatic hypotension in acute Plasmodium falciparum infection has been well described and is related to a combination of persisting relative bradycardia and insufficient peripheral vasoconstriction [9]. A case of severe orthostatic hypotension in a patient with a P. vivax infection, mimicking severe malaria is described. Haemodynamic profiles and possible pathophysiological features are discussed.
Case presentation
Patient is a 32-year old previously healthy Thai female without a history of malaria and not taking any medication before the disease episode. Two weeks prior to admission she had travelled to a malaria endemic forested area in Kanchanaburi Province, Thailand for camping and hiking with friends and her 6-year-old son. Eight days prior to admission she developed a high-grade fever with headache and chills without localizing symptoms. She had a history of poor appetite, nausea and reduced oral intake without vomiting or diarrhoea. On admission, she had a fever of 39.8 °C, a pulse rate of 78 beats per minute and a blood pressure of 90/60 mmHg. Her weight was 49 kg which were 1 kg lower from her base line of 50 kg. Her consciousness was normal, conjunctivae were not pale and sclerae were not icteric. She had no cold or clammy skin and her capillary refill time was less than 2 s. The liver span was 10 cm in the mid-clavicular line and the spleen was normal in size on palpitation.
Initial complete blood count revealed anaemia with 31% haematocrit, as well as thrombocytopenia of 74,000/µL. Liver function tests revealed mild elevated aspartate aminotransferase and alanine aminotransferase of 60 U/L and 86 U/L, respectively. Blood sugar, creatinine, glucose-6-phosphate dehydrogenase (G6PD) enzyme activity and urinary analysis were normal. Microscopic examination of a peripheral blood film showed an asexual stage P. vivax parasitaemia of 69,800 parasites/µL and the diagnosis was confirmed by a positive polymerase chain reaction (PCR) for P. vivax. In patients breathing spontaneously, inferior vena cava (IVC) collapsibility index measured by transthoracic echocardiogram is a predictor of fluid responsiveness when the value was more than 42% [10]. In this patient, IVC collapsibility index was 46%, which is predictive of a positive fluid responsiveness. She was admitted to the Hospital for Tropical Diseases and given 600 mg chloroquine orally and started on 5% dextrose in 0.9% Sodium Chloride infusion at a rate of 80 mL/h. After 10 h and infusion of 800 mL fluids, the patient complained of postural faintness while getting out of bed. At that moment, she had an upright blood pressure of 77/46 mmHg and a pulse rate of 103 beats/min which increased to 90/50 mmHg in the supine position. Her urine output was 0.5 to 1 mL/kg per an hour. After lying down, she had good consciousness, warm extremities and capillary refill less than 2 s. Her IVC collapsibility index was 31%. Twelve-lead electrocardiogram showed sinus tachycardia with a normal QTc interval.
She was initially diagnosed with severe Plasmodium vivax and given intravenous artesunate 2.4 mg/kg promptly followed by intravenous artesunate in the same dose after 12 h, which was repeated every 24 h for 5 days. Intravenous ceftriaxone was also started to cover potential concomitant bacterial septic shock awaiting blood culture results. Blood cultures obtained before start of antibiotics, however, remained without growth after which antibiotic therapy was discontinued on the 3rd day of admission. After transferring the patient to the intensive care unit, 400 mL normal saline was given over 1 h. After the fluid bolus, her blood pressure was 88/56 mmHg and her pulse rate was 74 beats/min in the supine position with falling to 77/50 mmHg and 72 beats/min while standing, and IVC collapsibility index of 16%, compatible with non-responsiveness to fluid resuscitation. Table 1 details her haemodynamic profiles during hospital admission. This prompted the start of intravenous norepinephrine at a dose of 0.13 µg/kg/min to maintain a blood pressure of 90/50 mmHg in an upright position. Her plasma lactate assessed at that moment was 1.8 mmol/L (normal value: < 2 mmol/L). Her morning serum cortisol on the next day was 32 µg/dL (normal level: > 6 µg/dL) making a diagnosis of primary or secondary adrenal insufficiency unlikely, and corticosteroids were not started. Haemodynamic monitoring by an ultrasound cardiac output monitor (USCOM) in the supine and upright position before receiving norepinephrine showed a marked drop in cardiac index from 3 L/min/m2 in the supine position to 1.9 L/min/m2 after standing for 3 min, despite adequate hydration. The upright positional drop in cardiac output in the upright position was explained by an absence of an increase in stroke volume, and an insufficient increase in heart rate (Table 1). This orthostatic hypotension persisted until 3 days after microscopically confirmed parasite clearance, necessitating continued vasopressor support with norepinephrine (Table 1) (Figs. 1, 2, 3, 4, 5 and 6). Orthostatic intolerance only resolved completely at the 12th day of follow up. After recovery, the patient received radical treatment with a 14-day course of (0.25 mg/kg daily) primaquine.Table 1 Daily clinical data, laboratories and haemodynamic profiles
Day of admission Admission Day 01 Day 02 Day 03 Day 04 Day 05 Day 06 Day 12
Position Supine Supine Standing 3 min Supine Standing 3 min Supine Standing 3 min Supine Standing 3 min Supine Standing 3 min Supine Standing 3 min Supine Standing 3 min
Temperature (°C) 39.8 39.4 38 36.8 36.5 36.8 37 36.8
Malaria
Microscopic exam (parasites/µL) 430 155 62 Negative Negative Negative Negative Negative
PCR Plasmodium vivax N/A N/A N/A Negative for malaria N/A N/A N/A
Norepinephrine dose (µg/kg/min) 0 0.13 0.08 0.04 0.03 – – –
Hemodynamic parameters
IVC maximum (cm) 1.23 1.72 N/A 1.57 N/A 1.73 N/A 1.38 N/A 1.13 N/A 1.23 N/A 1.5 N/A
IVC minimum (cm) 0.66 1.18 N/A 1.23 N/A 1.38 N/A 1.03 N/A 0.84 N/A 1.08 N/A 0.98 N/A
IVC collapsibility (%) 46.34 31.39 N/A 21.7 N/A 20.23 N/A 25.36 N/A 25.66 N/A 12.2 N/A 34.67 N/A
Stroke volume index (mL/m²) 36 46 27 54 32 46 29 45 25 44 30 42 40 37 39
Cardiac index (L/min/m²) 2.7 3 1.9 3.2 2.3 3 2.4 3 2.3 3.4 2.6 3.2 3 2.5 2.8
Laboratories
Hematocrit (%) 31.2 26.3 26.9 27.2 28.9 – 30
Platelet (/µL) 74,000 68,000 117,000 158,000 213,000 – 240,000
AST/ALT (U/L) 60/86 40/62 105/160 – 80/154 – 24/42
Lactate (mmol/L) 1.8 1.3 0.99 – – – –
Intake/output 1,584/1,100 3248/1618 2761/3630 1593/2335 1387/1860 – –
PCR polymerase chain reaction, IVC inferior vena cava, AST aspartate aminotransferase, ALT alanine aminotransferase, N/A not available
IVC collapsibility = (maximum diameter − minimum diameter)/(maximum diameter) × 100
Fig. 1 Daily heart rate in supine and standing for 3 min position
Fig. 2 Daily systolic blood pressure and diastolic blood pressure in supine position and standing for 3 min position
Fig. 3 Daily pulse pressure in supine position and standing for 3 min position
Fig. 4 Daily mean arterial pressure in supine position and standing for 3 min position
Fig. 5 Daily cardiac index in supine position and standing for 3 min position
Fig. 6 Daily stroke volume index in supine position and standing for 3 min position
Discussion
Hypotension meeting World Health Organization criteria for severe malaria has been reported in several case series of adult vivax malaria [11–14]. However, orthostatic hypotension which has been previously well documented during an acute P. falciparum infection [9] has been rarely described in P. vivax [1–3]. This case report describes a 5-day episode of orthostatic hypotension in a non-immune Thai woman with vivax malaria after start of treatment with chloroquine and after adequate fluid resuscitation. Her orthostatic intolerance was unlikely to be caused by an underlying disease or medication. Blood cultures have a low sensitivity for detecting bacteraemia, which might not exclude concurrent bacterial sepsis. Gram negative/Salmonella coinfection has been previously reported in vivax malaria [15]. However, the observed hypotension was not considered as a feature of septic shock from bacterial infection or severe malaria, since there were no signs of tissue hypoperfusion, with a normal plasma lactate concentration and normal capillary refill time, and no other indications of organ failure. She did receive low-dose vasopressor therapy, mainly to maintain an adequate blood pressure in an upright position. In falciparum malaria three potential mechanisms of orthostatic intolerance have been proposed. The first mechanism is autonomic dysfunction causing relative bradycardia and impaired capacity to increase vascular resistance in the upright position, which will cause a drop in mainly the diastolic blood pressure in the upright position, as also observed in the presented case.
In healthy young adults, the immediate response to a change in position from supine to upright is characterized by a prompt rise in heart rate of about 15 to 30%, and in total vascular resistance of 30 to 40% [8]. The main sensory receptors involved in the orthostatic neural reflex adjustment are the arterial mechanoreceptors (baroreceptors) located in the aortic arch and carotid sinuses and mechanoreceptors located in the heart and lungs (cardiopulmonary receptors). The cardiopulmonary receptors act in concert with the arterial baroreceptors to affect the necessary adjustment in sympathetic nerve action [16]. In patients with falciparum malaria, autonomic dysfunction causing an impaired neural reflex with insufficient compensatory tachycardia and arteriolar vasoconstriction is thought to be the primary cause of orthostatic hypotension in these patients [17], and the subsequent increased subdiaphragmatic pooling of venous blood will subsequently cause a reduction in venous return resulting in a further reduction in stroke volume and thus cardiac output, exaggerating the orthostatic fall in blood pressure.
A second mechanism is blood flow redistribution due to venous vasodilation caused by fever and other factors [18], with larger proportions of blood going to skin and muscle and decreased proportions to liver and kidney [19]. Combined with autonomic failure, this can further reduce venous return and thus cardiac output. Intravascular hypovolaemia can also contribute. Dehydration is common in patients with (falciparum) malaria, as illustrated by the frequently observed increase in the urea/creatinine ratio, increased plasma osmolarity and decreased fractional excretion of sodium, in the presence of an adequate antidiuretic hormone response [20]. Dehydration in patients with malaria is usually caused by transpiration, vomiting or diarrhea, and inadequate fluid intake because of the acute illness. In our case, however, the patient had been adequately rehydrated, as illustrated by the normal IVC collapsibility index after fluid administration.
Chloroquine has also been described to cause hypotension [21, 22] and negative chronotropic effect [23]. Chloroquine decreases vascular resistance [24] through veno-vasodilation via the release of endothelial nitric oxide in the venous circulation [25]. Through vasodilatation, chloroquine may thus reduce both cardiac preload and afterload causing hypotension. Chloroquine also impairs adaptation of the heart rate via reduction in the firing of the spontaneous action potential of the so-called ‘funny current, causing bradycardia [23]. The oral administration of chloroquine could also have triggered an initial vasovagal reaction, but this would not explain the persisting orthostatic symptoms in this patient. Since her orthostatic symptoms persisted after parasite clearance, it is likely that chloroquine therapy contributed to the orthostatic hypotension in our patient, since chloroquine has a long plasma half-life, with an initial t1/2 between 150 and 290 h [26]. In the acute phase of her illness, the described factors which have been identified contributing to orthostatic hypotension in falciparum malaria could have played a role, but this is difficult to substantiate.
In conclusion, this case report shows that orthostatic hypotension may occur in patients with uncomplicated P. vivax infection. This could result from chloroquine therapy, whereas P. vivax induced autonomic dysfunction may also contribute.
Abbreviations
G6PDGlucose-6-phosphate dehydrogenase
PCRPolymerase chain reaction
IVCInferior vena cava
Publisher’s note
Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
Acknowledgements
The authors would like to express gratitude to the patient and the staff of Hospital for Tropical Diseases, Faculty of Tropical Medicine, Mahidol University, Bangkok, Thailand and Miss Chatnapa Duangdee for diagnostic laboratory for malaria.
Authors’ contributions
CS, PW, AD and MS drafted the manuscript. CS and SK contributed in patient care. TT, KK contributed to facilitate in laboratory investigations. All authors contributed to revise the manuscript. All authors read and approved the final manuscript.
Funding
The publication of this work was granted by Faculty of Tropical Medicine, Mahidol University, Bangkok, Thailand.
Availability of data and materials
The data that support the findings of this study are available from Hospital for Tropical Diseases, but restrictions apply to the availability of these data and so are not publicly available. However, data are available from the authors upon reasonable request and with the permission of the institution.
Ethics approval and consent to participate
Exemption from obtaining ethics approval was granted due to a single case study and the patient was consented to participated in this study.
Consent for publication
Not applicable.
Conflict of interests
The authors declare that they have no competing interests. | Intravenous (not otherwise specified) | DrugAdministrationRoute | CC BY | 33413379 | 18,897,227 | 2021-01-07 |
What was the administration route of drug 'CEFTRIAXONE'? | Severe orthostatic hypotension in otherwise uncomplicated Plasmodium vivax infection.
Impaired autonomic control of postural homeostasis resulting in orthostatic hypotension has been described in falciparum malaria. However, severe orthostatic intolerance in Plasmodium vivax has been rarely reported. A case of non-immune previously healthy Thai woman presenting with P. vivax infection with well-documented orthostatic hypotension is described. In addition to oral chloroquine and intravenous artesunate, the patient was treated with fluid resuscitation and norepinephrine. During hospitalization, her haemodynamic profile revealed orthostatic hypotension persisting for another three days after microscopic and polymerase chain reaction confirmed parasite clearance. Potential causes are discussed.
Background
Impaired autonomic control of postural homeostasis resulting in orthostatic hypotension has been described in falciparum malaria, but severe orthostatic intolerance in Plasmodium vivax has been rarely reported [1–3]. Orthostatic hypotension is defined as a decrease in systolic blood pressure of 20 mmHg or a decrease in diastolic blood pressure of 10 mmHg within 3 min after a change from a reclining to upright posture, together with associated symptoms [4]. It can be a debilitating symptom in conditions characterized by autonomous nervous system dysfunction [5]. Symptoms are caused by decreased cerebral perfusion, including blurred vision, fatigue, dizziness, and, in the most extreme cases, syncope [6]. On standing, the gravitational volume shift causes a redistribution of circulating blood, with pooling in the capacitance vessels below the diaphragm [7]. A normal compensatory haemodynamic response to changes in posture requires normal function of the cardiovascular, endocrine, and autonomic nervous systems [4]. Preservation of an adequate blood pressure is ensured by a prompt rise in cardiac output, mainly through an increase in heart rate, and an increase in vascular resistance favoring the cerebral blood circulation [8]. In dysautonomic states, this response to circulatory redistribution is impaired, which may lead to a compromised cerebral blood flow. Orthostatic hypotension in acute Plasmodium falciparum infection has been well described and is related to a combination of persisting relative bradycardia and insufficient peripheral vasoconstriction [9]. A case of severe orthostatic hypotension in a patient with a P. vivax infection, mimicking severe malaria is described. Haemodynamic profiles and possible pathophysiological features are discussed.
Case presentation
Patient is a 32-year old previously healthy Thai female without a history of malaria and not taking any medication before the disease episode. Two weeks prior to admission she had travelled to a malaria endemic forested area in Kanchanaburi Province, Thailand for camping and hiking with friends and her 6-year-old son. Eight days prior to admission she developed a high-grade fever with headache and chills without localizing symptoms. She had a history of poor appetite, nausea and reduced oral intake without vomiting or diarrhoea. On admission, she had a fever of 39.8 °C, a pulse rate of 78 beats per minute and a blood pressure of 90/60 mmHg. Her weight was 49 kg which were 1 kg lower from her base line of 50 kg. Her consciousness was normal, conjunctivae were not pale and sclerae were not icteric. She had no cold or clammy skin and her capillary refill time was less than 2 s. The liver span was 10 cm in the mid-clavicular line and the spleen was normal in size on palpitation.
Initial complete blood count revealed anaemia with 31% haematocrit, as well as thrombocytopenia of 74,000/µL. Liver function tests revealed mild elevated aspartate aminotransferase and alanine aminotransferase of 60 U/L and 86 U/L, respectively. Blood sugar, creatinine, glucose-6-phosphate dehydrogenase (G6PD) enzyme activity and urinary analysis were normal. Microscopic examination of a peripheral blood film showed an asexual stage P. vivax parasitaemia of 69,800 parasites/µL and the diagnosis was confirmed by a positive polymerase chain reaction (PCR) for P. vivax. In patients breathing spontaneously, inferior vena cava (IVC) collapsibility index measured by transthoracic echocardiogram is a predictor of fluid responsiveness when the value was more than 42% [10]. In this patient, IVC collapsibility index was 46%, which is predictive of a positive fluid responsiveness. She was admitted to the Hospital for Tropical Diseases and given 600 mg chloroquine orally and started on 5% dextrose in 0.9% Sodium Chloride infusion at a rate of 80 mL/h. After 10 h and infusion of 800 mL fluids, the patient complained of postural faintness while getting out of bed. At that moment, she had an upright blood pressure of 77/46 mmHg and a pulse rate of 103 beats/min which increased to 90/50 mmHg in the supine position. Her urine output was 0.5 to 1 mL/kg per an hour. After lying down, she had good consciousness, warm extremities and capillary refill less than 2 s. Her IVC collapsibility index was 31%. Twelve-lead electrocardiogram showed sinus tachycardia with a normal QTc interval.
She was initially diagnosed with severe Plasmodium vivax and given intravenous artesunate 2.4 mg/kg promptly followed by intravenous artesunate in the same dose after 12 h, which was repeated every 24 h for 5 days. Intravenous ceftriaxone was also started to cover potential concomitant bacterial septic shock awaiting blood culture results. Blood cultures obtained before start of antibiotics, however, remained without growth after which antibiotic therapy was discontinued on the 3rd day of admission. After transferring the patient to the intensive care unit, 400 mL normal saline was given over 1 h. After the fluid bolus, her blood pressure was 88/56 mmHg and her pulse rate was 74 beats/min in the supine position with falling to 77/50 mmHg and 72 beats/min while standing, and IVC collapsibility index of 16%, compatible with non-responsiveness to fluid resuscitation. Table 1 details her haemodynamic profiles during hospital admission. This prompted the start of intravenous norepinephrine at a dose of 0.13 µg/kg/min to maintain a blood pressure of 90/50 mmHg in an upright position. Her plasma lactate assessed at that moment was 1.8 mmol/L (normal value: < 2 mmol/L). Her morning serum cortisol on the next day was 32 µg/dL (normal level: > 6 µg/dL) making a diagnosis of primary or secondary adrenal insufficiency unlikely, and corticosteroids were not started. Haemodynamic monitoring by an ultrasound cardiac output monitor (USCOM) in the supine and upright position before receiving norepinephrine showed a marked drop in cardiac index from 3 L/min/m2 in the supine position to 1.9 L/min/m2 after standing for 3 min, despite adequate hydration. The upright positional drop in cardiac output in the upright position was explained by an absence of an increase in stroke volume, and an insufficient increase in heart rate (Table 1). This orthostatic hypotension persisted until 3 days after microscopically confirmed parasite clearance, necessitating continued vasopressor support with norepinephrine (Table 1) (Figs. 1, 2, 3, 4, 5 and 6). Orthostatic intolerance only resolved completely at the 12th day of follow up. After recovery, the patient received radical treatment with a 14-day course of (0.25 mg/kg daily) primaquine.Table 1 Daily clinical data, laboratories and haemodynamic profiles
Day of admission Admission Day 01 Day 02 Day 03 Day 04 Day 05 Day 06 Day 12
Position Supine Supine Standing 3 min Supine Standing 3 min Supine Standing 3 min Supine Standing 3 min Supine Standing 3 min Supine Standing 3 min Supine Standing 3 min
Temperature (°C) 39.8 39.4 38 36.8 36.5 36.8 37 36.8
Malaria
Microscopic exam (parasites/µL) 430 155 62 Negative Negative Negative Negative Negative
PCR Plasmodium vivax N/A N/A N/A Negative for malaria N/A N/A N/A
Norepinephrine dose (µg/kg/min) 0 0.13 0.08 0.04 0.03 – – –
Hemodynamic parameters
IVC maximum (cm) 1.23 1.72 N/A 1.57 N/A 1.73 N/A 1.38 N/A 1.13 N/A 1.23 N/A 1.5 N/A
IVC minimum (cm) 0.66 1.18 N/A 1.23 N/A 1.38 N/A 1.03 N/A 0.84 N/A 1.08 N/A 0.98 N/A
IVC collapsibility (%) 46.34 31.39 N/A 21.7 N/A 20.23 N/A 25.36 N/A 25.66 N/A 12.2 N/A 34.67 N/A
Stroke volume index (mL/m²) 36 46 27 54 32 46 29 45 25 44 30 42 40 37 39
Cardiac index (L/min/m²) 2.7 3 1.9 3.2 2.3 3 2.4 3 2.3 3.4 2.6 3.2 3 2.5 2.8
Laboratories
Hematocrit (%) 31.2 26.3 26.9 27.2 28.9 – 30
Platelet (/µL) 74,000 68,000 117,000 158,000 213,000 – 240,000
AST/ALT (U/L) 60/86 40/62 105/160 – 80/154 – 24/42
Lactate (mmol/L) 1.8 1.3 0.99 – – – –
Intake/output 1,584/1,100 3248/1618 2761/3630 1593/2335 1387/1860 – –
PCR polymerase chain reaction, IVC inferior vena cava, AST aspartate aminotransferase, ALT alanine aminotransferase, N/A not available
IVC collapsibility = (maximum diameter − minimum diameter)/(maximum diameter) × 100
Fig. 1 Daily heart rate in supine and standing for 3 min position
Fig. 2 Daily systolic blood pressure and diastolic blood pressure in supine position and standing for 3 min position
Fig. 3 Daily pulse pressure in supine position and standing for 3 min position
Fig. 4 Daily mean arterial pressure in supine position and standing for 3 min position
Fig. 5 Daily cardiac index in supine position and standing for 3 min position
Fig. 6 Daily stroke volume index in supine position and standing for 3 min position
Discussion
Hypotension meeting World Health Organization criteria for severe malaria has been reported in several case series of adult vivax malaria [11–14]. However, orthostatic hypotension which has been previously well documented during an acute P. falciparum infection [9] has been rarely described in P. vivax [1–3]. This case report describes a 5-day episode of orthostatic hypotension in a non-immune Thai woman with vivax malaria after start of treatment with chloroquine and after adequate fluid resuscitation. Her orthostatic intolerance was unlikely to be caused by an underlying disease or medication. Blood cultures have a low sensitivity for detecting bacteraemia, which might not exclude concurrent bacterial sepsis. Gram negative/Salmonella coinfection has been previously reported in vivax malaria [15]. However, the observed hypotension was not considered as a feature of septic shock from bacterial infection or severe malaria, since there were no signs of tissue hypoperfusion, with a normal plasma lactate concentration and normal capillary refill time, and no other indications of organ failure. She did receive low-dose vasopressor therapy, mainly to maintain an adequate blood pressure in an upright position. In falciparum malaria three potential mechanisms of orthostatic intolerance have been proposed. The first mechanism is autonomic dysfunction causing relative bradycardia and impaired capacity to increase vascular resistance in the upright position, which will cause a drop in mainly the diastolic blood pressure in the upright position, as also observed in the presented case.
In healthy young adults, the immediate response to a change in position from supine to upright is characterized by a prompt rise in heart rate of about 15 to 30%, and in total vascular resistance of 30 to 40% [8]. The main sensory receptors involved in the orthostatic neural reflex adjustment are the arterial mechanoreceptors (baroreceptors) located in the aortic arch and carotid sinuses and mechanoreceptors located in the heart and lungs (cardiopulmonary receptors). The cardiopulmonary receptors act in concert with the arterial baroreceptors to affect the necessary adjustment in sympathetic nerve action [16]. In patients with falciparum malaria, autonomic dysfunction causing an impaired neural reflex with insufficient compensatory tachycardia and arteriolar vasoconstriction is thought to be the primary cause of orthostatic hypotension in these patients [17], and the subsequent increased subdiaphragmatic pooling of venous blood will subsequently cause a reduction in venous return resulting in a further reduction in stroke volume and thus cardiac output, exaggerating the orthostatic fall in blood pressure.
A second mechanism is blood flow redistribution due to venous vasodilation caused by fever and other factors [18], with larger proportions of blood going to skin and muscle and decreased proportions to liver and kidney [19]. Combined with autonomic failure, this can further reduce venous return and thus cardiac output. Intravascular hypovolaemia can also contribute. Dehydration is common in patients with (falciparum) malaria, as illustrated by the frequently observed increase in the urea/creatinine ratio, increased plasma osmolarity and decreased fractional excretion of sodium, in the presence of an adequate antidiuretic hormone response [20]. Dehydration in patients with malaria is usually caused by transpiration, vomiting or diarrhea, and inadequate fluid intake because of the acute illness. In our case, however, the patient had been adequately rehydrated, as illustrated by the normal IVC collapsibility index after fluid administration.
Chloroquine has also been described to cause hypotension [21, 22] and negative chronotropic effect [23]. Chloroquine decreases vascular resistance [24] through veno-vasodilation via the release of endothelial nitric oxide in the venous circulation [25]. Through vasodilatation, chloroquine may thus reduce both cardiac preload and afterload causing hypotension. Chloroquine also impairs adaptation of the heart rate via reduction in the firing of the spontaneous action potential of the so-called ‘funny current, causing bradycardia [23]. The oral administration of chloroquine could also have triggered an initial vasovagal reaction, but this would not explain the persisting orthostatic symptoms in this patient. Since her orthostatic symptoms persisted after parasite clearance, it is likely that chloroquine therapy contributed to the orthostatic hypotension in our patient, since chloroquine has a long plasma half-life, with an initial t1/2 between 150 and 290 h [26]. In the acute phase of her illness, the described factors which have been identified contributing to orthostatic hypotension in falciparum malaria could have played a role, but this is difficult to substantiate.
In conclusion, this case report shows that orthostatic hypotension may occur in patients with uncomplicated P. vivax infection. This could result from chloroquine therapy, whereas P. vivax induced autonomic dysfunction may also contribute.
Abbreviations
G6PDGlucose-6-phosphate dehydrogenase
PCRPolymerase chain reaction
IVCInferior vena cava
Publisher’s note
Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
Acknowledgements
The authors would like to express gratitude to the patient and the staff of Hospital for Tropical Diseases, Faculty of Tropical Medicine, Mahidol University, Bangkok, Thailand and Miss Chatnapa Duangdee for diagnostic laboratory for malaria.
Authors’ contributions
CS, PW, AD and MS drafted the manuscript. CS and SK contributed in patient care. TT, KK contributed to facilitate in laboratory investigations. All authors contributed to revise the manuscript. All authors read and approved the final manuscript.
Funding
The publication of this work was granted by Faculty of Tropical Medicine, Mahidol University, Bangkok, Thailand.
Availability of data and materials
The data that support the findings of this study are available from Hospital for Tropical Diseases, but restrictions apply to the availability of these data and so are not publicly available. However, data are available from the authors upon reasonable request and with the permission of the institution.
Ethics approval and consent to participate
Exemption from obtaining ethics approval was granted due to a single case study and the patient was consented to participated in this study.
Consent for publication
Not applicable.
Conflict of interests
The authors declare that they have no competing interests. | Intravenous (not otherwise specified) | DrugAdministrationRoute | CC BY | 33413379 | 18,897,227 | 2021-01-07 |
What was the administration route of drug 'CHLOROQUINE'? | Severe orthostatic hypotension in otherwise uncomplicated Plasmodium vivax infection.
Impaired autonomic control of postural homeostasis resulting in orthostatic hypotension has been described in falciparum malaria. However, severe orthostatic intolerance in Plasmodium vivax has been rarely reported. A case of non-immune previously healthy Thai woman presenting with P. vivax infection with well-documented orthostatic hypotension is described. In addition to oral chloroquine and intravenous artesunate, the patient was treated with fluid resuscitation and norepinephrine. During hospitalization, her haemodynamic profile revealed orthostatic hypotension persisting for another three days after microscopic and polymerase chain reaction confirmed parasite clearance. Potential causes are discussed.
Background
Impaired autonomic control of postural homeostasis resulting in orthostatic hypotension has been described in falciparum malaria, but severe orthostatic intolerance in Plasmodium vivax has been rarely reported [1–3]. Orthostatic hypotension is defined as a decrease in systolic blood pressure of 20 mmHg or a decrease in diastolic blood pressure of 10 mmHg within 3 min after a change from a reclining to upright posture, together with associated symptoms [4]. It can be a debilitating symptom in conditions characterized by autonomous nervous system dysfunction [5]. Symptoms are caused by decreased cerebral perfusion, including blurred vision, fatigue, dizziness, and, in the most extreme cases, syncope [6]. On standing, the gravitational volume shift causes a redistribution of circulating blood, with pooling in the capacitance vessels below the diaphragm [7]. A normal compensatory haemodynamic response to changes in posture requires normal function of the cardiovascular, endocrine, and autonomic nervous systems [4]. Preservation of an adequate blood pressure is ensured by a prompt rise in cardiac output, mainly through an increase in heart rate, and an increase in vascular resistance favoring the cerebral blood circulation [8]. In dysautonomic states, this response to circulatory redistribution is impaired, which may lead to a compromised cerebral blood flow. Orthostatic hypotension in acute Plasmodium falciparum infection has been well described and is related to a combination of persisting relative bradycardia and insufficient peripheral vasoconstriction [9]. A case of severe orthostatic hypotension in a patient with a P. vivax infection, mimicking severe malaria is described. Haemodynamic profiles and possible pathophysiological features are discussed.
Case presentation
Patient is a 32-year old previously healthy Thai female without a history of malaria and not taking any medication before the disease episode. Two weeks prior to admission she had travelled to a malaria endemic forested area in Kanchanaburi Province, Thailand for camping and hiking with friends and her 6-year-old son. Eight days prior to admission she developed a high-grade fever with headache and chills without localizing symptoms. She had a history of poor appetite, nausea and reduced oral intake without vomiting or diarrhoea. On admission, she had a fever of 39.8 °C, a pulse rate of 78 beats per minute and a blood pressure of 90/60 mmHg. Her weight was 49 kg which were 1 kg lower from her base line of 50 kg. Her consciousness was normal, conjunctivae were not pale and sclerae were not icteric. She had no cold or clammy skin and her capillary refill time was less than 2 s. The liver span was 10 cm in the mid-clavicular line and the spleen was normal in size on palpitation.
Initial complete blood count revealed anaemia with 31% haematocrit, as well as thrombocytopenia of 74,000/µL. Liver function tests revealed mild elevated aspartate aminotransferase and alanine aminotransferase of 60 U/L and 86 U/L, respectively. Blood sugar, creatinine, glucose-6-phosphate dehydrogenase (G6PD) enzyme activity and urinary analysis were normal. Microscopic examination of a peripheral blood film showed an asexual stage P. vivax parasitaemia of 69,800 parasites/µL and the diagnosis was confirmed by a positive polymerase chain reaction (PCR) for P. vivax. In patients breathing spontaneously, inferior vena cava (IVC) collapsibility index measured by transthoracic echocardiogram is a predictor of fluid responsiveness when the value was more than 42% [10]. In this patient, IVC collapsibility index was 46%, which is predictive of a positive fluid responsiveness. She was admitted to the Hospital for Tropical Diseases and given 600 mg chloroquine orally and started on 5% dextrose in 0.9% Sodium Chloride infusion at a rate of 80 mL/h. After 10 h and infusion of 800 mL fluids, the patient complained of postural faintness while getting out of bed. At that moment, she had an upright blood pressure of 77/46 mmHg and a pulse rate of 103 beats/min which increased to 90/50 mmHg in the supine position. Her urine output was 0.5 to 1 mL/kg per an hour. After lying down, she had good consciousness, warm extremities and capillary refill less than 2 s. Her IVC collapsibility index was 31%. Twelve-lead electrocardiogram showed sinus tachycardia with a normal QTc interval.
She was initially diagnosed with severe Plasmodium vivax and given intravenous artesunate 2.4 mg/kg promptly followed by intravenous artesunate in the same dose after 12 h, which was repeated every 24 h for 5 days. Intravenous ceftriaxone was also started to cover potential concomitant bacterial septic shock awaiting blood culture results. Blood cultures obtained before start of antibiotics, however, remained without growth after which antibiotic therapy was discontinued on the 3rd day of admission. After transferring the patient to the intensive care unit, 400 mL normal saline was given over 1 h. After the fluid bolus, her blood pressure was 88/56 mmHg and her pulse rate was 74 beats/min in the supine position with falling to 77/50 mmHg and 72 beats/min while standing, and IVC collapsibility index of 16%, compatible with non-responsiveness to fluid resuscitation. Table 1 details her haemodynamic profiles during hospital admission. This prompted the start of intravenous norepinephrine at a dose of 0.13 µg/kg/min to maintain a blood pressure of 90/50 mmHg in an upright position. Her plasma lactate assessed at that moment was 1.8 mmol/L (normal value: < 2 mmol/L). Her morning serum cortisol on the next day was 32 µg/dL (normal level: > 6 µg/dL) making a diagnosis of primary or secondary adrenal insufficiency unlikely, and corticosteroids were not started. Haemodynamic monitoring by an ultrasound cardiac output monitor (USCOM) in the supine and upright position before receiving norepinephrine showed a marked drop in cardiac index from 3 L/min/m2 in the supine position to 1.9 L/min/m2 after standing for 3 min, despite adequate hydration. The upright positional drop in cardiac output in the upright position was explained by an absence of an increase in stroke volume, and an insufficient increase in heart rate (Table 1). This orthostatic hypotension persisted until 3 days after microscopically confirmed parasite clearance, necessitating continued vasopressor support with norepinephrine (Table 1) (Figs. 1, 2, 3, 4, 5 and 6). Orthostatic intolerance only resolved completely at the 12th day of follow up. After recovery, the patient received radical treatment with a 14-day course of (0.25 mg/kg daily) primaquine.Table 1 Daily clinical data, laboratories and haemodynamic profiles
Day of admission Admission Day 01 Day 02 Day 03 Day 04 Day 05 Day 06 Day 12
Position Supine Supine Standing 3 min Supine Standing 3 min Supine Standing 3 min Supine Standing 3 min Supine Standing 3 min Supine Standing 3 min Supine Standing 3 min
Temperature (°C) 39.8 39.4 38 36.8 36.5 36.8 37 36.8
Malaria
Microscopic exam (parasites/µL) 430 155 62 Negative Negative Negative Negative Negative
PCR Plasmodium vivax N/A N/A N/A Negative for malaria N/A N/A N/A
Norepinephrine dose (µg/kg/min) 0 0.13 0.08 0.04 0.03 – – –
Hemodynamic parameters
IVC maximum (cm) 1.23 1.72 N/A 1.57 N/A 1.73 N/A 1.38 N/A 1.13 N/A 1.23 N/A 1.5 N/A
IVC minimum (cm) 0.66 1.18 N/A 1.23 N/A 1.38 N/A 1.03 N/A 0.84 N/A 1.08 N/A 0.98 N/A
IVC collapsibility (%) 46.34 31.39 N/A 21.7 N/A 20.23 N/A 25.36 N/A 25.66 N/A 12.2 N/A 34.67 N/A
Stroke volume index (mL/m²) 36 46 27 54 32 46 29 45 25 44 30 42 40 37 39
Cardiac index (L/min/m²) 2.7 3 1.9 3.2 2.3 3 2.4 3 2.3 3.4 2.6 3.2 3 2.5 2.8
Laboratories
Hematocrit (%) 31.2 26.3 26.9 27.2 28.9 – 30
Platelet (/µL) 74,000 68,000 117,000 158,000 213,000 – 240,000
AST/ALT (U/L) 60/86 40/62 105/160 – 80/154 – 24/42
Lactate (mmol/L) 1.8 1.3 0.99 – – – –
Intake/output 1,584/1,100 3248/1618 2761/3630 1593/2335 1387/1860 – –
PCR polymerase chain reaction, IVC inferior vena cava, AST aspartate aminotransferase, ALT alanine aminotransferase, N/A not available
IVC collapsibility = (maximum diameter − minimum diameter)/(maximum diameter) × 100
Fig. 1 Daily heart rate in supine and standing for 3 min position
Fig. 2 Daily systolic blood pressure and diastolic blood pressure in supine position and standing for 3 min position
Fig. 3 Daily pulse pressure in supine position and standing for 3 min position
Fig. 4 Daily mean arterial pressure in supine position and standing for 3 min position
Fig. 5 Daily cardiac index in supine position and standing for 3 min position
Fig. 6 Daily stroke volume index in supine position and standing for 3 min position
Discussion
Hypotension meeting World Health Organization criteria for severe malaria has been reported in several case series of adult vivax malaria [11–14]. However, orthostatic hypotension which has been previously well documented during an acute P. falciparum infection [9] has been rarely described in P. vivax [1–3]. This case report describes a 5-day episode of orthostatic hypotension in a non-immune Thai woman with vivax malaria after start of treatment with chloroquine and after adequate fluid resuscitation. Her orthostatic intolerance was unlikely to be caused by an underlying disease or medication. Blood cultures have a low sensitivity for detecting bacteraemia, which might not exclude concurrent bacterial sepsis. Gram negative/Salmonella coinfection has been previously reported in vivax malaria [15]. However, the observed hypotension was not considered as a feature of septic shock from bacterial infection or severe malaria, since there were no signs of tissue hypoperfusion, with a normal plasma lactate concentration and normal capillary refill time, and no other indications of organ failure. She did receive low-dose vasopressor therapy, mainly to maintain an adequate blood pressure in an upright position. In falciparum malaria three potential mechanisms of orthostatic intolerance have been proposed. The first mechanism is autonomic dysfunction causing relative bradycardia and impaired capacity to increase vascular resistance in the upright position, which will cause a drop in mainly the diastolic blood pressure in the upright position, as also observed in the presented case.
In healthy young adults, the immediate response to a change in position from supine to upright is characterized by a prompt rise in heart rate of about 15 to 30%, and in total vascular resistance of 30 to 40% [8]. The main sensory receptors involved in the orthostatic neural reflex adjustment are the arterial mechanoreceptors (baroreceptors) located in the aortic arch and carotid sinuses and mechanoreceptors located in the heart and lungs (cardiopulmonary receptors). The cardiopulmonary receptors act in concert with the arterial baroreceptors to affect the necessary adjustment in sympathetic nerve action [16]. In patients with falciparum malaria, autonomic dysfunction causing an impaired neural reflex with insufficient compensatory tachycardia and arteriolar vasoconstriction is thought to be the primary cause of orthostatic hypotension in these patients [17], and the subsequent increased subdiaphragmatic pooling of venous blood will subsequently cause a reduction in venous return resulting in a further reduction in stroke volume and thus cardiac output, exaggerating the orthostatic fall in blood pressure.
A second mechanism is blood flow redistribution due to venous vasodilation caused by fever and other factors [18], with larger proportions of blood going to skin and muscle and decreased proportions to liver and kidney [19]. Combined with autonomic failure, this can further reduce venous return and thus cardiac output. Intravascular hypovolaemia can also contribute. Dehydration is common in patients with (falciparum) malaria, as illustrated by the frequently observed increase in the urea/creatinine ratio, increased plasma osmolarity and decreased fractional excretion of sodium, in the presence of an adequate antidiuretic hormone response [20]. Dehydration in patients with malaria is usually caused by transpiration, vomiting or diarrhea, and inadequate fluid intake because of the acute illness. In our case, however, the patient had been adequately rehydrated, as illustrated by the normal IVC collapsibility index after fluid administration.
Chloroquine has also been described to cause hypotension [21, 22] and negative chronotropic effect [23]. Chloroquine decreases vascular resistance [24] through veno-vasodilation via the release of endothelial nitric oxide in the venous circulation [25]. Through vasodilatation, chloroquine may thus reduce both cardiac preload and afterload causing hypotension. Chloroquine also impairs adaptation of the heart rate via reduction in the firing of the spontaneous action potential of the so-called ‘funny current, causing bradycardia [23]. The oral administration of chloroquine could also have triggered an initial vasovagal reaction, but this would not explain the persisting orthostatic symptoms in this patient. Since her orthostatic symptoms persisted after parasite clearance, it is likely that chloroquine therapy contributed to the orthostatic hypotension in our patient, since chloroquine has a long plasma half-life, with an initial t1/2 between 150 and 290 h [26]. In the acute phase of her illness, the described factors which have been identified contributing to orthostatic hypotension in falciparum malaria could have played a role, but this is difficult to substantiate.
In conclusion, this case report shows that orthostatic hypotension may occur in patients with uncomplicated P. vivax infection. This could result from chloroquine therapy, whereas P. vivax induced autonomic dysfunction may also contribute.
Abbreviations
G6PDGlucose-6-phosphate dehydrogenase
PCRPolymerase chain reaction
IVCInferior vena cava
Publisher’s note
Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
Acknowledgements
The authors would like to express gratitude to the patient and the staff of Hospital for Tropical Diseases, Faculty of Tropical Medicine, Mahidol University, Bangkok, Thailand and Miss Chatnapa Duangdee for diagnostic laboratory for malaria.
Authors’ contributions
CS, PW, AD and MS drafted the manuscript. CS and SK contributed in patient care. TT, KK contributed to facilitate in laboratory investigations. All authors contributed to revise the manuscript. All authors read and approved the final manuscript.
Funding
The publication of this work was granted by Faculty of Tropical Medicine, Mahidol University, Bangkok, Thailand.
Availability of data and materials
The data that support the findings of this study are available from Hospital for Tropical Diseases, but restrictions apply to the availability of these data and so are not publicly available. However, data are available from the authors upon reasonable request and with the permission of the institution.
Ethics approval and consent to participate
Exemption from obtaining ethics approval was granted due to a single case study and the patient was consented to participated in this study.
Consent for publication
Not applicable.
Conflict of interests
The authors declare that they have no competing interests. | Oral | DrugAdministrationRoute | CC BY | 33413379 | 18,897,227 | 2021-01-07 |
What was the administration route of drug 'NOREPINEPHRINE'? | Severe orthostatic hypotension in otherwise uncomplicated Plasmodium vivax infection.
Impaired autonomic control of postural homeostasis resulting in orthostatic hypotension has been described in falciparum malaria. However, severe orthostatic intolerance in Plasmodium vivax has been rarely reported. A case of non-immune previously healthy Thai woman presenting with P. vivax infection with well-documented orthostatic hypotension is described. In addition to oral chloroquine and intravenous artesunate, the patient was treated with fluid resuscitation and norepinephrine. During hospitalization, her haemodynamic profile revealed orthostatic hypotension persisting for another three days after microscopic and polymerase chain reaction confirmed parasite clearance. Potential causes are discussed.
Background
Impaired autonomic control of postural homeostasis resulting in orthostatic hypotension has been described in falciparum malaria, but severe orthostatic intolerance in Plasmodium vivax has been rarely reported [1–3]. Orthostatic hypotension is defined as a decrease in systolic blood pressure of 20 mmHg or a decrease in diastolic blood pressure of 10 mmHg within 3 min after a change from a reclining to upright posture, together with associated symptoms [4]. It can be a debilitating symptom in conditions characterized by autonomous nervous system dysfunction [5]. Symptoms are caused by decreased cerebral perfusion, including blurred vision, fatigue, dizziness, and, in the most extreme cases, syncope [6]. On standing, the gravitational volume shift causes a redistribution of circulating blood, with pooling in the capacitance vessels below the diaphragm [7]. A normal compensatory haemodynamic response to changes in posture requires normal function of the cardiovascular, endocrine, and autonomic nervous systems [4]. Preservation of an adequate blood pressure is ensured by a prompt rise in cardiac output, mainly through an increase in heart rate, and an increase in vascular resistance favoring the cerebral blood circulation [8]. In dysautonomic states, this response to circulatory redistribution is impaired, which may lead to a compromised cerebral blood flow. Orthostatic hypotension in acute Plasmodium falciparum infection has been well described and is related to a combination of persisting relative bradycardia and insufficient peripheral vasoconstriction [9]. A case of severe orthostatic hypotension in a patient with a P. vivax infection, mimicking severe malaria is described. Haemodynamic profiles and possible pathophysiological features are discussed.
Case presentation
Patient is a 32-year old previously healthy Thai female without a history of malaria and not taking any medication before the disease episode. Two weeks prior to admission she had travelled to a malaria endemic forested area in Kanchanaburi Province, Thailand for camping and hiking with friends and her 6-year-old son. Eight days prior to admission she developed a high-grade fever with headache and chills without localizing symptoms. She had a history of poor appetite, nausea and reduced oral intake without vomiting or diarrhoea. On admission, she had a fever of 39.8 °C, a pulse rate of 78 beats per minute and a blood pressure of 90/60 mmHg. Her weight was 49 kg which were 1 kg lower from her base line of 50 kg. Her consciousness was normal, conjunctivae were not pale and sclerae were not icteric. She had no cold or clammy skin and her capillary refill time was less than 2 s. The liver span was 10 cm in the mid-clavicular line and the spleen was normal in size on palpitation.
Initial complete blood count revealed anaemia with 31% haematocrit, as well as thrombocytopenia of 74,000/µL. Liver function tests revealed mild elevated aspartate aminotransferase and alanine aminotransferase of 60 U/L and 86 U/L, respectively. Blood sugar, creatinine, glucose-6-phosphate dehydrogenase (G6PD) enzyme activity and urinary analysis were normal. Microscopic examination of a peripheral blood film showed an asexual stage P. vivax parasitaemia of 69,800 parasites/µL and the diagnosis was confirmed by a positive polymerase chain reaction (PCR) for P. vivax. In patients breathing spontaneously, inferior vena cava (IVC) collapsibility index measured by transthoracic echocardiogram is a predictor of fluid responsiveness when the value was more than 42% [10]. In this patient, IVC collapsibility index was 46%, which is predictive of a positive fluid responsiveness. She was admitted to the Hospital for Tropical Diseases and given 600 mg chloroquine orally and started on 5% dextrose in 0.9% Sodium Chloride infusion at a rate of 80 mL/h. After 10 h and infusion of 800 mL fluids, the patient complained of postural faintness while getting out of bed. At that moment, she had an upright blood pressure of 77/46 mmHg and a pulse rate of 103 beats/min which increased to 90/50 mmHg in the supine position. Her urine output was 0.5 to 1 mL/kg per an hour. After lying down, she had good consciousness, warm extremities and capillary refill less than 2 s. Her IVC collapsibility index was 31%. Twelve-lead electrocardiogram showed sinus tachycardia with a normal QTc interval.
She was initially diagnosed with severe Plasmodium vivax and given intravenous artesunate 2.4 mg/kg promptly followed by intravenous artesunate in the same dose after 12 h, which was repeated every 24 h for 5 days. Intravenous ceftriaxone was also started to cover potential concomitant bacterial septic shock awaiting blood culture results. Blood cultures obtained before start of antibiotics, however, remained without growth after which antibiotic therapy was discontinued on the 3rd day of admission. After transferring the patient to the intensive care unit, 400 mL normal saline was given over 1 h. After the fluid bolus, her blood pressure was 88/56 mmHg and her pulse rate was 74 beats/min in the supine position with falling to 77/50 mmHg and 72 beats/min while standing, and IVC collapsibility index of 16%, compatible with non-responsiveness to fluid resuscitation. Table 1 details her haemodynamic profiles during hospital admission. This prompted the start of intravenous norepinephrine at a dose of 0.13 µg/kg/min to maintain a blood pressure of 90/50 mmHg in an upright position. Her plasma lactate assessed at that moment was 1.8 mmol/L (normal value: < 2 mmol/L). Her morning serum cortisol on the next day was 32 µg/dL (normal level: > 6 µg/dL) making a diagnosis of primary or secondary adrenal insufficiency unlikely, and corticosteroids were not started. Haemodynamic monitoring by an ultrasound cardiac output monitor (USCOM) in the supine and upright position before receiving norepinephrine showed a marked drop in cardiac index from 3 L/min/m2 in the supine position to 1.9 L/min/m2 after standing for 3 min, despite adequate hydration. The upright positional drop in cardiac output in the upright position was explained by an absence of an increase in stroke volume, and an insufficient increase in heart rate (Table 1). This orthostatic hypotension persisted until 3 days after microscopically confirmed parasite clearance, necessitating continued vasopressor support with norepinephrine (Table 1) (Figs. 1, 2, 3, 4, 5 and 6). Orthostatic intolerance only resolved completely at the 12th day of follow up. After recovery, the patient received radical treatment with a 14-day course of (0.25 mg/kg daily) primaquine.Table 1 Daily clinical data, laboratories and haemodynamic profiles
Day of admission Admission Day 01 Day 02 Day 03 Day 04 Day 05 Day 06 Day 12
Position Supine Supine Standing 3 min Supine Standing 3 min Supine Standing 3 min Supine Standing 3 min Supine Standing 3 min Supine Standing 3 min Supine Standing 3 min
Temperature (°C) 39.8 39.4 38 36.8 36.5 36.8 37 36.8
Malaria
Microscopic exam (parasites/µL) 430 155 62 Negative Negative Negative Negative Negative
PCR Plasmodium vivax N/A N/A N/A Negative for malaria N/A N/A N/A
Norepinephrine dose (µg/kg/min) 0 0.13 0.08 0.04 0.03 – – –
Hemodynamic parameters
IVC maximum (cm) 1.23 1.72 N/A 1.57 N/A 1.73 N/A 1.38 N/A 1.13 N/A 1.23 N/A 1.5 N/A
IVC minimum (cm) 0.66 1.18 N/A 1.23 N/A 1.38 N/A 1.03 N/A 0.84 N/A 1.08 N/A 0.98 N/A
IVC collapsibility (%) 46.34 31.39 N/A 21.7 N/A 20.23 N/A 25.36 N/A 25.66 N/A 12.2 N/A 34.67 N/A
Stroke volume index (mL/m²) 36 46 27 54 32 46 29 45 25 44 30 42 40 37 39
Cardiac index (L/min/m²) 2.7 3 1.9 3.2 2.3 3 2.4 3 2.3 3.4 2.6 3.2 3 2.5 2.8
Laboratories
Hematocrit (%) 31.2 26.3 26.9 27.2 28.9 – 30
Platelet (/µL) 74,000 68,000 117,000 158,000 213,000 – 240,000
AST/ALT (U/L) 60/86 40/62 105/160 – 80/154 – 24/42
Lactate (mmol/L) 1.8 1.3 0.99 – – – –
Intake/output 1,584/1,100 3248/1618 2761/3630 1593/2335 1387/1860 – –
PCR polymerase chain reaction, IVC inferior vena cava, AST aspartate aminotransferase, ALT alanine aminotransferase, N/A not available
IVC collapsibility = (maximum diameter − minimum diameter)/(maximum diameter) × 100
Fig. 1 Daily heart rate in supine and standing for 3 min position
Fig. 2 Daily systolic blood pressure and diastolic blood pressure in supine position and standing for 3 min position
Fig. 3 Daily pulse pressure in supine position and standing for 3 min position
Fig. 4 Daily mean arterial pressure in supine position and standing for 3 min position
Fig. 5 Daily cardiac index in supine position and standing for 3 min position
Fig. 6 Daily stroke volume index in supine position and standing for 3 min position
Discussion
Hypotension meeting World Health Organization criteria for severe malaria has been reported in several case series of adult vivax malaria [11–14]. However, orthostatic hypotension which has been previously well documented during an acute P. falciparum infection [9] has been rarely described in P. vivax [1–3]. This case report describes a 5-day episode of orthostatic hypotension in a non-immune Thai woman with vivax malaria after start of treatment with chloroquine and after adequate fluid resuscitation. Her orthostatic intolerance was unlikely to be caused by an underlying disease or medication. Blood cultures have a low sensitivity for detecting bacteraemia, which might not exclude concurrent bacterial sepsis. Gram negative/Salmonella coinfection has been previously reported in vivax malaria [15]. However, the observed hypotension was not considered as a feature of septic shock from bacterial infection or severe malaria, since there were no signs of tissue hypoperfusion, with a normal plasma lactate concentration and normal capillary refill time, and no other indications of organ failure. She did receive low-dose vasopressor therapy, mainly to maintain an adequate blood pressure in an upright position. In falciparum malaria three potential mechanisms of orthostatic intolerance have been proposed. The first mechanism is autonomic dysfunction causing relative bradycardia and impaired capacity to increase vascular resistance in the upright position, which will cause a drop in mainly the diastolic blood pressure in the upright position, as also observed in the presented case.
In healthy young adults, the immediate response to a change in position from supine to upright is characterized by a prompt rise in heart rate of about 15 to 30%, and in total vascular resistance of 30 to 40% [8]. The main sensory receptors involved in the orthostatic neural reflex adjustment are the arterial mechanoreceptors (baroreceptors) located in the aortic arch and carotid sinuses and mechanoreceptors located in the heart and lungs (cardiopulmonary receptors). The cardiopulmonary receptors act in concert with the arterial baroreceptors to affect the necessary adjustment in sympathetic nerve action [16]. In patients with falciparum malaria, autonomic dysfunction causing an impaired neural reflex with insufficient compensatory tachycardia and arteriolar vasoconstriction is thought to be the primary cause of orthostatic hypotension in these patients [17], and the subsequent increased subdiaphragmatic pooling of venous blood will subsequently cause a reduction in venous return resulting in a further reduction in stroke volume and thus cardiac output, exaggerating the orthostatic fall in blood pressure.
A second mechanism is blood flow redistribution due to venous vasodilation caused by fever and other factors [18], with larger proportions of blood going to skin and muscle and decreased proportions to liver and kidney [19]. Combined with autonomic failure, this can further reduce venous return and thus cardiac output. Intravascular hypovolaemia can also contribute. Dehydration is common in patients with (falciparum) malaria, as illustrated by the frequently observed increase in the urea/creatinine ratio, increased plasma osmolarity and decreased fractional excretion of sodium, in the presence of an adequate antidiuretic hormone response [20]. Dehydration in patients with malaria is usually caused by transpiration, vomiting or diarrhea, and inadequate fluid intake because of the acute illness. In our case, however, the patient had been adequately rehydrated, as illustrated by the normal IVC collapsibility index after fluid administration.
Chloroquine has also been described to cause hypotension [21, 22] and negative chronotropic effect [23]. Chloroquine decreases vascular resistance [24] through veno-vasodilation via the release of endothelial nitric oxide in the venous circulation [25]. Through vasodilatation, chloroquine may thus reduce both cardiac preload and afterload causing hypotension. Chloroquine also impairs adaptation of the heart rate via reduction in the firing of the spontaneous action potential of the so-called ‘funny current, causing bradycardia [23]. The oral administration of chloroquine could also have triggered an initial vasovagal reaction, but this would not explain the persisting orthostatic symptoms in this patient. Since her orthostatic symptoms persisted after parasite clearance, it is likely that chloroquine therapy contributed to the orthostatic hypotension in our patient, since chloroquine has a long plasma half-life, with an initial t1/2 between 150 and 290 h [26]. In the acute phase of her illness, the described factors which have been identified contributing to orthostatic hypotension in falciparum malaria could have played a role, but this is difficult to substantiate.
In conclusion, this case report shows that orthostatic hypotension may occur in patients with uncomplicated P. vivax infection. This could result from chloroquine therapy, whereas P. vivax induced autonomic dysfunction may also contribute.
Abbreviations
G6PDGlucose-6-phosphate dehydrogenase
PCRPolymerase chain reaction
IVCInferior vena cava
Publisher’s note
Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
Acknowledgements
The authors would like to express gratitude to the patient and the staff of Hospital for Tropical Diseases, Faculty of Tropical Medicine, Mahidol University, Bangkok, Thailand and Miss Chatnapa Duangdee for diagnostic laboratory for malaria.
Authors’ contributions
CS, PW, AD and MS drafted the manuscript. CS and SK contributed in patient care. TT, KK contributed to facilitate in laboratory investigations. All authors contributed to revise the manuscript. All authors read and approved the final manuscript.
Funding
The publication of this work was granted by Faculty of Tropical Medicine, Mahidol University, Bangkok, Thailand.
Availability of data and materials
The data that support the findings of this study are available from Hospital for Tropical Diseases, but restrictions apply to the availability of these data and so are not publicly available. However, data are available from the authors upon reasonable request and with the permission of the institution.
Ethics approval and consent to participate
Exemption from obtaining ethics approval was granted due to a single case study and the patient was consented to participated in this study.
Consent for publication
Not applicable.
Conflict of interests
The authors declare that they have no competing interests. | Intravenous (not otherwise specified) | DrugAdministrationRoute | CC BY | 33413379 | 18,897,227 | 2021-01-07 |
What was the administration route of drug 'SODIUM CHLORIDE'? | Severe orthostatic hypotension in otherwise uncomplicated Plasmodium vivax infection.
Impaired autonomic control of postural homeostasis resulting in orthostatic hypotension has been described in falciparum malaria. However, severe orthostatic intolerance in Plasmodium vivax has been rarely reported. A case of non-immune previously healthy Thai woman presenting with P. vivax infection with well-documented orthostatic hypotension is described. In addition to oral chloroquine and intravenous artesunate, the patient was treated with fluid resuscitation and norepinephrine. During hospitalization, her haemodynamic profile revealed orthostatic hypotension persisting for another three days after microscopic and polymerase chain reaction confirmed parasite clearance. Potential causes are discussed.
Background
Impaired autonomic control of postural homeostasis resulting in orthostatic hypotension has been described in falciparum malaria, but severe orthostatic intolerance in Plasmodium vivax has been rarely reported [1–3]. Orthostatic hypotension is defined as a decrease in systolic blood pressure of 20 mmHg or a decrease in diastolic blood pressure of 10 mmHg within 3 min after a change from a reclining to upright posture, together with associated symptoms [4]. It can be a debilitating symptom in conditions characterized by autonomous nervous system dysfunction [5]. Symptoms are caused by decreased cerebral perfusion, including blurred vision, fatigue, dizziness, and, in the most extreme cases, syncope [6]. On standing, the gravitational volume shift causes a redistribution of circulating blood, with pooling in the capacitance vessels below the diaphragm [7]. A normal compensatory haemodynamic response to changes in posture requires normal function of the cardiovascular, endocrine, and autonomic nervous systems [4]. Preservation of an adequate blood pressure is ensured by a prompt rise in cardiac output, mainly through an increase in heart rate, and an increase in vascular resistance favoring the cerebral blood circulation [8]. In dysautonomic states, this response to circulatory redistribution is impaired, which may lead to a compromised cerebral blood flow. Orthostatic hypotension in acute Plasmodium falciparum infection has been well described and is related to a combination of persisting relative bradycardia and insufficient peripheral vasoconstriction [9]. A case of severe orthostatic hypotension in a patient with a P. vivax infection, mimicking severe malaria is described. Haemodynamic profiles and possible pathophysiological features are discussed.
Case presentation
Patient is a 32-year old previously healthy Thai female without a history of malaria and not taking any medication before the disease episode. Two weeks prior to admission she had travelled to a malaria endemic forested area in Kanchanaburi Province, Thailand for camping and hiking with friends and her 6-year-old son. Eight days prior to admission she developed a high-grade fever with headache and chills without localizing symptoms. She had a history of poor appetite, nausea and reduced oral intake without vomiting or diarrhoea. On admission, she had a fever of 39.8 °C, a pulse rate of 78 beats per minute and a blood pressure of 90/60 mmHg. Her weight was 49 kg which were 1 kg lower from her base line of 50 kg. Her consciousness was normal, conjunctivae were not pale and sclerae were not icteric. She had no cold or clammy skin and her capillary refill time was less than 2 s. The liver span was 10 cm in the mid-clavicular line and the spleen was normal in size on palpitation.
Initial complete blood count revealed anaemia with 31% haematocrit, as well as thrombocytopenia of 74,000/µL. Liver function tests revealed mild elevated aspartate aminotransferase and alanine aminotransferase of 60 U/L and 86 U/L, respectively. Blood sugar, creatinine, glucose-6-phosphate dehydrogenase (G6PD) enzyme activity and urinary analysis were normal. Microscopic examination of a peripheral blood film showed an asexual stage P. vivax parasitaemia of 69,800 parasites/µL and the diagnosis was confirmed by a positive polymerase chain reaction (PCR) for P. vivax. In patients breathing spontaneously, inferior vena cava (IVC) collapsibility index measured by transthoracic echocardiogram is a predictor of fluid responsiveness when the value was more than 42% [10]. In this patient, IVC collapsibility index was 46%, which is predictive of a positive fluid responsiveness. She was admitted to the Hospital for Tropical Diseases and given 600 mg chloroquine orally and started on 5% dextrose in 0.9% Sodium Chloride infusion at a rate of 80 mL/h. After 10 h and infusion of 800 mL fluids, the patient complained of postural faintness while getting out of bed. At that moment, she had an upright blood pressure of 77/46 mmHg and a pulse rate of 103 beats/min which increased to 90/50 mmHg in the supine position. Her urine output was 0.5 to 1 mL/kg per an hour. After lying down, she had good consciousness, warm extremities and capillary refill less than 2 s. Her IVC collapsibility index was 31%. Twelve-lead electrocardiogram showed sinus tachycardia with a normal QTc interval.
She was initially diagnosed with severe Plasmodium vivax and given intravenous artesunate 2.4 mg/kg promptly followed by intravenous artesunate in the same dose after 12 h, which was repeated every 24 h for 5 days. Intravenous ceftriaxone was also started to cover potential concomitant bacterial septic shock awaiting blood culture results. Blood cultures obtained before start of antibiotics, however, remained without growth after which antibiotic therapy was discontinued on the 3rd day of admission. After transferring the patient to the intensive care unit, 400 mL normal saline was given over 1 h. After the fluid bolus, her blood pressure was 88/56 mmHg and her pulse rate was 74 beats/min in the supine position with falling to 77/50 mmHg and 72 beats/min while standing, and IVC collapsibility index of 16%, compatible with non-responsiveness to fluid resuscitation. Table 1 details her haemodynamic profiles during hospital admission. This prompted the start of intravenous norepinephrine at a dose of 0.13 µg/kg/min to maintain a blood pressure of 90/50 mmHg in an upright position. Her plasma lactate assessed at that moment was 1.8 mmol/L (normal value: < 2 mmol/L). Her morning serum cortisol on the next day was 32 µg/dL (normal level: > 6 µg/dL) making a diagnosis of primary or secondary adrenal insufficiency unlikely, and corticosteroids were not started. Haemodynamic monitoring by an ultrasound cardiac output monitor (USCOM) in the supine and upright position before receiving norepinephrine showed a marked drop in cardiac index from 3 L/min/m2 in the supine position to 1.9 L/min/m2 after standing for 3 min, despite adequate hydration. The upright positional drop in cardiac output in the upright position was explained by an absence of an increase in stroke volume, and an insufficient increase in heart rate (Table 1). This orthostatic hypotension persisted until 3 days after microscopically confirmed parasite clearance, necessitating continued vasopressor support with norepinephrine (Table 1) (Figs. 1, 2, 3, 4, 5 and 6). Orthostatic intolerance only resolved completely at the 12th day of follow up. After recovery, the patient received radical treatment with a 14-day course of (0.25 mg/kg daily) primaquine.Table 1 Daily clinical data, laboratories and haemodynamic profiles
Day of admission Admission Day 01 Day 02 Day 03 Day 04 Day 05 Day 06 Day 12
Position Supine Supine Standing 3 min Supine Standing 3 min Supine Standing 3 min Supine Standing 3 min Supine Standing 3 min Supine Standing 3 min Supine Standing 3 min
Temperature (°C) 39.8 39.4 38 36.8 36.5 36.8 37 36.8
Malaria
Microscopic exam (parasites/µL) 430 155 62 Negative Negative Negative Negative Negative
PCR Plasmodium vivax N/A N/A N/A Negative for malaria N/A N/A N/A
Norepinephrine dose (µg/kg/min) 0 0.13 0.08 0.04 0.03 – – –
Hemodynamic parameters
IVC maximum (cm) 1.23 1.72 N/A 1.57 N/A 1.73 N/A 1.38 N/A 1.13 N/A 1.23 N/A 1.5 N/A
IVC minimum (cm) 0.66 1.18 N/A 1.23 N/A 1.38 N/A 1.03 N/A 0.84 N/A 1.08 N/A 0.98 N/A
IVC collapsibility (%) 46.34 31.39 N/A 21.7 N/A 20.23 N/A 25.36 N/A 25.66 N/A 12.2 N/A 34.67 N/A
Stroke volume index (mL/m²) 36 46 27 54 32 46 29 45 25 44 30 42 40 37 39
Cardiac index (L/min/m²) 2.7 3 1.9 3.2 2.3 3 2.4 3 2.3 3.4 2.6 3.2 3 2.5 2.8
Laboratories
Hematocrit (%) 31.2 26.3 26.9 27.2 28.9 – 30
Platelet (/µL) 74,000 68,000 117,000 158,000 213,000 – 240,000
AST/ALT (U/L) 60/86 40/62 105/160 – 80/154 – 24/42
Lactate (mmol/L) 1.8 1.3 0.99 – – – –
Intake/output 1,584/1,100 3248/1618 2761/3630 1593/2335 1387/1860 – –
PCR polymerase chain reaction, IVC inferior vena cava, AST aspartate aminotransferase, ALT alanine aminotransferase, N/A not available
IVC collapsibility = (maximum diameter − minimum diameter)/(maximum diameter) × 100
Fig. 1 Daily heart rate in supine and standing for 3 min position
Fig. 2 Daily systolic blood pressure and diastolic blood pressure in supine position and standing for 3 min position
Fig. 3 Daily pulse pressure in supine position and standing for 3 min position
Fig. 4 Daily mean arterial pressure in supine position and standing for 3 min position
Fig. 5 Daily cardiac index in supine position and standing for 3 min position
Fig. 6 Daily stroke volume index in supine position and standing for 3 min position
Discussion
Hypotension meeting World Health Organization criteria for severe malaria has been reported in several case series of adult vivax malaria [11–14]. However, orthostatic hypotension which has been previously well documented during an acute P. falciparum infection [9] has been rarely described in P. vivax [1–3]. This case report describes a 5-day episode of orthostatic hypotension in a non-immune Thai woman with vivax malaria after start of treatment with chloroquine and after adequate fluid resuscitation. Her orthostatic intolerance was unlikely to be caused by an underlying disease or medication. Blood cultures have a low sensitivity for detecting bacteraemia, which might not exclude concurrent bacterial sepsis. Gram negative/Salmonella coinfection has been previously reported in vivax malaria [15]. However, the observed hypotension was not considered as a feature of septic shock from bacterial infection or severe malaria, since there were no signs of tissue hypoperfusion, with a normal plasma lactate concentration and normal capillary refill time, and no other indications of organ failure. She did receive low-dose vasopressor therapy, mainly to maintain an adequate blood pressure in an upright position. In falciparum malaria three potential mechanisms of orthostatic intolerance have been proposed. The first mechanism is autonomic dysfunction causing relative bradycardia and impaired capacity to increase vascular resistance in the upright position, which will cause a drop in mainly the diastolic blood pressure in the upright position, as also observed in the presented case.
In healthy young adults, the immediate response to a change in position from supine to upright is characterized by a prompt rise in heart rate of about 15 to 30%, and in total vascular resistance of 30 to 40% [8]. The main sensory receptors involved in the orthostatic neural reflex adjustment are the arterial mechanoreceptors (baroreceptors) located in the aortic arch and carotid sinuses and mechanoreceptors located in the heart and lungs (cardiopulmonary receptors). The cardiopulmonary receptors act in concert with the arterial baroreceptors to affect the necessary adjustment in sympathetic nerve action [16]. In patients with falciparum malaria, autonomic dysfunction causing an impaired neural reflex with insufficient compensatory tachycardia and arteriolar vasoconstriction is thought to be the primary cause of orthostatic hypotension in these patients [17], and the subsequent increased subdiaphragmatic pooling of venous blood will subsequently cause a reduction in venous return resulting in a further reduction in stroke volume and thus cardiac output, exaggerating the orthostatic fall in blood pressure.
A second mechanism is blood flow redistribution due to venous vasodilation caused by fever and other factors [18], with larger proportions of blood going to skin and muscle and decreased proportions to liver and kidney [19]. Combined with autonomic failure, this can further reduce venous return and thus cardiac output. Intravascular hypovolaemia can also contribute. Dehydration is common in patients with (falciparum) malaria, as illustrated by the frequently observed increase in the urea/creatinine ratio, increased plasma osmolarity and decreased fractional excretion of sodium, in the presence of an adequate antidiuretic hormone response [20]. Dehydration in patients with malaria is usually caused by transpiration, vomiting or diarrhea, and inadequate fluid intake because of the acute illness. In our case, however, the patient had been adequately rehydrated, as illustrated by the normal IVC collapsibility index after fluid administration.
Chloroquine has also been described to cause hypotension [21, 22] and negative chronotropic effect [23]. Chloroquine decreases vascular resistance [24] through veno-vasodilation via the release of endothelial nitric oxide in the venous circulation [25]. Through vasodilatation, chloroquine may thus reduce both cardiac preload and afterload causing hypotension. Chloroquine also impairs adaptation of the heart rate via reduction in the firing of the spontaneous action potential of the so-called ‘funny current, causing bradycardia [23]. The oral administration of chloroquine could also have triggered an initial vasovagal reaction, but this would not explain the persisting orthostatic symptoms in this patient. Since her orthostatic symptoms persisted after parasite clearance, it is likely that chloroquine therapy contributed to the orthostatic hypotension in our patient, since chloroquine has a long plasma half-life, with an initial t1/2 between 150 and 290 h [26]. In the acute phase of her illness, the described factors which have been identified contributing to orthostatic hypotension in falciparum malaria could have played a role, but this is difficult to substantiate.
In conclusion, this case report shows that orthostatic hypotension may occur in patients with uncomplicated P. vivax infection. This could result from chloroquine therapy, whereas P. vivax induced autonomic dysfunction may also contribute.
Abbreviations
G6PDGlucose-6-phosphate dehydrogenase
PCRPolymerase chain reaction
IVCInferior vena cava
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Acknowledgements
The authors would like to express gratitude to the patient and the staff of Hospital for Tropical Diseases, Faculty of Tropical Medicine, Mahidol University, Bangkok, Thailand and Miss Chatnapa Duangdee for diagnostic laboratory for malaria.
Authors’ contributions
CS, PW, AD and MS drafted the manuscript. CS and SK contributed in patient care. TT, KK contributed to facilitate in laboratory investigations. All authors contributed to revise the manuscript. All authors read and approved the final manuscript.
Funding
The publication of this work was granted by Faculty of Tropical Medicine, Mahidol University, Bangkok, Thailand.
Availability of data and materials
The data that support the findings of this study are available from Hospital for Tropical Diseases, but restrictions apply to the availability of these data and so are not publicly available. However, data are available from the authors upon reasonable request and with the permission of the institution.
Ethics approval and consent to participate
Exemption from obtaining ethics approval was granted due to a single case study and the patient was consented to participated in this study.
Consent for publication
Not applicable.
Conflict of interests
The authors declare that they have no competing interests. | Intravenous (not otherwise specified) | DrugAdministrationRoute | CC BY | 33413379 | 18,897,227 | 2021-01-07 |
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